CN1344270A - Functionalized heterocycles as chemokine receptor modulators - Google Patents

Functionalized heterocycles as chemokine receptor modulators Download PDF

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Publication number
CN1344270A
CN1344270A CN99816475A CN99816475A CN1344270A CN 1344270 A CN1344270 A CN 1344270A CN 99816475 A CN99816475 A CN 99816475A CN 99816475 A CN99816475 A CN 99816475A CN 1344270 A CN1344270 A CN 1344270A
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Prior art keywords
methyl
quinolizine
chromene
decahydro
pyrrolo
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CN99816475A
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Inventor
G·C·哈里曼
C·N·科尔兹
J·R·卢利
B·D·罗斯
Y·宋
B·K·特里维迪
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THOUSAND YEARS MEDICAMENTS Inc
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THOUSAND YEARS MEDICAMENTS Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems

Abstract

The present invention is a novel series of functionalized heterocycles as chemokine receptor modulators of Formula (I) useful as modulators of chemokine receptor activity. The compounds are useful in the treatment and prevention of the AIDS virus. Intermediates useful in the prepartion of the final products, pharmaceutical compositions containing the final products are also taught.

Description

Functionalized heterocycles as chemokine receptor modulators
Background of invention
The present invention relates to (comprise CCR-1, CCR-2, CCR-2A, CCR-2B as Chemokine Receptors, CCR-3, CCR-4, CCR-5, CXCR1, CXCR2, CXCR-3 and/or CXCR4) functionalized heterocycles of conditioning agent and the pharmaceutical composition that contains these compounds and pharmaceutical carrier.More particularly, the present invention relates to suppress the communicable method of HIV.
The chemokine mediated short scorching reaction that acts on leukocytic certain limit is as chemotaxis, threshing and intigran activation (Baggiolini etc., Adv.Immunol., 1994; 55:97-179; Oppenheim etc., Annu.Rev.Immunol., 1991; 9:617-48; Miller etc., Crit.Rev.Immunol., 1992; 12:17-46).These effects by with seven-receptors bind of striding film-pass G albumen coupling mediates (Baggiolini etc., Adv.Immunol., 1994; 55:97-179; Murphy, Annu.Rev.Immunol., 1994; 12:593-633; Schall etc., Curr.Opin.Immunol., 1994; 6:865-73; Gerard etc., Curr.Opin.Immunol., 1994; 6; 140-5; Mackay, Curr. Bio., In press).Chemokine Receptors also enters intracellular accessory receptor as HIV-1.This conclusion derives from observes infection (Cocchi etc., Science (Wash.DC), 1995 that RANTES, MIP-1 α and MIP-1 β suppress the external permissive cell that the elementary HIV-1 isolate of close scavenger cell causes; 270:1811-5).Find that Chemokine Receptors CXCR-4 supports infection and CD4 that the pro t cell HIV-1 cell strain of laboratory transformation causes +The cytogamy of cell (Feng etc., Science (Wash.DC), 1996; 272:872-7).CCR-5, a kind of RANTES, MIP-1 α and MIP-1 beta receptor successively are confirmed as main accessory receptor (Choe etc., Cell, 1996 of elementary close scavenger cell strain; 85:1135-48; Alkhatib etc., Science (Wash.DC), 1996; 272:1955-8; Doranz etc., Cell, 1996; 85:1149-58; Deng etc., Nature (Lond.) 1996; 381:661-6; Dragic etc., Nature (Lond.), 1996; 381:667-3).Repeatedly contact HIV-1 but the expression of not infected yet some individual CCR-5 of shortage, importance (Liu etc., Cell, 1996 that CCR-5 transmits HIV-1 have been given prominence in the observation of this phenomenon; 86:367-77; Samson etc., Nature (Lond.), 1996; 382:722-5; Dean etc., Science (Wash.DC), 1996; 273:1856-62; Huang etc., Nature Med., 1996; 2:1240-3).Find these not the defective CCR-5 allelotrope of infected individuals isozygoty, contain inner 32-to base pair disappearance (CCR-5 Δ 32).The albumen of the shortening of this genes encoding is not obviously at cell surface expression.CCR-5 Δ 32 homozygous individuals contain and comprise about 1% Caucasia crowd and the individuality of heterozygosis comprises about 20%.In research, do not find Δ 32 homozygotes to about 2700 HIV-1 infected individuals.Compare the progress to AIDS very slow (Samson etc., Nature (Lond.), 1996 that the individuality of Δ 32CCR-5 allelotrope heterozygosis demonstrates with the wild-type homozygous individual; 382:722-5; Dean etc., Science (Wash.DC), 1996; 273:1856-62; Huang etc., Nature Med., 1996; 2:1240-3).Therefore, as the determining of the main accessory receptor of elementary HIV isolate, provide chance, the more important thing is the new approach of having determined that treatment HIV-1 infects for understanding pathogeny to CCR-5.
The present invention is a series of functionalized heterocycles, and they block the interaction of CD-4/GP-120 and CCR-5 acceptor, and therefore can be used for the treatment of the HIV infection that shows among the AIDS.
Summary of the invention
Compound of the present invention is used for regulating the method for the patient's who needs this adjusting chemokine receptor activity, and this method comprises this compound of using significant quantity.
The present invention relates to the heterocycle of above-mentioned replacement conditioning agent as chemokine receptor activity.Specifically, these compounds are as the conditioning agent of the Chemokine Receptors that comprises CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR1, CXCR2 and/or CXCR-4.Specifically, the present invention is preferably as the conditioning agent of Chemokine Receptors CCR-5.
Compound of the present invention is the compound or pharmaceutically acceptable salt thereof of formula I, and it can exist with the form of closed loop or open loop,
Figure A9981647500241
Wherein:
A is O, S, and when X be C-R 9The time, A can also be NR 1
When A is NR 1The time, X is N, perhaps
X is C-R 9, R wherein 9Be halogen, hydrogen atom, alkyl ,-CF 3, CH 2F, CHF 2,-(CH 2) m-OR 1, aryl, aralkyl ,-(CH 2) m-NR 7R 8Or Wherein m is 0 to 2 integer, and when occurring, m is 0 to 2 integer independently at every turn, and q is 0 to 1 integer, and r is 0 to 3 integer;
Y is hydrogen atom, alkyl, aralkyl, aryl, (CH 2) m-NR 7R 8,-N (R 1)-(CH 2) v-C (R 7R 8)-aryl or OR 10, R wherein 10Be hydrogen atom, alkyl, cycloalkyl, with aromatic ring condensed cycloalkyl, aryl, (CH 2) sAryl ,-CH 2CF 3, (CH 2) tC (R 7R 8)-(CH 2) uAryl,
Figure A9981647500261
Wherein s is 1 to 3 integer, and t is 0 to 3 integer, and u is 0 to 3 integer, and v is 1 to 3 integer, and w is 0 to 2 integer;
Z is CR or N;
R 1Be hydrogen atom or alkyl, and R when at every turn occurring 1Be hydrogen atom or alkyl independently;
R and R 2Be independently from each other:
Hydrogen atom,
Alkyl,
Halogen,
-CN，
-NO 2，
-(CH 2) m-NR 7R 8，
-(CH 2) m-COOR 7，
-(CH 2) m-CONR 7R 8，
-(CH 2) m-OR 7，
-(CH 2) m-SO 2NR 7R 8, and
-(CH 2) m-S (O) pR 7, when wherein occurring at every turn, R 7And R 8Be independently of one another hydrogen atom, alkyl, aryl, aralkyl ,-CF 3, or R 7And R 8The ring of 3 to 7 atoms can be formed together, O, S or NR can be contained in this ring 1, and p is 0 to 2 integer;
R 3Be hydrogen atom or alkyl;
R 4Be hydrogen atom, alkyl, aryl or aralkyl;
R 5Be alkyl, aryl, aralkyl, acyl group; Or
R 4And R 5Form the ring of 5 to 7 atoms with the atom that connects with them;
R 6Be hydrogen atom or alkyl;
When not with R 4One time-out, R 5Can with R 6Form the ring of 5 to 7 atoms with the atom that connects with them;
N-R 5It also is corresponding N-oxide compound;
R 11Be hydrogen atom or alkyl;
N is 1 to 3 integer; J is 1 to 2 integer, and when Y was hydrogen atom, alkyl, aralkyl or aryl, j was an integer 0;
Condition be do not comprise pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester.
Preferred compound is the compound of above-mentioned formula 1, wherein
R 1It is hydrogen atom.
Other preferred compound is the compound of above-mentioned formula 1, wherein
R 1Be hydrogen atom, and
X is C-R 9
Other preferred compound still is following compound, wherein
R 1Be hydrogen atom, and
X is C-R 9, R wherein 9It is alkyl.
Other preferred compound still is following compound, wherein
R 1Be hydrogen atom,
X is C-R 9, R wherein 9It is alkyl;
R 4And R 5Form the ring of 5-7 atom with the atom that connects with them; And
Y is OR 10
Other preferred compound still is following compound, wherein
R 1Be hydrogen atom,
X is C-R 9, R wherein 9It is alkyl;
R 4And R 5Form 6 yuan of rings together; And
Y is OR 10, R wherein 10Be alkyl, aryl or-(CH 2) sAryl ,-(CH 2) t-C (R 7R 8)-(CH 2) u-aryl.
Other preferred compound still is following compound, wherein
R 1Be hydrogen atom,
X is C-R 9, R wherein 9Be Me;
R 4And R 5Form 6 yuan of rings together;
R 6It is hydrogen atom;
N is 2; And
Y is OR 10, R wherein 10Be alkyl, aryl or R 10Be-(CH 2) t-C (R 7R 8)-(CH 2) u-aryl, wherein t is O, R 7And R 8Can be independently of one another
H，
Alkyl,
-(CH 2) vOH or (CH 2) uCOOR 7And-(CH 2) vNR 1R 2,
Wherein u and v definition as above.
Preferred compound be formula 1 and be selected from following compound:
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-bromo-3,7,8,9,10,12,13,14, and 14a, 15-decahydro-2-methyl-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2-dimethyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the cyclopropyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(piperidino) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(phenyl methyl)-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 2-ethyl-3,7,8,9,10,12,13,14, and 14a, the 15-decahydro-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 2-cyclopropyl-3,7,8,9,10,12,13,14, and 14a, the 15-decahydro-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-propyl group-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(2-methyl-propyl)-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl ethyl ester;
2,6a, 7-trimethylammonium-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diazacyclo penta [a] anthracene-1-ethyl formate;
7-ethyl-2,6a-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;
6a-ethyl-2,7-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;
6a, 7-diethyl-2-methyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;
7-benzyl-2,6a-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;
2,7-dimethyl-6a-phenyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-e] indoles-1-formic acid also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-, ethyl ester;
3H, 7H-pyrroles's piperazine be (Pyrrolizino) [1 ', 8 ': 5,6] pyrans [3,2-e] indoles-1-acetate also also, and 8,9,11,12,12a, 13-six hydrogen-2-methyl-, ethyl ester;
2-methyl-8,9,10,10a, 11,12,12a, 13-octahydro-3H, 6aH, 7H-6-oxa--3,6b-diaza-benzo [a] ring penta [h] anthracene-1-ethyl formate;
3H-pyrido [1 ", 2 ": 1 ' 2 '] azepines is [3 ' 2 ': 5,6] pyrans [3,2-e] indoles-1-acetate also also, 7,8,9,10,12,13,14,15,15a, 16-decahydro-2-methyl-, ethyl ester or
The 7H-azepines also [1 ", 2 ": 1 ' 2 '] pyrido [3 ', 2 ': 5,6] pyrans [3,2-e] indoles-1-acetate also, 3,8,9,10,11,13,14,15,15a, 16-decahydro-2-methyl-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-methane amide also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-N-(phenyl methyl)-;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-methane amide also, N-ethyl-8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formaldehyde also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-methane amide also, and 8,9,11,12,13,13a, 14,14a-octahydro-N, the 2-dimethyl-;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-, (4-fluorophenyl)-methyl esters;
Indazole is [4 ', 5 ': 5,6] pyrans [3,2-i] quinolizine-1-formic acid also also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,12, the 12-trimethylammonium-, the phenyl methyl esters,
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,10, the 10-trimethylammonium-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters;
12H-furo (Furo) [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluoro-7,8,9,10,13,14,14a, 15-octahydro-2-methyl-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 4,5-two fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 4,5-two chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-4,5-dimethoxy-2-methyl-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 5-dimethyl-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 4-dimethyl-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 4-dimethyl-, 1-(4-fluorophenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[3-(methoxycarbonyl) phenyl] and ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(3-carboxyl phenyl) ethyl ester;
1-third ammonium, N, N, the N-trimethylammonium-, with 1-(3-carboxyl phenyl) ethyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-nitrophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(3-cyano-phenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-[3-[(dimethylamino) and carbonyl] phenyl] ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-[3-[(dimethylamino) and methyl]-phenyl] ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,1,13,14,14a, 15-decahydro-2-methyl-, the 2-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(methoxycarbonyl) phenyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2 ,-methyl-, (4-carboxyl phenyl) methyl esters;
1-[3-(4-carboxyl-benzyloxycarbonyl)-5-hydroxy-2-methyl-1H-indoles-4-ylmethyl]-1,2,3,4,6,7,8,9-octahydro-quinolizine; Muriate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(hydroxymethyl) phenyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-2-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-naphthyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(methoxycarbonyl) phenyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(hydroxymethyl) phenyl]-methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-carboxyl phenyl) methyl esters);
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (3-carboxyl phenyl) methyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1]-chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [the 3-[(dimethylamino) methyl] phenyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [the 3-[(dimethylamino) carbonyl]-phenyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [2-(4-morpholinyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[1,1 '-xenyl]-4-base ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2, the 6-difluorophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1-phenyl-2,2,2-trifluoro) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[3-(trifluoromethyl) phenyl]-ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(1-pyrrolidyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(1-naphthyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring butyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-pyrazinyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-quinolyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-pyrimidyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-chloro-3,7,8,9,10,12,13,14, and 14a, 15-decahydro-2-methyl-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl, 1-(4-fluorophenyl) ethyl ester;
Quinolizine, the 1-[[(4-fluorophenyl) methoxyl group] carbonyl]-5-hydroxy-2-methyl-1H-indoles-4-yl] methyl]-1,2,3,4,6,7,8, the 9-octahydro-, muriate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-1, the 2-dimethyl-, (4-fluorophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-phenyl propyl ester;
Quinolizine, 1,2,3,4,6,7,8,9-octahydro-1-[[5-hydroxy-2-methyl-3-[(phenyl methoxyl group) carbonyl]-1H-indoles-4-yl] methyl]-, muriate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-nitrophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-the 1-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three fluoro-1-phenyl-1-(trifluoromethyl) ethyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, two ring [2.2.1] heptane-2-base ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl)-1-methyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring pentyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-phenyl cyclohexyl;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(hydroxymethyl) phenyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(hydroxy phenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(4-pyridyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [6-(methoxycarbonyl)-2-pyridyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 2-pyridyl methyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (6-carboxyl-2-pyridyl) methyl esters;
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (6-carboxyl-2-pyridyl) methyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [5-(methoxycarbonyl)-3-pyridyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (5-carboxyl-3-pyridyl) methyl esters;
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (5-carboxyl 3-pyridyl) methyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4 '-methyl [1,1 '-xenyl]-3-yl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2, the 6-3,5-dimethylphenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S, 2R)-2-(dimethylamino)-1-phenyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R, 2S)-2-(dimethylamino)-1-phenyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-naphthalene ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenylbenzene methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-2,3-dihydro-1H-indenes-1-base ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2-dihydro-1-acenaphthene ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, cyclohexyl (phenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 9H-fluorenes-9-base ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2,3,4-tetrahydrochysene-1-naphthalene ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [(2R, 3R)-3-phenyl epoxy ethyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-oxo-1,2-phenylbenzene ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 10,11-dihydro-5H-dibenzo [a, d] suberene-5-base ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-aminomethyl phenyl) phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, cyclopropyl (4-fluorophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3,4-dihydro-2H-1-benzo thiapyran-4-base ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(2-bromophenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2, the 2-trifluoro ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [(2S, 3S)-3-phenyl epoxy ethyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three fluoro-1-methyl isophthalic acids-(trifluoromethyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three fluoro-1-(4-fluorophenyl)-1-(trifluoromethyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-cyclopentyl-1-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[1,1 '-xenyl]-4-base-1-methyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl isophthalic acid-phenyl-2-propynyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-phenylbenzene ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl isophthalic acid, 2-phenylbenzene ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) cyclohexyl;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2-phenylbenzene ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-phenyl-2-propynyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [1,1 '-xenyl]-4-base methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 4-pyridyl methyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2,3,4-tetrahydrochysene-7,8-dimethoxy-2-methyl-4-isoquinoline 99.9 ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[3-(dimethylamino) phenyl]-ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl-2-pyrazinyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-(dipropyl amino)-1,1-dimethyl-2-butyne ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-2,3-dihydro-1H-indenes-1-base ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S, 2S)-2-(dimethylamino)-1-phenyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(trifluoromethyl) phenyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-chloro-phenyl-) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, the 15-decahydro-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, the 15-decahydro-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 2-hydroxy methacrylate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-aminomethyl phenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-the 1-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carbothioic acid carbothiolic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, S-(phenyl methyl) ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridyl methyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[4-(trifluoromethyl) phenyl]-ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(pentafluorophenyl group) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2, the 6-difluorophenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(2-furyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(4-morpholinyl)-1-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-1-(2-furyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methoxyl group-2-oxo-1-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(3-pyridyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (S)-carboxyl (phenyl) methyl esters;
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (S)-carboxyl (phenyl) methyl, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-2-methoxyl group-2-oxo-1-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (R)-carboxyl (phenyl) methyl esters;
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (R) carboxyl (phenyl) methyl, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 4-pyridyl methyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-pyridyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-pyridyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-thienyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(4-fluorophenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-1-(4-fluorophenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridyl methyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-oxyethyl group-2-oxo-ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-furyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-nitrophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-furyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-chloro-phenyl-) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, carboxyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2, the 6-dichlorophenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-p-methoxy-phenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(5-carboxyl-3-pyridyl) ethyl ester;
1, the 3-phthalic acid, 5-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole be [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-yl also also) carbonyl] the oxygen base] methyl]-, diethyl ester;
1, the 3-phthalic acid, 5-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole be [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-yl also also) carbonyl] the oxygen base] methyl]-;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (5-amino-2-chloro-phenyl-) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-acetate also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-. alpha-oxo--, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,4, the 5-trimethylammonium-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl-2-propynyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three chloro-1,1-dimethyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, three rings [3.3.1.13,7] last of the ten Heavenly stems-1-ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl isophthalic acid-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl cyclohexane ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1,2-trimethylammonium propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1) chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl ring pentyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-cyclohexyl-1-methyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,4-dimethyl-4-piperidine ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-fluorobenzene ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-methyl phenyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(methoxycarbonyl) phenyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridine ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(trifluoromethyl)-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [the 5-[(dimethylamino) methyl]-the 2-furyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-carboxyl-2-methyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(dimethylamino)-2,2-dimethyl propyl ester;
With 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1]-chromene propanedioic acid of [3,2-i] quinolizine-1-formic acid also, an acid anhydrides, 1,1-dimethyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino)-2-methyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(1H-imidazoles-1-yl) ethyl ester:
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-benzofuryl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R, 2S)-2-(dimethylamino)-1-phenyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S, 2R)-2-(dimethylamino)-1-phenyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) encircles propyl ester;
Pyridine, 3-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-yl also) carbonyl] the oxygen base] methyl]-the 1-methyl-, mesylate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the carbonyl of 11-dimethyl-1-[(S)-(1-phenyl ethoxy)]-, mesylate; And
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-and the 1-phenyl chlorocarbonate, the 11-oxide compound.
The present invention includes the pharmaceutical composition of formula 1 compound and the method for regulating chemokine receptor activity with these compounds, they all are used in prevention or treatment HIV infects, and postpone the AIDS outbreak, and treatment AIDS also treats inflammatory diseases.
Detailed Description Of The Invention
In the present invention, the compound of formula I can exist with two kinds of forms (closed loop and open loop form) in dicyclo aminal part.Balance between these two kinds of forms depends on pH.Under neutrality or alkaline pH (pH 〉=7.0), these compounds mainly exist with closed loop.But under acid pH scope (pH＜7.0), these molecules can exist with the form of closed loop and open loop mixture.The ratio of closed loop and open loop form depends on pH and solvent, and substituent R, R 2-R 6Characteristic with n.
In the compound of formula I, the term alkyl refers to have the straight or branched alkyl of 1 to 8 carbon atom, and comprise, for example, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl etc.This alkyl can be replaced by fluorine, and for example, these alkyl can also be selected from following substituting group by 1 to 3 and replace: alkoxyl group, carboxyl, hydroxyl, nitro, halogen, amino and the amino that replaces, and so that other active compound to be provided.Alkyl comprises the cycloalkyl of 3 to 7 carbon atoms, and for example, it can be selected from following substituting group by 1 to 3 and replace: alkyl, alkoxyl group, carboxyl, hydroxyl, nitro, halogen and amino amino and that replace.Cycloalkyl can with aromatic ring such as phenyl, pyridyl etc. condense.
Alkoxyl group is the O-alkyl, and wherein alkyl is the alkyl that defines 1 to 6 carbon atom as above.Acyl group is
Figure A9981647500451
, wherein the alkyl definition as above.
Term aryl refers to aromatic group, it is a phenyl, by 1 to 4 be selected from as above alkoxyl group of as above alkyl of definition, definition, hydroxyl, halogen, trifluoromethyl, amino, wherein alkyl defines as above alkylamino, alkyl definition dialkyl amido, nitro, cyano group, carboxyl, SO as above wherein 3H, CHO, wherein alkyl definition is as above
Figure A9981647500461
, wherein alkyl defines as above
Figure A9981647500462
, wherein alkyl definition is as above
Figure A9981647500463
, n wherein 2Be integer-(CH of 1 to 5 2) n 2-NH 2, wherein alkyl and n 2The definition as above-(CH 2) n 2-NH-alkyl, wherein alkyl and n 2The definition as above-(CH 2) n 2-N (alkyl) 2The phenyl that replaces.This term also comprises heteroaryl, and it is list or bicyclic heteroaryl, has 5 to 10 atoms, can contain one or more heteroatomss such as N, O, S, it comprises, for example, 2-or 3-thienyl, 2-or 3-furyl, 2-or 3-pyrryl, 2-, 3-, or 4-pyridyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidyl, 3-or 4-pyridazinyl or 2-, 3-, 4-, 5-, 6-or 7-indyl.These heterocycles can not be substituted or be substituted as above-mentioned aryl.
Term aralkyl or arylalkyl refer to be connected with on the aryl alkyl, and wherein aryl and alkyl define as above, for example, and benzyl, fluorenyl methyl etc.
Halogen is fluorine, chlorine, bromine or iodine.
Some compounds of closed loop I can further form N-oxide compound and N-season alkyl salt on the N-11 theheterocyclic nitrogen atom.In addition, some compounds of closed loop I are at R 10In can further form N-oxide compound and N-season alkyl salt on the nitrogen-atoms that arbitrarily selectivity exists.These structure formations within the scope of the invention.
Some compounds of formula I can further form medicinal acid addition salt and/or alkali salt.All these forms within the scope of the invention.
The medicinal acid addition salt of formula I compound comprises the salt that derives from nontoxic mineral acid, as spirit of salt, nitric acid, phosphoric acid, sulfuric acid, Hydrogen bromide, hydroiodic acid HI, hydrofluoric acid, phosphorous acid etc., and the salt that derives from non-toxic organic acid, paraffinic acid, hydroxyl alkane acid, chain docosandioic acid, aromatic acid, aliphatic series and the aromatic sulfonic acid etc. of single and dicarboxylic acid, phenyl replacement as aliphatic series.Therefore, these salt comprise vitriol, pyrosulphate, hydrosulfate, sulphite, hydrosulphite, nitrate, phosphoric acid salt, monohydric phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate salt, hydrochloride, hydrobromate, hydriodate, acetate, trifluoroacetate, propionic salt, octylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chloro benzoate, tolyl acid salt, dinitro-benzoate, phthalate, benzene sulfonate, tosylate, phenylacetate, citrate, lactic acid salt, maleic acid salt, tartrate, mesylate etc.Also can considered amino acid such as the salt of arginine etc., and gluconate, galacturonic hydrochlorate (see, for example, Berge S.M. etc., " Pharmaceutical Salts, " J.of Pharma.Sci., 1977; 66:1).
The acid salt of described basic cpd contacts preparation in a usual manner by free alkali with the required acid of capacity.This free alkali form can be by this salt form contact alkali and separated free alkali regeneration in a usual manner.Free alkali form and their corresponding salt forms in some physical properties as there being difference in a way aspect the solubleness in polar solvent, but on the other hand for the object of the invention, its corresponding free alkali of these salt is of equal value.
With metal or amine such as alkalies and alkaline earth or organic amine formation medicinal basic additive salt.Example as cationic metal comprises sodium, potassium, magnesium, calcium ion etc.The example of suitable amine is N, N '-dibenzyl ethylene diamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, quadrol, N-methyl glucoside amine and PROCAINE HCL, PHARMA GRADE (seeing that for example, ibid for Berge, 1977).
The base addition salt of described acidic cpd contacts preparation in a conventional manner by free acid form with the required alkali of capacity.This free acid form can also separate this free acid regeneration in a usual manner by this salt and acid contact.Free acid form and their corresponding salt forms in some physical properties as there being difference in a way aspect the solubleness in polar solvent, but on the other hand for the object of the invention, its corresponding free acid of these salt is of equal value.
Some compound of the present invention can exist with the non-solvent form, also can exist with the form of solvation, comprises hydrate forms.In a word, this solvation form comprises hydrate forms, with the non-solvent form be of equal value, and comprise within the scope of the invention.
There are one or more chiral centres in some compound of the present invention, and each center can exist with R or S configuration.The present invention includes all diastereomers, enantiomer and epimer and suitable mixture thereof.In addition, compound of the present invention can exist with the form of geometrical isomer.The present invention includes all cis (cis, syn or Z), trans (trans, anti or E) isomer and suitable mixture thereof.
Compound of the present invention can prepare and with a lot of oral and non-parenteral dosage forms administrations.Therefore, compound of the present invention can pass through drug administration by injection, promptly in intravenously, intramuscular, intracutaneous, subcutaneous, the duodenum or the intraperitoneal administration.In addition, compound of the present invention can pass through inhalation, as sucking in the nose.In addition, compound of the present invention can transdermal administration.The apparent following dosage forms of those skilled in the art can contain the compound of formula I or formula I compound corresponding medicinal salt as active ingredient.
For by compound pharmaceutical composition of the present invention, pharmaceutical carrier can be solid or liquid.But the solid form preparation comprises powder, tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carrier can be one or more materials, and it also can be used as thinner, correctives, solubility promoter, lubricant, suspending agent, tackiness agent, sanitas, tablet disintegrant or coating material.
In powder, carrier is a fine particle solid, and it mixes with the fine particle active ingredient.
In tablet, active ingredient is mixed in the proper ratio with the carrier with necessary bond property, and is compressed to required shape and size.
Powder and granule preferably contain 5 or 10 to about 70% active compound.Suitable carrier is magnesiumcarbonate, Magnesium Stearate, talcum, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.Terms " formulation " refers to comprise active compound and the prescription that capsular coating material is provided as carrier, contains or do not contain other carrier in the capsule, and the active ingredient suppressed by vector surrounds, and therefore, carrier and active ingredient are linked together.Equally, comprise lozenge and cachet.Tablet, powder, capsule, pill, cachet and lozenge can be as the solid dosages that is suitable for oral administration.
In order to prepare suppository, mixture or the theobroma oil with low melt wax such as glycerin fatty acid ester melts earlier, and this active ingredient is evenly dispersed in wherein, for example by stirring.Again the fused uniform mixture is poured in the mould of conventional size, cooling, and solidify thereupon.
Liquid absorption member comprises solution, suspensoid and emulsion, for example, and water or aqueous solution of propylene glycol.For the injection of non-enteron aisle, can be in the polyoxyethylene glycol aqueous solution obtaining liq preparation.
The aqueous solution that is suitable for orally using can by with this solubilization of active ingredient in water and add required adequate colouration agent, correctives, stablizer and thickening material and prepare.
The aqueous suspensions that is suitable for orally using can prepare by fine grain active ingredient is dispersed in the water, has added thickening material in the water, as natural or synthetical glue, resin, methylcellulose gum, Xylo-Mucine and other suspending agent of knowing.
Also comprise solid dosage, change liquid form preparation in its short period of time before use, so that oral administration.This type of liquid form comprises solution, suspensoid and emulsion.Except that active ingredient, can contain tinting material, correctives, stablizer, buffer reagent, artificial and natural sweeteners, dispersion agent, thickening material, solubility promoter etc. in these preparations.
Pharmaceutical preparation preferred unit dosage form.In this form, preparation is subdivided into the unitary dose that contains an amount of active ingredient.This unit dosage can be the packing preparation, this packing comprises the discontinuous amount of preparation, as the packing tablet, capsule and be contained in bottle or ampoule in powder.In addition, this unit dosage itself can be capsule, tablet, cachet or lozenge, and perhaps it can be any of these form that is contained in the proper number in the packaged form.
In unit dose formulations the amount of active ingredient can change or according to the effectiveness of specific application and active ingredient at 1mg to 1000mg, adjust between the preferred 10mg to 100mg.If desired, this composition can also contain other compatible therapeutical agent.
Treating in the therepic use of HIV infection as system, the compound that is used for method of pharmacy of the present invention can be with the about 1mg of initial dose every kg body weight every day to about 100mg administration.The preferred about 25mg of per daily dose scope is to about 75mg/ kg body weight.But, can change dosage according to patient's needs, the sanatory seriousness of institute and employed compound.Determine it is the general knowledge of this area for the suitable dosage of particular case.Generally speaking, use the dosage littler to begin than this compound optimal dose.After this, progressively increase this dosage up to obtaining best effect in the case in a small amount.For simplicity, total per daily dose is separable and if desired in this day gradation administration.
The compound of formula I is valuable CCR-5 chemokine receptor anagonists.Estimate in suppressing the HIV infection, effectively and therefore to be used for the treatment of AIDS as the compound of CCR-5 chemokine receptor anagonists.Compound of the present invention is estimated in the experiment of CCR-5 receptors bind.
The experiment of CCR-5 receptors bind
Be similar to Wu etc. at Nature, 1996; Description among the 384:179-183 is carried out 125I-gp120/sCD4/CCR-5 is in conjunction with experiment.In brief, derive from HIV-1 JR-FL (Trkola etc., Nature, 1996; Coating gp120 albumen 384:184-186), a kind of close scavenger cell (M-tropic) strain is with the specific activity of solid phase lactoperoxidase iodate to 20 μ Ci/ μ g.To each association reaction (binding buffer liquid [50mM HEPES, pH7.5, the 1mM CaCl of final volume 100 μ L 2, 5mM MgCl 2And 0.5%BSA]), the compound that 25 μ L are dissolved in DMSO (DMSO ultimate density 0.5%) exist or not in the presence of, film by the 25 μ L (2.5 μ g) of CCR-5/L1.2 cell preparation mixes with 25 μ L (3nM) sCD4, adds the radiolabeled gp120 of 25 μ L (0.1nM) subsequently.To react and at room temperature hatch 45 to 60 minutes, by this mixture being transferred to GFB screen plate stopped reaction, then with the binding buffer liquid washing that contains 0.5M sodium-chlor 3 to 4 times.With this plate drying, and before counting, add the MicroScint scintillating liquid.
The compounds block sCD-4/GP-120 of the present invention that formula I represents combines with the CCR-5 acceptor, and its avidity is less than or equal to 200 μ M.
Synthesizing of CCR-5 analogue
Scheme 1 has provided the synthetic of final target compound.At protonic solvent, the Compound I I in the preferred alcohol uses water-containing acetal and dimethylamine under 0-99 ℃ of temperature, handles down, obtains Mannich alkali III for preferred 25-60 ℃.III and enamine are at 50-100 ℃, and preferably under 80-100 ℃, under nitrogen atmosphere, condensation in aprotic solvent such as diox obtains compound IV.In the preferred DMF of aprotic solvent, under nitrogen atmosphere,, preferably under 0-25 ℃, with the IV alkylation, obtain Compound I (R wherein with NaH and alkyl halide at-10 to 25 ℃ 1Not H).
Scheme II has provided the preparation of indoles intermediate.At aprotic solvent, among the preferred THF, in the presence of active zinc, under nitrogen atmosphere, monobromo-acetic acid and nitrile reaction obtain amino crotonate V.Perhaps, amino crotonate V can react acquisition by corresponding 'beta '-ketoester and ammonia in ethanol.This 'beta '-ketoester can derive from 2,2,6-trimethylammonium-4H-1,3-dioxin (dioxin)-4-ketone and corresponding alcohol.The benzoquinones of amino crotonate V and replacement is at solvent, in preferred acetate, ethanol or the Nitromethane 99Min., 25 ℃ to the temperature of backflow, the 5-oxyindole VI that obtains replacing.At 50-100 ℃, preferably under reflux temperature, under nitrogen atmosphere, K-281 VI hydrolysis obtains corresponding sour VII with aqueous sodium hydroxide solution.In order to suppress decarboxylic reaction, importantly after this reaction is finished, this reaction mixture is cooled to 0 ℃ in ice-water bath, and uses the concentrated acid acidifying, preferably use HCl, produce this acid down at 0 ℃.In some standard step of esterification or after, can prepare ester or acid amides IX by sour VIII with the standard amide synthesis step of HBTU as coupling agent.Synthetic for ester, preferred Mitsunobu method is wherein used suitable alcohol, DEAD and PH 3P, and this reaction is at room temperature carried out.Another preferable methods of preparation ester is to use alkali, and preferred DBU and alkyl halide or aralkyl halide at polar solvent, in preferred DMF or the acetonitrile, at room temperature, are handled this acid.
Following scheme is for example understood the method for using in the final compound of preparation.The known version of skilled chemist is a part of the present invention.
Scheme 1
The preparation of final target compound
Scheme 2
The preparation of the indole derivatives that replaces
Figure A9981647500521
Scheme 3
Figure A9981647500531
The 5-hydroxyl benzofuran (C) that replaces
The 5-hydroxyl benzofuran (C) that replaces by will be suitable 1,4-benzoquinones (A) and suitable 3-amino crotonate (B) condensation prepared in acetate.Solvent removed in vacuo, and this product is carried out flash chromatography by recrystallization or on silica gel carry out purifying.
Mannich alkali (E)
The 5-hydroxyl benzofuran (C D) handles down at 50 ℃ in ethanol with dimethylamine agueous solution and formalin, perhaps uses N, N, and N ', N '-tetramethyl-diamino methane reacts completely in backflow De diox.Solution decompression concentrates and recrystallization purifying.
Cumarone (G)
This mannich alkali (E) is joined enamine, and (in the F) De dioxane solution, this enamine is extracted into this enamine in the ether by handle its perchlorate with aqueous sodium hydroxide solution, dry and this extract prepared fresh of vacuum concentration.Gained solution is heated up to reacting completely down at 80-100 ℃.Carry out the flash chromatography purifying by recrystallization or on silica gel with this mixture vacuum concentration and with this product.
Scheme 4
Synthesizing of the similar thing of 7-azaindole
Figure A9981647500541
Method:
With the beginning of the 3-hydroxyl that is purchased-2-phenylazo pyridine (1), by in the presence of hydrogen (57 crust) and Pd/C in acetate, under 65 ℃, reduce 1, (Synthesis 1990:681) obtains amine 2 to synthesize corresponding aminopyridine.Then, by at room temperature reacting with iodine and acetate, with amine 2 change into 2-amino-5-hydroxyl-3-iodo pyridine (Synthesis, 1990:681).Iodo pyridine 3 carries out the reaction changing into of palladium catalyzed cyclization azaindole 4 (Tetrahedron Lett., 1998 by the alkynes with suitable replacement again; 39:5355; TetrahedronLett., 1993; 34:2823).3 change 4 into after, then in the presence of salt of wormwood, use KMnO 4The hydroxyl methylene radical is oxidized to corresponding sour 5 (Gazz.Chim.Ital., 1932; 62:844).Perhaps finish 3 to 5 direct transformation with the alkynes of carboxyl substituted.Is required ester (J.Org.Chem., 1995 with imide coupling agent and required alcohol with 5 esterifications; 60:5214).(Tetrahedron Lett. 1966:4459) obtains 7 with formaldehyde and dimethylamine substituted pyridines ring.Intermediate 7 obtains the similar thing 8 of final azaindole (J.Het.Chem., 1970 by 7 with the reaction in the ethanol that refluxes of quinolizine alkane (quinolizidine) imines again; 7:131)
Scheme 5
By the final target compound of new intermediate preparation
Figure A9981647500561
At aprotic solvent, among preferred ether, methylene dichloride or the THF, with the oxalyl chloride that is present in the identical aprotic solvent, at-10 to 30 ℃, under preferred 0 to the 25 ℃ temperature, handle Compound I, then the amine of selecting by treatment of selected in aprotic solvent obtains required product II.Compound I and oxalyl chloride at-10 to 30 ℃, are handled under preferred 0 to the 25 ℃ temperature in the preferred ether of aprotic solvent, methylene dichloride or THF, then selected alcohol are handled in aprotic solvent, can obtain required product III.Perhaps in aprotic solvent such as ether, methylene dichloride or THF, react and to prepare required product III by Compound I and compound IV.
Scheme 6
The preparation of mixed acid anhydride
Total description
At non-proton polar solvent, among the preferred THF, benzyl ester I carries out hydrogenolysis and obtains sour II under the room temperature.In the presence of organic bases such as triethylamine, handle sour II with Benzoyl chloride subsequently and obtain the mixing acid anhydride III.
Scheme 7
By the synthetic ester of mixed acid anhydride
Figure A9981647500581
In a word bright
Mixed acid anhydride I is mixed with required alcohol, the gained reaction mixture is heated to 100 to 180 ℃, obtain corresponding ester up to this mixed anhydride reaction.
The invention still further relates to compound of the present invention and the cooperative programs that are used to prevent or treat one or more preparations of AIDS.For example, compound of the present invention can with the effective administration of cooperative programs of anti-HIV compound, immunomodulator, anti-infective or the prevention of the known significant quantity of those of ordinary skills or treatment vaccine, no matter be before or after contact virus.
Antiviral drug
The medicine name Manufacturers Indication
097 Hoechst/Bayer HIV infects, AIDS, ARC (non-nucleoside reverse transcriptase (RT) inhibitor)
GW141?W94/VX478 Glaxo?Wellcome HIV infects, AIDS, ARC (proteinase inhibitor)
Amprenavir GW1592U89?Abacavir Glaxo?Wellcome HIV infects, AIDS, ARC (RT inhibitor)
Acemannan Carrington Labs(Irving，TX) ARC
Acyclovir Burroughs Wellcome HIV infects, AIDS, and ARC share with AZT
AD-439 Tanox?Biosystems HIV infects, AIDS, ARC
AD-519 Tanox?Biosystems HIV infects, AIDS, ARC
Adefovir?dipivoxil Gilead?Sciences HIV infects
AL-721 Ethigen(Los Angeles，CA) ARC, the PGL HIV positive, AIDS
Interferon-alpha Glaxo?Wellcome Kaposi, HIV in combination
The Alferon Interferon, rabbit Interferon Sciences Kaposi, HIV in combination
Ansamycin LM427 Adria Laboratories(Dubl in，OH) Erbamont(Stamford ，CT) ARC
In and the antibody of the unusual Interferon, rabbit of the unsettled α of pH Advanced Biotherapy Concepts(Rockvill e，MD) AIDS，ARC
AR77 B-F-ddA Aronex?Pharm?Nat’l Cancer?Institute HIV infects, AIDS, ARC AIDS relative disease
BMS-232623 (CGP-73547) Bristol-Myers Squibb/Novartis HIV infects, AIDS, ARC (proteinase inhibitor)
BMS-234475 (CGP-61755) Bristol-Myers Squibb/Novartis HIV infects, AIDS, ARC (proteinase inhibitor)
(-) 6-chloro-4 (S)-cyclopropyl acethlene base-4 (S)-three fluoro-methyl isophthalic acids, 4-dihydro 2H-3,1-benzoxazine-2-ketone Merck HIV infects, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)
C1-1012 Warner-Lambert HIV-1 infects
Cidofovir Gilead?Science The CMV retinitis, bleb, papillomavirus
Combivir?AZT+3TC Glaxo?Wellcome HIV infects, AIDS, ARC
Curdlan?sulfate AJI?Pharma?USA HIV infects
Cytomegalovirus immunobead albumen MedImmune The CMV retinitis
Cytovene Ganciclovir Syntex/Roche The CMV that eyesight is coerced, periphery CMV, the retinitis
Delaviridine Pharmacia-Upjohn HIV infects, AIDS, ARC (RT inhibitor)
The sulfuric acid dextran Ueno?Fine?Chem. Ind?Ltd.(Osaka， Japan) AIDS, ARC, the HIV positive is asymptomatic
HIVID (ddc) zalcitabine Hoffman-La?Roche HIV infects, AIDS, ARC
The ddI didanosine Bristol-Myers Squibb HIV infects, AIDS, ARC; Share with AZT/d4T
DMP-450 Triangle Pharmaceutical HIV infects, AIDS, ARC (proteinase inhibitor)
Efavirenz(DMP?266) DuPont?Merck HIV infects, AIDS, ARC (non-nucleoside RT inhibitor)
EL10 Elan?Corp， PLC(Gainesville， GA) HIV infects
Famciclovir Smith?Kline Zoster, herpes simplex
Foscavir/ phosphine formic acid Astra CMV，HSV1-2
FTC Triangle Pharmaceutical HIV infects, AIDS, ARC (reverse transcriptase inhibitors)
GS840 Gilead HIV infects, AIDS, ARC (reverse transcriptase inhibitors)
HBY097 Hoechst?Marion HIV infects, AIDS, and ARC is (non-
Roussel Nucleoside reverse transcriptase inhibitor)
Hypericin VIMRx?Pharm. HIV infects, AIDS, ARC
The recombinant human interferon- Triton Biosciences(Almed a，CA) AIDS, Kaposi, ARC
Alferon N Interferon Sciences ARC，AIDS
Indinavir Merck HIV infects, AIDS, and ARC, the asymptomatic HIV positive is also share with AZT/ddI/ddC
ISIS?2922 ISIS Pharmaceuticals The CMV retinitis
JE 2147 (KN1-764) proteinase inhibitor Japan?Energy/ Agouron?PI HIV infects, AIDS, ARC (reverse transcriptase inhibitors); Also share with AZT
KNI-272 Nat’l?Cancer Institute The HIV-relative disease
Lamivudine, 3TC Glaxo?Wellcome HIV infects, AIDS, ARC (reverse transcriptase inhibitors); Also share with AZT
Lobucavir Bristol-Myers Squibb Cmv infection-HBV infects
Nelfinavir Agouron Pharmaceuticals HIV infects, AIDS, ARC (proteinase inhibitor)
Naphthalene Wei Laping Boeheringer Ingleheim HIV infects, AIDS, ARC (RT inhibitor)
Novapren Novaferon?Labs， Inc.(Akron，OH) Hiv inhibitor
Peptide T octapeptide sequence Peninsula Labs(Belmont，CA) AIDS
PNU-140690 Pharmacia?Upjohn HIV infects, AIDS, ARC (egg
White enzyme inhibitors)
Probucol Vyrex HIV infects, AIDS
RBD-CD4 Sheffield??Med. Tech(Houston，TX) HIV infects, AIDS, ARC
Ritonavir Abbott HIV infects, AIDS, ARC (proteinase inhibitor)
S-1153 Agouron/Shionogi NnRTI
Saquinavir Hoffmann-La?Roche HIV infects, AIDS, ARC (proteinase inhibitor)
Stavudine; D4T two dehydrogenation deoxidation chest glucosides Bristol-Myers Squibb HIV infects, AIDS, ARC
Valacyclovir Glaxo?Wellcome Sexual organ HSV﹠CMV infects
Virazole ribavirin (Ribavirin) Viratek/ICN(Costa Mesa，CA) The asymptomatic HIV positive, LAS, ARC
Zidovudine; AZT Glaxo?Wellcome HIV infects, AIDS, and ARC, Kaposi is with other treatment associating
Immunomodulator
The medicine name Manufacturers Indication
AS-101 Wyeth-Ayerst AIDS
Bropirimine Pharmacia?Upjohn The AIDS that worsens
Acemannan Carrington?Labs， Inc.(Irving，TX) AIDS，ARC
CL246，738 American?Cyanamid Lederle?Labs AIDS, Kaposi
EL10 Elan?Corp， PLC(Gainesville，GA) HIV infects
FP-21399 Fuki?I?mmunoPharm Blocks?HIV?fusion withCD4+cells
IFN- Genentech ARC, (tumour is bad with w/TNF
Necrosis factor) associating
RHuGM-CSF Genetics?Institute Sandoz AIDS
RHuGM-CSF Hoeschst-Roussel Immunex AIDS
RHuGM-CSF Schering-Plough AIDS unites with w/AZT
HIV nuclear slug particle immunostimulant Rorer Seropositivity HIV
The IL-2 interleukin-2 Cetus AIDS share with w/AZT
The IL-2 interleukin-2 Hoffman-La?roche Immunex AIDS, ARC, HIV share with w/AZT
IL-2 interleukin-2 (aldeslukin) Chiron AIDS，increase?in CD4?cell?counts
Vein immunoglobulin (Ig) (people) Cutter Biological(Berkeley， CA) Paediatrics AIDS share with w/AZT
IMREG-1 Imreg(New?Orleans， LA) AIDS, Kaposi, ARC, PGL
IMREG-2 Imreg(New?Orleans， LA) AIDS, Kaposi, ARC, PGL
The Imuthiol diethyldithiocarbamate Merieux?Institute AIDS，ARC
α-2 Interferon, rabbit Schering?Plough Kaposi w/AZT, AIDS
Met-enkephalin TNI Pharmaceutical(Chica go，IL) AIDS，ARC
MTP-PE muramyl-tripeptides Ciba-Geigy?Corp. Kaposi
Granulocyte colony-stimulating factor Amgen AIDS share with w/AZT
Remune Immune?ResponseCorp. Immunotherapy
The rCD4 recombinant soluble human CD4 Genentech AIDS，ARC
rCD4-IgG?Hybrids AIDS，ARC
The recombinant soluble human CD4 Biogen AIDS，ARC
Interferon alpha 2a Hoffman-La?Roche Kaposi AIDS, ARC share with w/AZT
SK﹠F106528 soluble T 4 Smith?Kline HIV infects
Thymopentin Immunobiology Research Institute(Annandale， NJ) HIV infects
Tumour necrosis factor; TNF Genentech ARC unites with the w/ IFN-
Anti-infective
The medicine name Manufacturers Indication
Clindamycen and primaquine Pharmacia?Upjohn PCP
Fluconazole Pfizer Crypotococcal, moniliosis
Lozenge nystatin Squibb?Corp. The prevention oral candidiasis
Ornidyl Eflornithine Merrell?Dow PCP
Pentamidine isethionate (IM﹠IV) LyphoMed (Rosemont，IL) The PCP treatment
Trimethoprim Antiseptic-germicide
Trimethoprim/sulfa Antiseptic-germicide
Piritrexim Burroughs?Wellcome The PCP treatment
Suck pentamidine isethionate Fisons?Corporation The PCP prevention
Spiramycin Base Rhone-Poulenc Cryptosporidium diarrhoea
Intraconazole- R51211 Janssen?Pharm. Histoplasmosis; Crypotococcal
Trimetrexate Warner-Lambert PCP
Other
The medicine name Manufacturers Indication
Daunorubicin NeXstar，Sequus Kaposi
The recombinant human erythropoietin Ortho?Pharm.Corp. With the relevant serious anaemia of AZT treatment
The recombinant human somatropin Serono AIDS is relevant to become thin emaciation
Magace Bristol-Myers Squibb Treat the anorexia relevant with w/AIDS
Testosterone Alza，Smith?Kline AIDS-is relevant to become thin
Total enteral nutrition Norwich?Eaton Pharmaceuticals Diarrhoea relevant and malabsorption with AIDS
Should understand that The compounds of this invention and AIDS are antiviral, that the scope of the cooperative programs of immunomodulator, anti-infection agent or vaccine is not limited to table is listed, but comprise in principle and the cooperative programs that are used for the treatment of any pharmaceutical composition of AIDS.
The following example is used for illustrating intermediate and final compound and preparation method thereof.They are not to be used for limiting the scope of the invention.
Experiment
The synthetic intermediate indole derivatives
5-acetoxyl group-2-Methyl-1H-indole-3-formic acid (A)
5-hydroxy-2-methyl-1-H-indole-2-formate (8.54g, 44.7mmol) be dissolved in aqueous sodium hydroxide solution (2N, 45mL).1-ethanoyl-1H-2, and the 3-triazolo (4,5-b-)-(7.24g 44.7mmol) is dissolved in THF (30mL), and this solution is joined in the solution of 5-hydroxy-2-methyl-1-H-indole-2-formate pyridine.This mixture is stirred to seldom or does not have initiator residual, about 30 minutes; Form white precipitate.This mixture is cooled to 0 ℃ and to drip concentrated hydrochloric acid be-1 up to pH.The gained white solid after filtration, (2 * 50mL) washings are used ethyl alcohol recrystallization, and vacuum-drying to water, obtain 6.95g (67%); Mp233-235 ℃ (decomposition); IR:3331,1740,1642,1234,1207cm -1. 1HNMR (DMSO-d 6) δ: 2.21 (s, 3HCH 3CO 2), 2.59 (s, 1H, ArCH 3), 6.79 (d, J=6.84Hz, 1H, ArH), 7.27 (d, J=8.55Hz, 1H, ArH), 7.53 (s, 1H, ArH), 11.77 (s, 1H, NH) 11.93 (s, 1H, COOH) .MS (APCI+): m/z234.1 (MH +) .C 12H 11N 1O 4Computational analysis value: C, 61.80; H, 4.75; N, 6.01. measured value: C, 61.48; H, 4.66; N, 5.86.
Method A. prepares total method of ester
5-hydroxy-2-methyl-1-H-indole-2-formate or 5-acetoxyl group-2-Methyl-1H-indole-3-formic acid (4-28g) mixes so that dissolve with enough THF.Triphenylphosphine (1eq) and favourable alcohol (2.5-4.0eq is according to solubleness) join in this THF solution.In 1-1.5 hour, (DEAD 1eq) is added drop-wise in this mixture the diethylazodicarboxylate.Spend the night stirring under this mixture room temperature.This solution for vacuum concentration obtains oily mixture; The solution of 1: 1 hexane/ethyl acetate is used for dissolving oily matter again.Required product is passed through the flash chromatography purifying.Grind the diethyl hydrazine dicarboxylic ester of removing remnants in this product with hot water; The gained solid is 40 ℃ of following vacuum-dryings.For the compound with 5-acetoxyl group-2-Methyl-1H-indole-3-formic acid preparation, the 5-ethanoyl is removed in the following manner: protected ester (1eq) is dissolved in MeOH in a small amount.Add NaOMe (4eq) and this mixture is stirred to and do not have initiator residual (about 45 minutes).Add the pH regulator to 1 of hydrochloric acid, produce a lot of white precipitates this solution.This solid after filtration, (2 * 20mL) washings are and 40 ℃ of following vacuum-dryings for water.Perhaps, add the pH regulator to 1 of hydrochloric acid with this solution, and (2 * 25mL) extractions of this solution ethyl acetate.Organic layer obtains solid with dried over sodium sulfate and evaporation.This solid can be by being further purified with the appropriate solvent recrystallization.According to method A, intermediate B-G is synthesized.
5-acetoxyl group-2 methyl indole-3-benzyl formate (B) yield: 8.32g (21.6%); Mp152-154 ℃;
IR：3310，1752，1662，1226，1094cm -1； 1HNMR
(DMSO-d 6)δ2.21(s，3H，CH 3CO 2)，2.60(s，3H，ArCH 3)，5.28(s，2H，CH 2Ph)，
6.82(dd，J＝8.55，2.44Hz，1H，ArH)，7.26-7.41(m，6H，ArH)，7.53(d，
J＝2.44Hz，1H，ArH)，11.9(s，1H，NH).MS(APCI+)：324.1(MH +).
C 19H 17N 1O 4Computational analysis value: C, 70.58; H, 5.30; N, 4.33. measured value: C, 70.47; H,
5.43；N，4.24.
5-hydroxy-2-methyl indole-3-carboxylic acid benzyl ester (C) yield: 5.03g (76%); Mp191-193 ℃;
IR:3227,1654,1472,1429,1094cm -1. 1H NMR (DMSO-d 6) δ 2.54 (s, 3H, alkyl CH 3), 5.26 (s, 2H, PhCH 2), 6.55 (d, J=6.10Hz, 1H, ArH), 7.08 (d, J=8.8Hz, 1H, ArH), 7.24-7.42 (m, 6H, ArH), 8.82 (s, 1H, aromatics OH), 11.55 (s, 1H, NH) .MS (APCI+): m/z282.0 (MH +) .C 17H 15N 1O 3Computational analysis value: C, 71.71; H, 5.44; N, 4.92. measured value: C, 71.72; H, 5.49; N, 4.85.
Perhaps, intermediate C can be by intermediate B according to embodiment 9, and the method that steps A is described is synthetic.
5-acetoxyl group-2 methyl indole-3-propyl formate (D) yield: 2.16g (37%); Mp134-136 ℃;
IR:3263,2966,1758,1677,1657,1215cm -1. 1H NMR (DMSO-d 6) δ 0.99 (t, J=7.51Hz, 3H, CH 2CH 2CH 3), 1.71 (sextet, J=7.33Hz, 3H, CH 2CH 2CH 3), 2.26 (s, 3H, CH 3CO), 2.63 (s, 3H, ArCH 3), 4.17 (t, J=6.41Hz, 2H, CH 2CH 2CH 3), 6.86 (dd, J=8.61,2.20Hz, 1H, ArH), 7.34 (d, J=8.61Hz, 1H, ArH), 7.55 (d, J=2.20Hz, 1H, ArH), 11.9 (s, 1H, NH) .MS (APCI+): m/z276.0 (MH +) .C 15H 17N 1O 4Computational analysis value: C, 65.44; H, 6.22; N, 5.09. measured value: C, 65.13; H, 6.28; N, 5.10.
5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 2-isopropyl ester (E) yield: 0.720g (12%); Mp188-189 ℃;
IR:3409,3391,1663,1467,1181,1095 (cm -1). 1H NMR (DMSO-d 6) δ 1.27 (d, J=6.35Hz, 6H, CH (CH 3) 2), 2.52 (s, 3H, CH 3), 5.04 (septet, J=6.35Hz, 1H, CH (CH 3) 2), 6.53 (dd, J=8.55,2.44 Hz, 1H, ArH), 7.06 (d, J=8.55Hz, 1H, ArH), 7.25 (d, J=2.44Hz, 1H, ArH), 8.77 (s, 1H, OH) 11.4 (s, 1H, NH) .MS (APCI+): m/z234.1 (MH +) .C 13H 15N 1O 3Computational analysis value: C, 66.94; H, 6.48; N, 6.00. measured value: C, 66.79; H, 6.53; N, 5.88.
Yield: 0.532gmp187-188 ℃ of 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid cyclopropyl methyl esters (F);
IR:3388,3297,1663,1466,1179,1094cm -1. 1H NMR (DMSO-d 6) δ 0.00-0.04 (m, 2H, cyclopropyl CH 2CH 2), 0.22-0.26 (m, 2H, cyclopropyl CH 2CH 2), 0.86-0.93 (m, 1H, CH 2CH), 2.27 (s, 3H, ArCH 3), 3.72 (d, J=7.32 Hz, 2H, CH 2CH), 6.27 (dd, J=8.55,2.44Hz, 1H, ArH), 6.79 (d, J=8.55,1H, ArH), 6.99 (d, J=2.20,1H, ArH), 8.51 (s, 1H, OH), 11.2 (s, 1H, NH) .MS (APCI+): m/z246.1 (MH +) .C 14H 15N 1O 3Computational analysis value: C, 68.56; H, 6.16; N, 5.71. measured value: C, 68.50; H, 6.19; N, 5.67.
5-acetoxyl group-2 methyl indole-3-formic acid 1-phenyl-propyl ester (G) yield: 1.36g (23%);
Mp144-145.5 ℃; IR:3289,1755,1661,1459,1216,1204,1089cm -1. 1H NMR (DMSO-d 6) δ 0.863 (t, J=7.32Hz, 3H, CH 2CH 3), 1.82-1.98 (m, 2H, CHCH 2CH 3), 2.22 (s, 3H, CH 3CO), 2.63 (s, 3H, ArCH 3), 5.80 (t, J=6.84Hz, 1H, benzyl CH), 6.83 (dd, J=8.79,2.20Hz, 1H, ArH), 7.21-7.36 (m, 6H, ArH), 7.60 (d, J=2.20Hz, 1H, ArH), 11.9 (s, 1H, NH) .MS (APCI-): m/z 350.1 (M-1) .C 21H 21N 1O 4Computational analysis value: C, 71.78; H, 6.02; N, 3.99. measured value: C, 71.53; H, 6.02; N, 3.81.
5-hydroxy-2-methyl-1H-indole-3-carboxylic acid isobutyl ester (H) 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid isobutyl ester is synthetic and with hexane/CH according to total method A 2Cl 2Recrystallization obtains the white solid of 1.39g (26.2%): mp188-190 ℃;
IR (KBr) 385,3272,2963,1655,1630,1464,1174,1094cm -1 1H NMR (400MHz, DMSO-d 6) δ 0.95 (d, J=6.84Hz, 6H, CH (CH 3) 2), 1.94 (n, J=6.84Hz, 1H, CH (CH 3) 2), 2.54 (s, 3H, CCH 3), 3.95 (d, J=1.95Hz, 2H, OCH 2), 6.54 (dd, J=8.55,2.44Hz, 1H, ArH), 7.07 (d, J=8,1H, ArH), 7.25 (s, 1H, ArH), 8.81 (s, 1H, OH), 11.49 (s, 1H, NH); MS (APCI+): m/z248.1 (MH +) .C 14H 17NO 3Computational analysis value: C, 68.00; H, 6.93; N, 5.66. measured value: C, 67.92; H, 6.87; N, 5.54.
5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 2,2-dimethyl-propyl ester (I)
5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 2,2-dimethyl-propyl ester synthesizes according to total method A and obtains white solid: mp195-196 ℃ of 2.31g (33.8%) with the methylene dichloride recrystallization;
IR (KBr) 3262,2960,1652,1464,1170,1094cm -11HNMR (400MHz, DMSO-d 6) δ 0.97 (s, 9H, C (CH 3) 3), 2.55 (s, 3H, ArCH 3), 3.87 (s, 2H, OCH 2), 6.55 (dd, J=8.55,2.44Hz, 1H, ArCH), 7.07 (d, J=8.55Hz, 1H, ArCH), 7.29 (s, 1H, ArH), 8.82 (s, 1H, OH), 11.50 (s, 1H, NH); MS (APCI+): m/z262.1 (MH +) .C 15H 19NO 3Computational analysis value: C, 68.94; H, 7.33; N, 5.36. measured value: C, 68.55; H, 7.23; N, 5.41.
Method B: another kind of total method of preparation ester
In 1 hour, with 5-acetoxyl group-2-Methyl-1H-indole-3-formic acid (Aldrich, 5.00g, 21.4mmol) and the diethylazodicarboxylate (7mL THF drips of solution 21.4mmol) is added to triphenylphosphine (Aldrich for Aldrich, 3.73g, 5.62g, 21.4mmol) and selected alcohol (Aldrich, 2.00-4.00g is 32.2mmol) in the mixture of 32mL THF.Stir under the room temperature after 24 hours, this mixture concentrates.This product is by flash column chromatography purifying (10%MeOH, CHCl on silica gel 3) obtain corresponding ester.
5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 2-piperidines-1-base-ethyl ester (J)
5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 2-piperidines-1-base-ethyl ester synthesizes according to method B and obtains white solid: mp210-212 ℃ of 0.350g (26.9%) with the hexane/ethyl acetate recrystallization; IR (KBr) 3203,2934,1690,1455,1175,1067cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.31 (m, 2H, NCH 2CH 2CH 2), 1.42 (m, 4H, NCH 2CH 2), 2.38 (m, 4H, NCH 2CH 2CH 2), 2.53 (s, 3H, ArCH 3), 2.59 (t, J=6.10Hz, 2H, OCH 2CH 2), 4.22 (t, J=6.10Hz, 2H, OCH 2CH 2N), 6.54 (dd, J=8.66,2.32Hz, 1H, ArH), 7.06 (d, J=8.55Hz, 1H, ArH), 7.27 (s, 1H, ArH), 8.77 (s, 1H, OH), 11.48 (s, 1H, NH); MS (APCI+): m/z303.1 (MH +) .C 17H 22N 2O 3Computational analysis value: C, 67.05; H, 7.28; N, 9.20. measured value: C, 66.93; H, 7.28; N, 9.00.
Method C: total method (K-O) of synthetic 3-alkyl-amino ethyl crotonate of 3-
Activate zinc: in the 3N HCl solution (50mL) that stirs, add Zn (20g) and also at room temperature stirred 15 minutes.Decant HCl solution, and with twice of this process repetition.With distilled water (2x, 100mL), ethanol (2x, 50mL) and ether (2x 50mL) washs this activatory zinc.Then, at 40 ℃ this activatory zinc was placed under the decompression 12 hours.(3.27g 50mmol) in the solution of Jiao Baning, under the rare gas element atmosphere, adds 0.2mL bromoethyl acetate (1) under the room temperature for dry THF (30mL) in being contained in flame-dried 100ml round-bottomed flask and activated zinc.Then this reaction is heated to backflow.After this solution becomes green (15-30 minute), add alkyl prussiate (10mmol) immediately, and (4.44mL 40mmol), refluxed 30 minutes again, was cooled to room temperature then to drip bromoethyl acetate in 30 minutes.In the solution that stirs, add THF (30mL) and K 2CO 3(13mL, 50%w/w), and vigorous stirring 30 minutes.This solution places centrifuge tube and centrifugal again.Supernatant decanted liquid, and with the particle resuspending in THF (30mL), acutely shake and centrifugal (method repeat twice).The supernatant liquor dried over mgso that merges is filtered, and concentrating under reduced pressure obtains 3-alkyl-3-amino ethyl crotonate crude product, and it is directly used in the next step.
3-amino-3-benzyl ethyl crotonate (K)
1HNMR(250MHz，CDCl 3)δ1.26(t，J＝7.1Hz，3H)，3.46(s，2H)，4.12(q，J＝7.15Hz，2H)，4.64(s，1H)，7.27(m，5H).
3-amino-3-ethyl crotonic acid ethyl ester (L)
1H?NMR(250MHz，CDCl 3)δ1.47(t，J＝7.5Hz，3H)，1.26(t，J＝7.1Hz，3H)，2.16(q，5.7Hz，2H)，4.11(q，J＝5.4Hz，2H)，4.55(s，1H). 13CNMR(62.5MHz，CDCl 3)δ12.0，14.5，29.3，30.3，58.5，82.6，164.9，170.5.
3-amino-3-cyclopropyl ethyl crotonate (M)
1H NMR (250MHz, CDCl 3) δ 0.74 (m, 2H), 0.86 (m, 2H), 1.25 (t, J=7Hz, 3H), 2.27 (s, 1H), 4.10 (q, J=7Hz, 2H), 4.45 (s, 1H). 13CNMR (62.5MHz, CDCl 3) δ 7.1,14.6,15.8,58.5,80.7,165.1,170.4.LC/MS (150mm * 4.6mm, C-18,5 microns, 10mM NH 4OAc/CH 3CN, APCI+) t=7.24min, m/z=156 (M+1).
3-amino-3-propyl group ethyl crotonate (N)
1H NMR (250MHz, CDCl 3) δ 0.95 (t, J=7.3Hz, 3H), 1.26 (t, J=7.1Hz, 3H), 1.56 (s, J=7.3Hz, 2H), 2.10 (d, J=7.3Hz, 2H), 4.1 (q, J=7.2Hz, 2H), 4.53 (s, 1H). 13C NMR (62.5MHz, CDCl 3) δ 13.5,14.5,21.1,38.4,58.30,84LC/MS (150mm * 4.6mm, C-18,5 microns, 10mM NH 4OAc/CH 3CN, APCI+) t=8.02min, m/z=158.4 (M+1).
3-amino-3-isobutyl-ethyl crotonate (O)
1H NMR (250MHz, CDCl 3) δ 0.95 (d, J=6.4Hz, 6H), 1.26 (t, J=7.1Hz, 3H), 1.9 (m, 1H), 1.96 (d, J=7.0Hz, 2H), 4.11 (q, J=7.1Hz, 2H), 4.51 (s, 1H) .LC/MS (150mm * 4.6mm, C-18,5 microns, 10mM NH 4OAc/CH 3CN, APCI+) t=8.69min, m/z=172.4 (M+1).
Method D: Synthetic 2-alkyl-5-hydroxyl 3-indolecarboxylic acid ethyl ester (P-T)
In acetate (50mL) solution that stir, the amino ethyl crotonate of 3-alkyl-3-(15.3mmol), add 1, the 4-benzoquinones (3.3g, 30.5mmol).Stir under this solution room temperature and spend the night and filter by frit again.This solid is with the cold distilled water washing and use P in Abderhalden (Abderhalden) moisture eliminator 2O 5Drying obtains 2-alkyl-5-hydroxyl-3-indolecarboxylic acid ethyl ester.
2-benzyl-5-hydroxyl-3-indole-carboxylic acid ethyl ester (P) 70% yield (by initial nitrile) is white powder.
1H NMR (250MHz, DMSO) δ 1.32 (t, J=7.08Hz, 3H), 4.26 (q, J=7.05Hz, 2H), 4.41 (s, 2H), 6.63 (dd, J=8.5,2.2Hz, 1H), 7.25 (m, 7H), 8.88 (s, 1H), 11.64 (s, 1H). 13(62.5MHz, DMSO) δ 14.5,17.3,32.8,58.7,102.1,105.4,111.8,126.2,127.8,128.4,129.3,139.0,146.1,152.3,165.1.LC/MS (150mm * 4.6mm, C-18,5 microns, 10mMNH for C NMR 4OAc/CH 3CN, APCI+) t=7.83, m/z=296.3 (M+1).
2-ethyl-5-hydroxyl-3-indole-carboxylic acid ethyl ester (Q) 54% yield (by initial nitrile) is white powder.
1H NMR (250MHz, DMSO) δ 1.23 (t, J=7.6Hz, 3H), 1.33 (t, J=7.1Hz, 3H), 3.04 (q, J=7.5Hz, 2H), 4.24 (q, J=7.1Hz, 2H), 6.5 (dd, J=8.7,2.4Hz, 1H), 7.14 (d, J=8.5Hz, 1H), 7.33 (d, J=2.4Hz, 1H), 8.82, (s, 1H), 11.48 (s, 1H). 13(62.5MHz, DMSO) δ 13.6,14.4,20.7,58.4,105.3,111.3,111.6,127.9,128.9,150.0,152.2,165.0.LC/MS (150mm * 4.6mm, C-18,5 microns 10mM NH for C NMR 4OAc/CH 3CN, APCI+) t=7.60min, m/z=234.3 (M+1).
2-cyclopropyl-5-hydroxyl-3-indole-carboxylic acid ethyl ester (R) 83% yield (by initial nitrile) is white powder.
1HNMR (250MHz, DMSO) δ 0.97 (m, 2H), 1.10 (m, 2H), 1.35 (t, J=7.1Hz, 3H), 3.00 (m1H), 4.26 (q, J=7.0Hz, 2H), 6.59 (dd, 8.7,2.4Hz, 1H), 7.8 (d, J=8.7Hz, 1H), 7.30 (d, J=2.4Hz, 1H), 8.81 (s, 1H), 10.93 (s, 1H). 13(62.5MHz, DMSO) δ 8.8,9.2,14.5,17.2,21.0,58.5,102.9,105.1,111.1,111.4,127.9,128.8,150.1,152.1,165.4,171.9.LC/MS (150mm * 4.6mm, C-18,5 microns 10mM NH for CNMR 4OAc/CH 3CN, APCI+) t=7.03min, m/z=246.3 (M+1).
5-hydroxyl-2-propyl group-3-indole-carboxylic acid ethyl ester (S) 62% yield (by initial nitrile) is white powder.
1H NMR (250MHz, DMSO) δ 0.93 (t, J=7.3Hz, 3H), 1.35 (t, J=7.1Hz, 3H), 1.67 (m, 2H) 3.01 (t, J=9.0Hz, 2H), 4.26 (q, J=7.1Hz, 2H), 6.77 (dd, J=8.7,2.2Hz, 1H), 7.16 (d, J=8.6Hz, 1H), 7.35 (d, J=2.2Hz, 1H), 8.86 (s, 1H), 11.51 (s, 1H). 13(62.5MHz, DMSO) δ 13.7,14.4,17.2,22.3,29.2,58.4,105.2,111.3,115.5,127.9,128.9,148.4,149.6,152.1, LC/MS (150mm * 4.6mm, C-18,5 microns, 10mM NH for C NMR 4OAc/CH 3CN, APCI+) t=7.21min, m/z=248.4 (M+1).
2-isobutyl--5-hydroxyl-3-indole-carboxylic acid ethyl ester (T) 68% yield (by initial nitrile) is white powder.
1H NMR (250MHz, DMSO) δ 0.91 (d, J=6.6Hz, 6H), 1.35 (t, J=7.1Hz, 3H), 2.06 (m, 1H), 2.91 (d, J=7.2Hz, 2H), 4.25 (q, J=7.1Hz, 2H), 6.62 (dd, J=8.6,2.4Hz, 1H), 7.16 (d, J=8.5Hz, 1H), 7.35 (d, J=2.4Hz, 1H), 8.85 (s, 1H), 11.5 (s, 1H). 13(62.5MHz, DMSO) δ 14.4,17.2,22.3,28.6,36.2,58.4,102.0,105.2,111.2,111.4,127.9,128.8,147.6,152.1,165.0.LC/MS (150mm * 4.6mm, C-18,5 microns, 10mM NH for C NMR 4OAc/CH 3CN, APCI+) t=7.69min, m/z=262.4 (M+1).
Method E: total method of preparation indole amides
(1.0g 4.3mmol) is dissolved in 10mL DMF, and adds Et with 5-acetoxyl group-2-Methyl-1H-indole-3-formic acid 3N (0.6mL, 1eq).This solution stirring 5 minutes.This solution be cooled to 0 ℃ and add HBTU (1.63g, 4.3mmol), restir 15 minutes.(2N in THF, 4eq), and exhausts this solution stirring to initiator, about 1 hour, adds entry to add this amine.With the pH regulator to 5 of HCl (1N), and use ethyl acetate extraction with the gained mixture.The dry also evaporation of organic layer obtains crude product, and it can be further purified by flash chromatography or recrystallization.
Intermediate U-V is synthetic according to method E.
Acetate 2-methyl-3-methylamino formyl radical-1H-indoles-5-base ester (U) yield: 0.093g (18%); Mp 201-203 ℃;
IR:3402,1748,1609,1218,1170cm -1.1H NMR (DMSO-d 6) δ 2.21 (s, 3H, CH 3CO), 2.45 (s, 3H, ArCH 3), 2.72 (d, J=4.39Hz, 3H, NHCH 3), 6.76 (dd, J=8.79,1.46 Hz, 1H, ArH), 7.24 (d, J=8.79Hz, 1H, ArH), 7.25 (bs, 1H, CONHCH 3), 7.41 (s, 1H, ArH), 11.5 (s, 1H, indoleNH) .MS (APCI+): m/z247.1 (MH +); C 13H 14N 2O 30.9H 2O computational analysis value; C, 59.49; H, 6.07; N, 10.67. measured value: C, 59.51; H, 6.12; N, 10.55.
Acetate 3-benzylamino formyl radical-2-Methyl-1H-indole-5-base ester (V) yield: 0.454g (33%); Mp182-184 ℃;
IR:3413,3319,3222,3191,1750,1609,1228,1216,1170cm -1. 1H NMR (DMSO-d 6) δ 2.20 (s, 3H, CH 3CO), 2.54 (s, 3H, ArCH 3), 4.42 (d, J=6.1Hz, 2H, NHCH 2Ph), 6.77 (dd, J=8.55,1.95Hz, 1H, ArH), 7.15-7.19 (m, 1H, ArH), 7.25-7.34 (m, 5H, ArH), 7.45 (d, J=1.71Hz, 1H, ArH), 7.89 (t, J=6.10Hz, 1H, CONHCH 2Ph), 11.5 (s, 1H, indoles NH) .MS (APCI+): m/z323.2 (MH +); C 19H 18N 2O 3Computational analysis value: C, 70.79, H, 5.63, N, 8.69. measured value: C, 70.62, H, 5.78, N, 8.60.
Method F: total method of acid amides removal of acylation
Useful acid amides (1eq) is dissolved among the MeOH in a small amount.Adding MeONa (4eq) and this mixture is stirred to does not have initiator residual, about 45 minutes.Add the pH regulator to 1 of aqueous hydrochloric acid with this solution, and with this solution with 2 * 25mL ethyl acetate extraction.The dry also evaporation of organic layer obtains solid.Obtain white solid by re-crystallizing in ethyl acetate.
Intermediate W-X is synthetic according to method F.
5-hydroxy-2-methyl-1H-indole-3-carboxylic acid methyl nitrosourea (W) yield: 0.201g (70%); Mp226-227 ℃; IR:3366,1602,1558,1552,1215,1198cm -1. 1HNMR (DMSO-d 6) δ 2.45 (s, 3H, ArCH 3. blured by the DMSO peak), 2.70 (d, J=4.40Hz, 3H, CONHCH 3), 6.51 (d, J=8.55Hz, 1H, ArH), 7.02 (d, J=8.55Hz, 1H, ArH), 7.07 (s, 1H, ArH), 7.13-7.14 (m, 1H, CONHCH 3), 8.65 (s, 1H, OH), 11.0 (s, 1H, indoles NH) .MS (APCI+): m/z205.1 (MH +); C 11H 12N 2O 2Computational analysis value: C, 64.69; H, 5.92; N, 13.72. measured value: C, 64.53; H, 5.91; N, 13.44.
5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl acid amides (X) yield: 0.228g (65.7%); Mp:194-196 ℃;
IR:3392,3246,1610,1528,1465,1214,1188cm -1. 1H NMR (DMSO-d 6) δ: 2.48 (s, 3H, ArCH 3), 4.41 (d, J=5.86Hz, 2H, NHCH 2Ph), 6.52 (d, J=8.06,1H, ArH), 7.04 (d, J=8.55,1H, ArH), 7.12 (s, 1H, ArH) 7.17-7.31 (m, 5H, ArH), 7.71-7.78 (m, 1H, CONHCH 2Ph), 8.68 (s, 1H, OH), 11.1 (s, 1H, indole NH) .MS (APCI+): m/z281.1 (MH +); C 17H 16N 2O 2Computational analysis value: C, 72.84; H, 5.75; N, 9.99. measured value: C, 72.78; H, 5.70; N, 9.87.
Embodiment 1
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester
According to J.Het.Chem., 1970; The method that 7:1311-1319 describes is synthetic.
Embodiment 2
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-, (4-fluorophenyl) methyl esters
Figure A9981647500761
Steps A: 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-fluoro-benzyl ester
To 5-hydroxy-2-methyl-1-H-indole-2-formate (4.6g, in DMF 24.1mmol) (100mL) solution, add DBU (3.67g, 24.1mmol), then add the 4-fluoro benzyl bromide (5.0g, 26.5mmol).Under nitrogen atmosphere, will stir 3 days under the gained mixture room temperature, between ethyl acetate (200mL) and water (200mL), distribute then.Separate organic phase, wash with water (2 * 100mL), obtain white solid with dried over sodium sulfate and vacuum concentration then.Obtain the pure title compound of 3.4g (47%) with re-crystallizing in ethyl acetate, be white solid: mp209-210 ℃;
IR3412,3377,3305,1667,1512,1466,1221,1176,1094cm -1 1H NMR (DMSO-d 6) δ 2.53 (s, 3H, CH 3), 5.23 (s, 2H, CH 2), 6.55 (dd, J=8.79,2.20Hz, 1H, ArH), 7.08 (d, J=8.79Hz, 1H, ArH), 7.14-7.17 (m, 2H, ArH), 7.19 (d, J=2.20Hz, 1H, ArH), 7.44-7.48 (m, 2H, ArH), 8.81 (s, 1H, OH), 11.55 (s, 1H, NH); MS (APCI +): m/z300.1 (MH +) .C 17H 14FNO 3Computational analysis value: C, 68.22; H, 4.71; N, 4.68. measured value: C, 67.91; H, 4.65; N, 4.59.
Step B:4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-fluoro-benzyl ester
With 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-fluoro-benzyl ester (2.90g, 9.69mmol) and dimethylamine agueous solution (40%, 2.67mL 21.3mmol) mixes with 22mL EtOH, add then the HCHO aqueous solution (37%, 0.940g, 11.6mmol).The gained reaction mixture is heated to heating gun and obtains clear solution.This reaction mixture was stirred 16 hours down at 50 ℃.This reaction mixture was placed 15 hours down at 4 ℃, formed white precipitate.Filter the pure title compound that also vacuum-drying obtains 1.56g (45%), be white solid: mp131-133 ℃ (decomposition); IR3376,3214,1693,1686,1513,1424,1259,1227,1085,806cm -1 1H NMR (DMSO-d 6) δ 2.12 (s, 6H, N (CH 3) 2), 2.45 (s, 3H, ArCH 3), 3.97 (s, 2H, ArCH 2NMe 2), 5.23 (s, 2H, CO 2CH 2Ar), 6.56 (d, J=8.61Hz, 1H, ArH), 7.06 (d, J=8.61Hz, 1H, ArH), 7.18-7.24 (m, 2H, ArH), 7.49-7.54 (m, 2H, ArH), 11.5 (bs, 1H, exchangeable protons); MS (APCI +): m/z357.2 (MH +) .C 20H 21N 2O 3F 10.1H 2O computational analysis value: C, 67.06; H, 5.97; N, 7.82; F, 5.30; H 2O, 0.50. measured value: C, 66.90; H, 5.81; N, 7.53; F, 5.33; H 2O, 0.20.
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-, (4-fluorophenyl) methyl esters
In the mixture of perchlorate (embodiment 3, step B for 1.27g, 5.36mmol) and 50mL ether, add 50mL aqueous sodium hydroxide solution (2N).The gained mixture shaken in separating funnel up to all solids dissolve.Be divided into two-layerly, water layer is with extracted with diethyl ether (2 * 50mL).The ether layer that merges is with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 15mL diox, add then indoles mannich alkali (1.47g, 4.12mmol); The gained reaction mixture refluxed 5.5 hours under nitrogen atmosphere.This reaction mixture is cooled to room temperature and vacuum concentration obtains brown solid.Use CH 3The CN recrystallization obtains the pure title compound of 1.63g (88%), is brown solid: mp209-214 ℃ (decomposition);
IR2934,1704,1152,1431,1235,1148,1078,827cm -1 1H NMR (DMSO-d 6) δ 1.06-1.67 (m, 10H, fatty CH 2And CH), 1.81-1.86 (m, 1H, fatty CH), 2.30-2.46 (m, 2H are blured by the DMSO peak, fatty CH), 2.46 (s, 3H, ArCH 3), 2.60-2.70 (m, 2H, fatty CH), 2.84-2.91 (m, 1H, fatty CH), 3.17 (dd, J=18.3,6.78Hz, 1H, fatty CH), 5.21 (AB q, J Ab=11.9Hz, ν Ab=19.0Hz, 2H, CO 2CH 2Ar), 6.59 (d, J=8.61Hz, 1H, ArH), 7.03 (d, J=8.61Hz, 1H, ArH), 7.17-7.25 (m, 2H, ArH), 7.48-7.52 (m, 2H, ArH), 11.5 (bs, 1H, NH); MS (APCI +): m/z449.3 (MH +) .C 27H 29N 2O 3F 10.08CH 3CN: computational analysis value: C, 72.20; H, 6.52; N, 6.45; F, 4.20. measured value: C, 71.88; H, 6.35; N, 6.42; F, 4.15.
Embodiment 3 (intermediate)
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine also, and 3,7,8,9,10,12,13,14,14a, the 15-decahydro-
Steps A: 4-dimethylaminomethyl-1H-indoles-5-alcohol
With the 5-oxyindole (Aldrich, Milwaukee, WI, 5.09g 38.2mmol) is dissolved among the 25mL EtOH, add dimethylamine agueous solution (40%, 5.28mL, 42.1mmol), add subsequently the HCHO aqueous solution (37%, 3.65g, 45.9mmol).Stirred under the gained reaction mixture room temperature 1.5 hours, during form precipitation.Filter the pure title compound that also vacuum-drying obtains 4.13g (57%), be beige solid: mp137-139 ℃;
IR3316,1625,1592,1523,1450,1239,1198,724cm -1 1H NMR (DMSO-d 6) δ 2.25 (s, 6H, CH 2N (CH 3) 2, 3.76 (s, 2H, CH 2N (CH 3) 2), 6.29-6.30 (m, 1H, ArH), 6.54 (d, J=8.61Hz, 1H, ArH), 7.10 (d, J=8.60Hz, 1H, ArH), 7.18-7.20 (m, 1H, ArH), 10.8 (bs, 1H, exchangeable protons); MS (APCI +): m/z191.1 (MH +) .C 11H 14N 2O computational analysis value: C, 69.45; H, 7.42; N, 14.72. measured value: C, 69.36; H, 7.38; N, 14.71.
Step B:1,2,3,4,6,7,8,9-octahydro-quinolizine perchlorate
Figure A9981647500782
Should synthetic see David A.Evans, new interior cyclenes amine synthetic.JACS, 1970; 92:7593-7595 and Leonard N.J., Hay A.S., Fulmer R.W., GashV.W., unsaturated amine, III. introduces α, β-nonsaturation by mercuric acetate: Δ 1 (10)-dehydrogenation quinolizine alkane, J.Am.Chem.Suc., 1955; 77:439-444.
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine also, and 3,7,8,9,10,12,13,14,14a, the 15-decahydro-
In the mixture of perchlorate (embodiment 3, step B for 406mg, 1.71mmol) and 20mL ether, add 30mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layerly, water layer is with extracted with diethyl ether (2 * 30mL).The ether layer that merges is with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 5mL diox, and (250mg, 1.31mmol), the gained reaction mixture refluxed 4 hours under nitrogen atmosphere to add 4-dimethylaminomethyl-1H-indoles-5-alcohol then.This reaction mixture is cooled to room temperature and forms precipitation.Filter and obtain the pure title compound of 0.17g (46%), be beige solid: mp＞250 ℃ with re-crystallizing in ethyl acetate;
IR3414,3148,1454,1242,1148,888cm -1 1H NMR (DMSO-d 6) δ 1.13-1.65 (m, 9H, fatty CH 2And CH), 1.76-1.91 (m, 2H, fatty CH), (m is blured by the DMSO peak 2.36-2.52,3H, fatty CH), 2.68-2.77 (m, 1H, fatty CH), 2.88-2.96 (m, 1H, fatty CH), 3.06 (dd, J=17.6,6.78Hz, 1H, fat CH), and 6.22-6.23 (m, 1H, ArH), 6.56 (d, J=8.61Hz, 1H, ArH), 7.07 (d, J=8.61Hz, 1H, ArH), 7.19-7.21 (m, 1H, ArH), 10.8 (bs, 1H, NH); MS (APCI +): m/z383.1 (MH +) .C 18H 22N 2O0.1H 2O computational analysis value: C, 76.08; H, 7.87; N, 9.86; H 2O, 0.63. measured value: C, 76.09; H, 7.81; N, 9.83; H 2O, 0.74.
Embodiment 4 (intermediate)
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-
Steps A: 2-Methyl-1H-indole-5-alcohol
5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (Aldrich, Milwaukee, WI, 20.0g, 91.2mmol) (2N, 365mL 730mmol) mix, and the gained reaction mixture refluxed 1 hour under nitrogen atmosphere with aqueous sodium hydroxide solution.After being cooled to 70 ℃, this reaction soln is handled to pH=1 with concentrated hydrochloric acid.Gained dark brown solution extracted with diethyl ether (3 * 300mL).The diethyl ether solution that merges obtains brown solid with dried over sodium sulfate and vacuum concentration.Use EtOAc/CH 2Cl 2Recrystallization obtains the pure title compound of 11.7g (87%), is light brown solid: mp129-130 ℃; IR3387,3333,1588,1453,1368,1173,783cm -1 1H NMR (DMSO-d 6) δ 2.29 (s, 3H, ArCH 3), 5.88-5.89 (m, 1H, ArH), 6.45 (dd, J=8.42,2.38Hz, 1H, ArH), 6.68 (d, J=2.38Hz, 1H, ArH), 7.00 (d, J=8.42Hz, 1H, ArH), 8.44 (s, 1H, NH), 10.5 (bs, 1H, OH); MS (APCI +): m/z148.1 (MH +) .C 9H 9The NO computational analysis
Value: C, 73.45; H, 6.16; N, 9.52 measured values: C, 7.13; H, 6.18; N, 9.41.
Step B:4-dimethylaminomethyl-2-Methyl-1H-indole-5-alcohol
With 2-Methyl-1H-indole-5-alcohol (5.00g 34.0mmol) is dissolved in 20mL EtOH, add dimethylamine agueous solution (40%, 9.40mL, 74.7mmol), then add the HCHO aqueous solution (37%, 3.30g, 40.8mmol).Stirred 2 hours under the gained reaction mixture room temperature, mix with 50ml water then, form precipitation.Filter and obtain the pure title compound of 3.0g (43%), be white solid: mp133-135 ℃ with ethyl alcohol recrystallization (＜50 ℃);
IR3404,3385,1598,1515,1428,1271,1204,798,778cm -1 1H NMR (DMSO-d 6) δ 2.23 (s, 6H, N (CH 3) 2), 2.30 (s, 3H, ArCH 3), 3.68 (s, 2H, CH 2N), 5.98 (s, 1H, ArH), 6.42 (d, J=8.42Hz, 1H, ArH), 6.95 (d, J=8.79Hz, 1H, ArH), 10.6 (bs, 1H, exchangeable protons); MS (APCI +): m/z205.2 (MH +) .C 12H 16N 2O computational analysis value: C, 70.56; H, 7.90; N, 13.71. measured value: C, 70.39; H, 7.87; N, 13.75.
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-
In the mixture of perchlorate (embodiment 3, step B for 973 mg, 4.10mmol) and 30mL ether, add 40mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layerly, water layer is with extracted with diethyl ether (2 * 40mL).The ether layer that merges is with dried over sodium sulfate and vacuum concentration.The oily matter of remnants is dissolved in the 7mL diox, and (697mg, 3.41mmol), the gained reaction mixture refluxed 16 hours under nitrogen atmosphere to add 4-dimethylaminomethyl-2-Methyl-1H-indole-5-alcohol then.This reaction mixture is cooled to room temperature and vacuum concentration obtains brown solid.Grind the pure title compound that obtains 1.01g (59%) with ethyl acetate, be beige solid: mp267-270 ℃ (decomposition);
IR3407,3189,2926,1435,1212,1197,774cm -1 1H NMR (DMSO-d 6) δ 1.13-1.64 (m, 9H, fatty CH 2And CH), 1.74-1.89 (m, 2H, fatty CH), 2.31 (s, 3H, CH 3), 2.35-2.50 (m is blured by the DMSO peak, 3H, fatty CH), (2.67-2.75 m, 1H, fatty CH), 2.87-3.31 (m, 2H, fatty CH), 5.92 (m, 1H, ArH), 6.45 (d, J=8.61Hz, 1H, ArH), 6.94 (d, J=8.79Hz, 1H, ArH), 10.6 (bs, 1H, exchangeable protons); MS (APCI +): m/z297.1 (MH +) .C 19H 24N 2O computational analysis value: C, 76.99; H, 8.16; N, 9.45. measured value: C, 76.79; H, 8.19; N, 9.35.
Embodiment 5
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-bromine 3,7,8,9,10,12,13,14, and 14a, 15-decahydro-2-methyl-, ethyl ester
Figure A9981647500811
Steps A: 6-bromo-4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester
6-bromo-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester is according to literature method preparation [Bell M.R.; Oesterlin R.; Beyler A.L.; Harding H.R.; PottsG.O., J.Med.Chem., 1967; 10:264-266], (3.01g, 10.1mmol) and dimethylamine agueous solution (40%, 2.79mL 22.2mmol) mixes with 30mL EtOH, this mixture with heating gun heating up to obtaining clear solution.After being cooled to room temperature, and the adding HCHO aqueous solution (37%, 0.982g, 12.1mmol).Stirred 48 hours under the gained reaction mixture room temperature, form white precipitate during this.Filter the pure title compound that also vacuum-drying obtains 1.91g (53%), be white solid: mp179-180 ℃ (decomposition);
IR3339,1700,1688,1426,1092,833cm -1 1HNMR (DMSO-d 6) δ 1.30 (t, J=7.14Hz, 3H, CH 2CH 3), 2.26 (s, 6H, N (CH 3) 2), 2.49 (s, 3H are blured ArCH by the DMSO peak 3), 4.16 (s, 2H, ArCH 2NMe 2), 4.23 (q, J=6.96Hz, 2H, CH 2CH 3), 7.38 (s, 1H, ArH), 11.6 (bs, 1H, exchangeable protons); MS (APCI +): m/z355.0 (MH +) .C 15H 19N 2O 3Br
Computational analysis value: C, 50.72; H, 5.39; N, 7.89; Br, 22.49. measured value: C, 50.71; H, 5.31; N, 7.75; Br, 22.67.
Step B:
In the mixture of perchlorate (embodiment 3, step B for 1.40g, 5.90mmol) and 50mL ether, add 50mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layerly, water layer is with extracted with diethyl ether (2 * 50mL).The ether layer that merges is with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 20mL diox, and (1.61g, 4.54mmol), the gained reaction mixture refluxed 4 hours under nitrogen atmosphere to add bromo indoles Mannich alkali then.This reaction mixture is cooled to room temperature and vacuum concentration obtains thickness oily matter.Crude product further obtains white foam by chromatogram purification (50%EtOAc is in hexane), grinds the pure title compound that obtains 1.42g (54%) with the EtOAc/ hexane, is white solid: mp184-185 ℃;
IR3295,2930,1662,1426,1185,1110,1081,869cm -1 1H NMR (CDCl 3) δ 1.15-2.08 (m, 11H, fatty CH 2And CH), 1.39 (t, J=7.14Hz, 3H, CH 2CH 3), 2.45-2.65 (m, 2H, fatty CH), 2.60 (s, 3H, ArCH 3), 2.85-3.00 (m, 2H, fatty CH), 3.17-3.30 (m, 1H, fatty CH), 3.50 (dd, J=18.0,6.96Hz, 1H, fatty CH), 4.34 (q, J=7.14Hz, CH 2CH 3), 7.35 (s, 1H, ArH), 8.10 (bs, 1H, NH); MS (APCI +): m/z447.1 (MH +) .C 22H 27N 3O 3Br
Computational analysis value: C, 59.06; H, 6.08; N, 6.26; Br, 17.86. measured value: C, 59.11; H, 6.07; N, 6.07; Br, 17.97.
Embodiment 6
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, propyl ester
Steps A: 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid propyl ester
(intermediate D, 2.04g 7.42mmol) with the 20mL methanol mixed, add NaOCH to 5-acetoxyl group-2-Methyl-1H-indole-3-propyl formate then 3(1.60g, 29.6mmol).Stirred 1.5 hours under the gained reaction mixture room temperature.This reaction mixture is mixed with 20mL water, and the gained reaction mixture is handled to pH=1 with 5%HCl and is obtained white precipitate.This solid of filtering separation also obtains the pure title compound of 1.39g (80%) with EtOAc/ hexane recrystallization, is beige solid, mp188-189 ℃ (decomposition);
IR3381，3297，1661，1457，1178，1090，794，783cm -1； 1H?NMR(DMSO-d 6)δ0.989(t，J＝7.51Hz，3H，CH 2CH 2CH 3)，1.72(sextet，J＝7.14Hz，2H，CH 2CH 2CH 3)，2.57(s，3H，ArCH 3)，4.14(t，J＝6.41Hz，2H，CH 2CH 2CH 3)，6.58(dd，J＝8.42，2.20Hz，1H，ArH)，7.11(d，J＝8.61Hz，1H，ArH)，7.29(d，J＝2.20Hz，1H，ArH)，8.83(s，1H，OH)，11.5(bs，1H，NH)；MS(APCI +)：m/z234.1(MH +).C 13H 15NO 3·0.06H 2O：
Computational analysis value: C, 66.63; H, 6.50; N, 5.98. measured value: C, 66.27; H, 6.38; N, 5.84.
Step B:4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid propyl ester
With 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid propyl ester (1.27g, 5.43mmol) and dimethylamine agueous solution (40%, 1.50mL 12.0mmol) mixes with 10mL EtOH, and this mixture is heated to the acquisition clear solution with heating gun.After being cooled to room temperature, and the adding HCHO aqueous solution (37%, 0.528g, 6.52mmol).Stirred 3 days under the gained reaction mixture room temperature.With this reaction mixture vacuum concentration, volume is reduced half then.Form precipitation.Filter the pure title compound that also vacuum-drying obtains 0.86g (54%), be white solid: mp135-137 ℃ (decomposition); IR3217,2969,1684,1420,1141,1075cm -1 1H NMR (DMSO-d 6) δ 0.953 (t, J=7.32Hz, 3H, CH 2CH 2CH 3), 1.70 (sextet, J=7.33Hz, 2H, CH 2CH 2CH 3), 2.19 (s, 6H, N (CH 3) 2), 2.49 (s, 3H are blured ArCH by the DMSO peak 3), 4.06 (s, 2H, ArCH 2NMe 2), 4.13 (t, J=6.78Hz, 2H, CH 2CH 2CH 3), 6.56 (d, J=8.61Hz, 1H, ArH), 7.07 (d, J=8.42Hz, 1H, ArH), 11.5 (bs, 1H, exchangeable protons); MS (APCI +): m/z291.1 (MH +) .C 16H 22N 2O 3Computational analysis value: C, 66.19; H, 7.64; N, 9.65. measured value: C, 65.94; H, 7.67; N, 9.31.
Step C:
In the mixture of perchlorate (embodiment 3, step B for 0.763g, 3.21mmol) and 30mL ether, add 30mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layerly, water layer is with extracted with diethyl ether (2 * 30mL).The ether layer that merges is with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 5.0mL diox, add then indoles Mannich alkali (0.717g, 2.47mmol); The gained reaction mixture refluxed 3 hours under nitrogen atmosphere.This reaction mixture is cooled to room temperature and vacuum concentration obtains thickness oily matter.Crude product further obtains white solid by chromatogram purification (50%EtOAc is in hexane).Use CH 3The CN recrystallization obtains the pure title compound of 0.67g (70%), is white solid: mp162-164 ℃;
IR3329,2931,1702,1665,1434,1235,1200,1149,1079,948,781cm -1 1HNMR (CDCl 3) δ 0.992 (t, J=7.32Hz, 3H, CH 2CH 2CH 2CH 3), 1.76 (sextet, J=7.08Hz, 2H, CH 2CH 2CH 3), 1.29-1.86 (m, 10H, fatty CH 2And CH), 2.11 (d, J=13.43Hz, 1H, fatty CH), 2.27-2.58 (m, 2H, fatty CH), 2.58 (s, 3H, ArCH 3), 2.82-2.86 (m, 2H, fatty CH), 3.00-3.10 (m, 1H, fatty CH), 3.46 (dd, J=18.1,6.84Hz, 1H, fatty CH), 4.21 (t, J=6.84Hz, CH 2CH 2CH 3), 6.73 (d, J=8.79Hz, 1H, ArH), 7.01 (d, J=8.79Hz, 1H, ArH), 8.06 (bs, 1H, NH); MS (APCI +): m/z383.1 (MH +) .C 23H 30N 2O 3Computational analysis value: C, 72.22; H, 7.91; N, 7.32. measured value: C, 72,19; H, 7.88; N, 7.36.
Embodiment 7
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methyl propyl ester
Figure A9981647500851
Steps A:
With 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid isobutyl ester (intermediate H, 1.03g, 4.17mmol) and dimethylamine agueous solution (40%, 1.15mL 9.17mmol) mixes with 4mL EtOH, add then the HCHO aqueous solution (37%, 0.406g, 5.01mmol).The gained reaction mixture is heated to the acquisition clear solution with heating gun.This reaction mixture was stirred 4.5 hours down at 50 ℃.This reaction mixture was placed 16 hours down at 4 ℃ again.Form the cotton shape white crystals.Filter the pure title compound that also vacuum-drying obtains 0.62g (49%), be white solid: mp122-124 ℃ (decomposition);
IR3229,2957,1686,1424,1242,1085,1000cm -1 1H NMR (DMSO-d 6) δ 0.951 (d, J=6.59Hz, 6H, CH 2CH (CH 3) 2), 1.98 (m, J=6.59Hz, 1H, CH 2CH (CH 3) 2), 2.18 (s, 6H, N (CH 3) 2), 2.50 (s, 3H are blured ArCH by the DMSO peak 3), 3.97 (d, J=6.59Hz, 2H, CH 2CH (CH 3) 2), 4.07 (s, 2H, ArCH 2NMe 2), 6.56 (d, J=8.61Hz, 1H, ArH), 7.06 (d, J=8.42Hz, 1H, ArH), 11.5 (bs, 1H,
Exchangeable protons); MS (APCI +): m/z305.2 (MH +) .C 17H 24N 2O 31.03H 2O
Computational analysis value: C, 63.23; H, 8.13; N, 8.67. measured value: C, 62.84; H, 7.30; N, 8.44.
Step B:
In the mixture of perchlorate (embodiment 3, step B for 0.458g, 1.93mmol) and 30mL ether, add 30mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layerly, water layer is with extracted with diethyl ether (2 * 30mL).The ether layer that merges is with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 5.0mL diox, and (0.451g, 1.48mmol), the gained reaction mixture refluxed 3 hours under nitrogen atmosphere to add indoles mannich alkali then.This reaction mixture is cooled to room temperature and vacuum concentration, obtains thickness oily matter.Crude product further obtains the pure title compound of 0.40g (52%) by chromatogram purification (50%EtOAc is in hexane), be white solid: mp203-204.5 ℃;
IR3341,2933,1700,1673,1434,1236,1082,886,781cm -1 1HNMR (CDCl 3) δ 0.984 (d, J=6.84Hz, 6H, CH 2CH (CH 3) 2), 1.32-1.90 (m, 10H, fatty CH 2And CH), 2.04 (m, J=6.59Hz, 1H, CH 2CH (CH 3) 2), 2.08-2.18 (m, 1H, fatty CH), 2.40-2.60 (m, 2H, fatty CH), 2.59 (s, 3H, ArCH 3), 2.84-2.88 (m, 2H, fatty CH), 2.97-3.10 (m, 1H, fatty CH), 3.46 (dd, J=18.1,6.84Hz, 1H, fatty CH), 4.00-4.09 (m, 2H, CH 2CH (CH 3) 2), 6.73 (d, J=8.79Hz, 1H, ArH), 7.02 (d, J=8.79Hz, 1H, ArH), 8.05 (bs, 1H, NH); MS (APCI +): m/z397.2 (MH +) .C 24H 32N 2O 3Computational analysis value: C, 72.70; H, 8.1 3; N, 7.06. measured value: C, 72.85; H, 8.19; N, 7.00.
Embodiment 8
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2-dimethyl propyl ester
Figure A9981647500861
Steps A:
With 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 2,2-dimethyl propyl ester (intermediate compound I, 1.55g, 5.93mmol) and dimethylamine agueous solution (40%, 1.64mL 13.1mmol) mixes with 4mLEtOH, add then the HCHO aqueous solution (37%, 0.406g, 5.01mmol).The gained reaction mixture is heated to the acquisition clear solution with heating gun.This reaction mixture was stirred 4.5 hours down at 50 ℃.This reaction mixture is mixed with the 50ml ethyl acetate, and (2 * 50ml) wash this mixture to water, obtain thickness oily matter with dried over sodium sulfate organic phase and vacuum concentration.This crude product is further obtained the pure title compound of 0.90g (48%) by flash chromatography purifying (10%-20% methyl alcohol is in chloroform), be white solid: mp150-151 ℃ (decomposition);
IR3251,2953,1690,1424,1238,1081,801cm -1 1H NMR (DMSO-d 6) δ 0.970 (s, 9H, CH 2C (CH 3) 3), 2.18 (s, 6H, N (CH 3) 2), 2.52 (s, 3H, ArCH 3), 3.91 (s, 2H, CH 2C (CH 3) 3), 4.08 (s, 2H, ArCH 2NMe 2), 6.57 (d, J=8.42Hz, 1H, ArH), 7.07 (d, J=8.61Hz, 1H, ArH), 11.5 (bs, 1H, exchangeable protons); MS (APCI +): m/z319.2 (MH +) .C 18H 26N 2O 3Computational analysis value: C, 67.90; H, 8.23; N, 8.80. measured value: C, 67.53; H, 8.04; N, 8.57.
Step B:
In the mixture of perchlorate (embodiment 3, step B for 0.710g, 2.23mmol) and 30mL ether, add 30mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layerly, water layer is with extracted with diethyl ether (2 * 30mL).The ether layer that merges is with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 5.0mL diox, and (0.690g 2.90mmol) adds indoles Mannich alkali, and the gained reaction mixture refluxed 4 hours under nitrogen atmosphere then.This reaction mixture is cooled to room temperature and vacuum concentration, obtains thickness oily matter.Crude product further obtains white solid by chromatogram purification (50%EtOAc is in hexane).Use CH 3The CN recrystallization obtains the pure title compound of 0.92g (44%), is white solid: mp240-243 ℃;
IR3187,2934,1700,1433,1235,1077,883,780cm -1 1H NMR (DMSO-d 6) δ 0.96 (d, 9H, CH 2C (CH 3) 3), 1.19-1.57 (m, 9H, fatty CH 2And CH), 1.70-1.80 (m, 1H, fatty CH), 1.76-1.85 (m, 1H, fatty CH), 2.34-2.45 (m, 2H is by the fuzzy fatty CH in DMSO peak), 2.53 (s, 3H, ArCH 3), 2.63-2.79 (m, 2H, fatty CH), 2.85-2.95 (m, 1H, fatty CH), 3.25-3.35 (m, 1H is by the fuzzy fatty CH in water peak), 3.94 (AB q, J Ab=10.62Hz, ν Ab=24.1Hz, 2H, CH 2C (CH 3) 3), 6.61 (d, J=8.42Hz, 1H, ArH), 7.04 (d, J=8.61Hz, 1H, ArH), 11.51 (bs, 1H, NH); MS (APCI +): m/z411.3 (MH +) .C 24H 32N 2O 3Computational analysis value: C, 73.14; H, 8.35; N, 6.82. measured value: C, 73.16; H, 8.52; N, 6.77.
Total method of method G:Mannich reaction
(2.2-17.9mmol 1eq) is dissolved in the ethanol by stirring this solution of heating simultaneously with selected 5-oxyindole ester; With this solution cooling.Add the HCHO aqueous solution (37%, 1.2eq) and dimethylamine agueous solution (40%, 2.2eq), and with this be reflected at 50 ℃ down stirring be constant up to the ratios of initiator and product.Vacuum is removed ethanol, and brown oil (is used MeOH/CHCl by the flash chromatography purifying 3As eluent) obtain required product.
Embodiment 9
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters
Figure A9981647500881
Steps A:
4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester is synthetic by intermediate C according to method G.Yield: 3.36g (55%);
1H?NMR(DMSO-d 6)δ2.10(s，6H，CH 2N(CH 3) 2)，2.45(s，3H，ArCH 3)，3.97(s，2H，CH 2NMe 2)，5.21(s，2H，CO 2CH 2Ph)，6.53(d，J＝8.30Hz，1H，ArH)，7.04(d，J＝8.55Hz，1H，ArH)，7.29-7.43(m，5H，ArH)，11.5(s，1H，NH).MS(APCI +)：m/z339.1(MH +).
Step B:
By being similar to embodiment 7, the method for step C obtains: 3.30g (77%); Mp162-164 ℃;
IR:2930,2855,1700,1432,1077cm -1. 1H NMR (DMSO-d 6) δ 1.11-1.67 (m, 10H, fatty CH 2And CH), 1.82-1.86 (m, 1H, fatty CH), 2.30-2.48 (m, 2H are blured by the DMSO peak, fatty CH), 2.48 (s, 3H, ArCH 3), 2.62-2.70 (m, 2H, fatty CH), 2.86-2.92 (m, 1H, fatty CH), 3.19 (dd, J=18.3,6.78Hz, 1H, fatty CH), 5.23 (AB q, J Ab=12.1Hz, ν Ab=16.4Hz, 2H, CO 2CH 2Ph), 6.59 (d, J=8.61Hz, 1H, ArH), 7.03 (d, J=8.61Hz, 1H, ArH), 7.30-7.46 (m, 5H, ArH), 11.5 (bs, 1H, NH); MS (APCI+): 431.2 (MH +) .C 27H 30N 2O 3Computational analysis value: C, 75.35; H, 7.02; N, 6.51. measured value: C, 75.16; H, 6.97; N, 6.47.
Embodiment 10
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl ethyl ester
Figure A9981647500891
Steps A:
4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid isopropyl ester is synthetic by intermediate E according to method G.Yield: 0.490g (61%);
1H NMR δ 1.26 (d, J=6.35Hz, 6H, CH (CH 3) 2), 2.17 (s, 6H, CH 2N (CH 3) 2), 2.45 (s, 3H, ArCH 3), 4.03 (s, 2H, CH 2NMe 2), 5.04 (sextet, J=6.35,1H, CO 2CH (CH 3) 2), 6.52 (d, J=8.55Hz, 1H, ArH), 7.02 (d, J=8.55Hz, 1H, ArH), 11.4 (s, 1H, NH) .MS (APCI +): m/z291.1 (MH +).
Step B:
By being similar to embodiment 7, the method for step C obtains: 0.390g (60.4%); Mp186-188 ℃;
IR:2976,2930,2856,1703,1433,1079cm -1. 1H NMR (DMSO-d 6) δ 1.10-1.57 (m, 9H, fatty CH 2And CH), 1.23 (d, J=5.62Hz, 3H, CH 3), 1.25 (d, J=5.86Hz, 3H, CH 3), 1.71-1.74 (m, 1H, fatty CH), 1.85-1.88 (m, 1H, fatty CH), 2.32-2.44 (m, 2H are blured by the DMSO peak, fatty CH), 2.44 (s, 3H, ArCH 3), 2.63-2.74 (m, 2H, fatty CH), 2.83-2.89 (m, 1H, fatty CH), 3.21-3.28 (fatty CH is blured by the water peak for m, 1H), 5.01 (septet, 1H, CO 2CH (CH 3) 2), 6.56 (d, J=8.79Hz, 1H, ArH), 6.99 (d, J=8.80Hz, 1H, ArH), 11.4 (bs, 1H, NH); MS (APCI+): 383.1 (MH +) .C 23H 30N 2O 3Computational analysis value: C, 72.22; H, 7.91; N, 7.32. measured value: C, 71.98; H, 7.85; N, 7.29.
Embodiment 11
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the cyclopropyl methyl esters
Figure A9981647500901
Steps A:
4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid cyclopropyl methyl esters is synthetic by intermediate F according to method G.Yield: 0.406g (62.1%);
1H NMR (DMSO-d 6) δ 0.309-0.346 (m, 2H, cyclopropyl CH 2CH 2), 0.538-0.584 (m, 2H, cyclopropyl CH 2CH 2), 1.16-1.24 (m, 1H, cyclopropyl CH), 2.23 (s, 6H, CH 2N (CH 3) 2), 2.52 (s, 3H, ArCH 3), 4.02 (d, J=7.32,2H, CO 2CH 2CH), 4.10 (s, 2H, CH 2NMe 2), 6.58 (d, J=8.55Hz, 1H, ArH), 7.09 (d, J=8.55Hz, 1H, ArH), 11.5 (s, 1H, NH) .MS (APCI +): m/z303.1 (MH +).
Step B:
By being similar to embodiment 7, the method for step C obtains.Yield: 0.269g (50.7%); Mp199-200 ℃;
IR:3376,3337,2932,2857,1698,1669,1433,1081cm -1. 1H NMR (CDCl 3) δ 0.337-0.373 (m, 2H, cyclopropyl CH 2CH 2), 0.596-0.641 (m, 2H, cyclopropyl CH 2CH 2), 1.21-1.89 (m, 10H, fatty CH 2And CH), 2.15-2.18 (m, 1H, fatty CH), 2.48-2.64 (m, 2H, quilt: ArCH 3The peak is fuzzy, fatty CH), 2.64 (s, 3H, ArCH 3), 2.86-2.96 (m, 2H, fatty CH), 3.00-3.10 (m, 1H, fatty CH), 3.52 (dd, J=18.1,6.84Hz, 1H, fatty CH), 4.07-4.17 (m, 1H, CO 2CH 2), 6.77 (d, J=8.55Hz, 1H, ArH), 7.06 (d, J=8.79Hz, 1H, ArH), 8.10 (bs, 1H, NH); MS (APCI+): 395.1 (MH +) .C 24H 30N 2O 3Computational analysis value: C, 73.07; H, 7.66; N, 7.10 measured values: C, 72.96; H, 7.70; N, 6.97.
Embodiment 12
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(piperidino) ethyl ester
Steps A:
5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 2-piperidines-1-base-ethyl ester (intermediate J, 0.770g, 2.55mmol) and dimethylamine agueous solution (40%, 0.704mL, 5.60mmol) mix with 2mL EtOH, add the HCHO aqueous solution (37% then, 0.248g, 3.06mmol).The gained reaction mixture heats up to obtaining clear solution with heating gun.This reaction mixture was stirred 2 days down at 50 ℃.Again with the ethyl acetate dilution, wash and use this reaction mixture with water dried over sodium sulfate then.This solution for vacuum concentration obtains oily matter.Crude product further obtains oily matter (402mg, 44% thick yield) by flash chromatography purifying (10%-20%MeOH is in chloroform), and it is the required product that has small amount of impurities:
1H NMR (DMSO-d 6) δ 1.31-1.33 (m, 2H, piperidines CH 2), 1.40-1.45 (m, 4H, 2 * piperidines CH 2), 2.16 (s, 6H, CH 2N (CH 2N (CH 3) 2), 2.30-2.40 (m, 4H, 2 * piperidines CH 2), 2.47 (s, 3H, ArCH 3), 2.52-2.55 (m, 2H, OCH 2CH 2N), 4.01 (s, 2H, CH 2N (CH 3) 2), 4.22 (t, J=5.86Hz, 2H, OCH 2CH 2N), 6.52 (d, J=8.55Hz, 1H, ArH), 7.02 (d, J=8.55Hz, 1H, ArH), 11.4 (bs, 1H, exchangeable protons); MS (APCI+): m/z360.2 (MH +).
Step B:
By being similar to embodiment 7, the method for step C obtains.Yield: 0.137g (37%); Mp169-171 ℃;
IR:2928,1696,1434,1094,1081cm -1. 1H NMR (DMSO-d 6) δ 1.11-1.54 (m, 15H, fatty CH 2And CH), 1.71-1.74 (m, 1H, fatty CH), 1.86-1.90 (m, 1H, fatty CH), 2.34-2.47 (m, 6H are blured by the DMSO peak, fatty CH), 2.47 (s, 3H, ArCH 3), 2.52 (t, J=5.62Hz, 2H, OCH 2CH 2N), 2.62-2.71 (m, 2H, fatty CH), 2.84-2.89 (m, 1H, fatty CH), 3.24-3.33 (fatty CH is blured by the water peak for m, 1H), 4.14-4.26 (m, 2H, OCH 2CH 2N), 6.56 (d, J=8.79Hz, 1H, ArH), 7.00 (d, J=8.55Hz, 1H, ArH), 11.5 (bs, 1H, NH); MS (APCI+): m/z452.3 (MH +) .C 27H 37N 3O 30.15H 2O
Computational analysis value: C, 71.38; H, 8.28; N, 9.25; H 2O, 0.59. measured value: C, 71.08; H, 8.25; N, 9.02; H 2O, 0.21.
Method H: total method of Synthetic 2-alkyl-4-(dimethylamino) methylene radical-5-hydroxyl-3-indolecarboxylic acid ethyl ester
In ethanol (8mL) solution of the 2-alkyl-5-hydroxyl-3-indole-carboxylic acid ethyl ester (2.63mmol) that stirs, add formaldehyde (0.24mL, 3.16mmol) and dimethylamine (0.73mL, 5.80mmol).This solution was stirred 3 hours cooling and concentrating under reduced pressure down at 45 ℃.This resistates is carried out flash column chromatography (SiO 2, 1: 1 ethyl acetate/hexane, 10: 1 ethyl acetate/ethanol then) and obtain required product.
Method I: total method of Synthetic 2-alkyl-[(pyrans is [2,3-b] quinolizine alkane also) [5,6-e]] indole-3-carboxylic acid ethyl ester
To the NaOH that stirs (50%w/w, 100mL) and in the solution of ether (20mL), adding perchloric acid imino-ammonium salt (embodiment 3, step B for 0.42g, 1.78mmol).This solution extracted with diethyl ether (10 * 100mL), obtain enamine with dried over mgso and concentrating under reduced pressure, be white solid.In stirring De diox (2.5mL/mmol) solution, add this enamine (0.197g, 1.43mmol) and indoles (1.43mmol).This solution refluxed overnight is cooled to room temperature, and concentrating under reduced pressure also carries out flash column chromatography (SiO 2, 99: 1 methylene chloride) and obtain required product.
Embodiment 13
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(phenyl methyl)-, ethyl ester
Figure A9981647500931
Steps A:
2-benzyl-4-(dimethylamino) methylene radical-5-hydroxyl-3-indole-carboxylic acid ethyl, 84% yield is white solid, and is synthetic by intermediate P according to method H.
1H NMR (250MHz, CD 3OD) δ 1.38 (t, J=7.2Hz, 3H), 4.32 (q, J=8.5Hz, 2H), 4.46 (s, 2H), 6.68 (dd, J=6.8,2.5Hz, 1H), 7.17 (m, 5H) 7.47 (d, J=2.25Hz, 1H) .LC/MS (150mm * 4.6mm, C-18,5 microns, 10mM NH 4OAc/CH 3CN, APCI+) t=7.86min, m/z=353.2 (M+1).
Step B:
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(phenyl methyl)-, ethyl ester is synthetic according to method I.68% yield is white solid.
1H NMR (250MHz, CDCl 3) δ 1.36 (t, J=7.2Hz, 3H), 1.42 (m, 3H), 1.68 (m, 5H), 1.92 (m, 2H), 2.15 (d, J=13.3Hz, 1H), 2.53 (m, 2H), 2.85 (m, 2H), 3.09 (m, 1H), 3.48 (dd, J=20.0,7.5Hz, 1H), 4.35 (q, J=7.1Hz, 2H), 4.40 (s, 2H), 6.75 (d, J=8.6Hz, 1H), 6.96 (d, J=8.7Hz, 1H), 7.29 (m, 5H), 7.90 (s, 1H). 13C NMR (62.5MHz, CDCl 3) δ 14.5,19.7,25.0,25.5,27.0,30.2,31.2,34.5,36.7,49.6,59.9,67,87.2,107,109.6,111.4,114.1,126,127.0,128.9,129.1,138,144,149,167.LC/MS (150mm * 4.6mm, C-18,5 microns, 10mM NH 4OAc/CH 3CN, APCI+) t=10.73, m/z=445.6 (M+1) ultimate analysis calculated value: C, 75.64; H, 7.25; N, 6.30. measured value: C, 75.71; H, 7.34; N, 6.23.
Embodiment 14
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 2-ethyl 3,7,8,9,10,12,13,14, and 14a, the 15-decahydro-, ethyl ester
Figure A9981647500941
Steps A:
4-(dimethylamino) methylene radical-2-ethyl-5-hydroxyl-3-indole-carboxylic acid ethyl ester is synthetic by intermediate Q according to method H.55% yield is white solid.
1H NMR (250MHz, DMSO) δ 1.23 (t, J=7.4Hz, 3H), 1.32 (t, J=7.0Hz, 3H), 2.46 (s, 6H), 2.91 (q, J=7.6Hz, 2H), 4.30 (q, J=7.1Hz, 2H), 4.44 (s, 2H), 6.61 (d, J=8.6Hz, 1H), 7.11 (d, J=84Hz, 1H), 9.70 (bs, 1H). 13(62.5MHz, DMSO) δ 14.1,14.3,17.3,21.1,58.2,59.1,103.2,110.8,111.6,112.1,125.3,129.4,148.1,153.0,165.6.LC/MS (150mm * 4.6mm, C-18,5 microns, 10mM NH for C NMR 4OAc/CH 3CN, APCI+) t=6.25min, m/z=291.3 (M+1).
Step B:
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 2-ethyl-3,7,8,9,10,12,13,14, and 14a, the 15-decahydro-, ethyl ester is synthetic according to method I, and 43% yield is white solid.
1H NMR (250MHz, CDCl 3) δ 1.34 (t, J=7.6Hz, 3H), 1.36 (t, J=7.2Hz, 3H), 1.63 (m, 5H), 1.88 (m, 3H), 2.15 (d, J=13.3Hz, 1H), 2.47 (m, 2H), 2.82 (m, 2H), 3.02 (q, J=7.5Hz, 2H), 3.48 (dd, J=17.9,6.8Hz, 1H), 4.35 (q, J=7.2Hz, 2H), 6.77 (d, J=8.7Hz, 1H), 7.06 (d, J=8.7Hz, 1H), 7.26 (s, 1H), 8.19 (s, 1H). 13C NMR (62.5MHz, CDCl 3) δ 13.7,14.4,19.7,21.8,25.0,25.5,27.0,30.1,31.1,36.7,49.6,59.8,67.0,87.1,106,109.4,113.8,126,130,148,149,167.LC/MS (150mm * 4.6mm, C-18,5 microns, 10mM NH 4OAc/CH 3CN, APCI+) t=10.75, m/z=383.5 (M+1)
Ultimate analysis: calculated value C, 72.22; H, 7.90; N 7.32. measured value: C, 72.03; H, 7.96; N, 7.19.
Embodiment 15
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 2-cyclopropyl-3,7,8,9,10,12,13,14, and 14a, the 15-decahydro-, ethyl ester
Figure A9981647500951
Steps A:
2-cyclopropyl-4-(dimethylamino) methylene radical-5-hydroxyl-3-indole-carboxylic acid ethyl ester is synthetic by intermediate R according to method H.64% yield is white solid.
1H?NMR(250MHz，DMSO)δ0.92(m，2H)，1.04(m，2H)，1.33(t，J＝7.1Hz，3H)，2.22(s，6H)，3.98(s，2H)，4.27(q，J＝7.1Hz，2H)，6.58(d，J＝8.4Hz，1H)，7.14(d，J＝8.8Hz，1H)，10.88(s，1H). 13CNMR(62.5MHz，DMSO)δ8.4，8.9，14.3，1703，43.9，58.3，59.2，110.6，111.3，112.0，129.1，147.3，152.8，165.9.
Step B:
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 2-cyclopropyl-3,7,8,9,10,12,13,14, and 14a, the 15-decahydro-, ethyl ester is synthetic according to method I.60% yield is white solid.
1H NMR (250MHz, CDCl 3) δ 0.79 (m, 2H), 1.07 (d, J=8.54,2H), 1.37 (m, 3H), 1.40 (t, J=7.2Hz, 3H), 1.61 (m, 9H), 1.92 (m, 1H), 2.17 (d, J=15.0Hz, 2H), 2.60 (m, 3H), 2.83 (m, 2H), 3.48 (dd, J=17.9,6.8Hz, 1H), 4.37 (q, J=7.1Hz, 2H), 6.75 (d, J=8.6Hz, 1H), 7.03 (d, J=8.7Hz, 1H), 7.84 (s, 1H). 13C NMR (62.5MHz, CDCl 3) δ 4.8,6.0,7.5,7.7,9.5,14.5,19.7,25.0,25.5,27.0,30.0,36.7,49.6,59.8,71.1,74.8,75.3,75.8,76.0,77.5,87.1,109.4,111.1,113.8.LC/MS (150mm * 4.6mm, C-18,5 microns, 10mM NH 4OAc/CH 3CN, APCI+) t=10.70min, m/z=395.5 (M+1). ultimate analysis: calculated value (as hydrate) C, 69.88; H, 7.82; N, 6.79. measured value C, 69.92; H, 7.87; N, 6.67.
Embodiment 16
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-propyl group-, ethyl ester
Figure A9981647500961
Steps A:
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-propyl group-, ethyl ester is synthetic by intermediate S according to method H.24% yield is white solid.LC/MS (150mm * 4.6mm, C-18,5 microns, 10mM NH 4OAc/CH 3CN, APCI+) t=7.45min, m/z=305.3 (M+1).
Step B:
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-propyl group-, ethyl ester is synthetic according to method I.28% yield is white solid.
1H NMR (250MHz, CDCl 3) δ 0.99 (t, J=7.3Hz, 3H), 1.40 (m, 4H), 1.44 (t, J=7.1Hz, 3H), 1.68 (m, 7H), 1.92 (m, 1H), 2.12 (d, J=12.0Hz, 1H), 2.55 (m, 2H), 2.92 (m, 5H), 3.47 (dd, J=16.7,6.6Hz, 1H), 4.35 (q, J=7.1Hz, 2H), 6.77 (d, J=8.7Hz, 1H), 7.05 (d, J=8.7Hz, 1H), 8.12 (s, 1H). 13C NMR (62.5MHz, CDCl 3) δ 13.9,14.4,19.8,23.0,25,26,27.0,30.1,30.5,36.7,49.6,59.7,87.1,110,111,113.8,127,129,146,149,167.LC/MS (150mm * 4.6mm, C-18,5 microns, 10mMNH 4OAc/CH 3CN, APCI+) t=11.56 min, m/z=397.5 (M+1). ultimate analysis: calculated value C, 72.69; H, 8.13; N, 7.06. measured value C, 72.30; H, 8.18; N, 6.79,
Embodiment 17
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(2-methyl-propyl)-, ethyl ester
Figure A9981647500971
Steps A:
2-isobutyl--4-(dimethylamino) methylene radical-5-hydroxyl-3-indole-carboxylic acid ethyl ester is synthetic by intermediate T according to method H.39% yield is white solid.LC/MS (150mm * 4.6mm, C-18,5 microns, 10mM NH 4OAc/CH 3CN, APCI+) t=7.86min, m/z=319.3 (M+1).
Step B:
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(2-methyl-propyl)-, ethyl ester is synthetic according to method I.27% yield is white solid.
1H NMR (250MHz, CDCl 3) δ 0.95 (d, J=4.3Hz, 3H), 0.98 (d, J=4.3Hz, 3H) 1.23 (m, 1H), 1.39 (t, J=7.1Hz, 3H), 1.42 (m, 6H), 1.63 (m, 6H), 1.88 (m, 1H), 2.00 (m, 1H), 2.16 (d, J=13.3Hz, 1H), 2.53 (m, 2H), 2.86 (m, 4H), 3.01 (m, 1H), 3.47 (dd, J=17.4,7.2Hz, 1H), 4.34 (q, J=7.1,2H), 6.77 (d, J=8.6Hz, 1H), 7.06 (d, J=8.7Hz, 1H), 8.04 (s, 1H). 13C NMR (62.5MHz, CDCl 3) δ 14.5,19.8,22.5,22.6,25.0,25.5,27.0,29.4,30.1,31.2,36.7,37.5,49.5,59.7,87.1,109.3,111.4,113.8,166.1.LC/MS (150mm * 4.6mm, C-18,5 microns, 10mMNH 4OAc/CH 3CN, APCI+) t=6.43min, m/z=411.4 (M+1). ultimate analysis:
Calculated value C, 73.14; H, 8.35; N, 6.82. measured value C, 73.04; H, 8.55; N, 6.60.
Embodiment 18
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl ethyl ester
Steps A:
3-amino-3-methylcrotonic acid the tert-butyl ester
Activate zinc: in the 3N HCl solution (50mL) that stirs, add Zn (20g) and also at room temperature stirred 15 minutes.Decant HCl solution, and with twice of this process repetition.With distilled water (2 *, 100mL), ethanol (2 *, 50mL) and ether (2 *, 50mL) wash this activatory zinc.Then, under the room temperature this activatory zinc placed following 12 hours of decompression.(0.83g 13mmol) in the suspension of Jiao Baning, adds 5 monobromo-acetic acid tert-butyl esters under the room temperature for dry THF (10mL) in being contained in flame-dried 100ml round-bottomed flask and activated zinc.Then this mixture heating up was refluxed 15 minutes.Add acetonitrile 0.60ml (6mmol) immediately, and in 30 minutes dripping bromine for tert.-butyl acetate (1.50ml, 10mmol).When the monobromo-acetic acid tert-butyl ester that adds about 2/3, this reaction mixture turns green.This mixture was refluxed 30 minutes again, be cooled to room temperature then.In the solution that stirs, add THF (30mL) and K 2CO 3(2g is dissolved in the 3mL water), and vigorous stirring 30 minutes.This solution places centrifuge tube and centrifugal again.Supernatant decanted liquid, and with the particle resuspending in THF (30mL), acutely shake and centrifugal (2 *).The supernatant liquor dried over mgso that merges is filtered, and concentrating under reduced pressure obtains 3-amino-3-methylcrotonic acid tert-butyl ester of 0.78g (83%), is weak yellow liquid, its 0 ℃ down curing obtain faint yellow solid. 1H?NMR(250MHz，CDCl 3)δ1.45(s，9H)，1.84(s，3H)，4.43(s，2H)。 13C?NMR(62.5MHz，CDCl 3)δ22.3，28.6，78.1，86.0，158.9，171.1。
Step B:
5-hydroxy-2-methyl-3-indolecarboxylic acid tertiary butyl ester 1, (3.30g 30mmol) heats in ethanol (15mL) and dissolves up to all solids the 4-benzoquinones.(5.50g 35mmol) joins in this hot solution, and with this reaction mixture refluxed 6 hours, cooling, and concentrating under reduced pressure will to be present in 3-amino-3-methylcrotonic acid tertiary butyl ester in the ethanol (15ml).This resistates is carried out flash column chromatography (Al 2O 3, ethyl acetate) and obtain 3.57g title compound (14.4mmol, 48%), be brown crystallization.mp114.0-116.0℃。
1H?NMR(250MHz，DMSO)δ1.57(s，9H)，2.55(s，3H)，6.57(dd，J＝8.6，2.3Hz，1H)，7.09(d，J＝8.6Hz，1H，)，7.28(d，J＝2.3?Hz，1H)，8.78(s，1H)，11.41(s，1H). 13CNMR(62.5MHz，d 6-MeOH)δ14.4，29.1，80.6，105.3，106.8，112.2，129.9，131.1，145.9，153.1，161.7.167.9.
Step C:
4-(dimethylamino) methylene radical-5-hydroxy-2-methyl-3-indolecarboxylic acid tert-butyl ester
To the 5-hydroxy-2-methyl that is present in ethanol (the 4.5ml)-3-indole-carboxylic acid tert-butyl ester that stirs (1.48g, add in 6.0mmol) formaldehyde (0.55mL, 7.2mmol) and dimethylamine (1.66mL, 13.2mmol).This solution stirred 10 hours down at 60 ℃, cooling and concentrating under reduced pressure.This resistates filters with extracted with diethyl ether (30mL), and solvent evaporated under reduced pressure obtains 1.54g title compound (5.05mmol, 84%) once more, is brown crystallization.Mp151.0 ℃ (decomposition).
1H NMR (250MHz, d 6-MeOH) δ 1.63 (s, 9H), 1.88 (s, 3H), 2.61 (s, 3H), 2.90 (s, 6H), 4.76 (s, 2H), 6.81 (d, J=8.7Hz, 1H), 7.27 (d, J=8.6Hz, 1H). 13C NMR (62.5MHz, d 6-MeOH) δ 16.1,24.2,29.0,43.1,55.4,82.0,107.7,112.4,115.4,131.6,146.5,154.1,161.7.LC/MS (150mm * 4.6mm, C-18,5 microns, 10mMNH 4OAc/CH 3CN, APCI+) t=7.75min, m/z=305.4 (M+1).
Step D:
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl ethyl ester
To stir, NaOH (50%w/w, 100mL) and in the solution of ether (20mL), adding 0.082g (0.20mmol) imino-ammonium salt (embodiment 3, step B).This solution extracted with diethyl ether (3 * 30mL), obtain enamine with dried over mgso and concentrating under reduced pressure, be white solid.1.0mL diox joins this enamine, (0.061g 0.20mmol), then adds the 0.5mL diox to add 4-(dimethylamino) methylene radical-5-hydroxy-2-methyl-3-indole-carboxylic acid tert-butyl ester then.This solution refluxed overnight is cooled to room temperature, and concentrating under reduced pressure also carries out flash column chromatography (SiO 2, 1: 1 hexane/ethyl acetate) and obtain the required product of 0.031g (0.08mmol, 40%), be white solid; Mp214.0 ℃ (decomposition).
1H NMR (250MHz, CDCl 3) δ 1.45 (m, 4H), 1.61 (s, 9H), 1.69 (m, 5H), 1.89 (m, 1H), 2.14 (d, J=15Hz, 1H), 2.49 (m, 2H), 2.56 (s, 3H), 2.84 (d, J=6Hz, 2H), 3.06 (m, 1H), 3.48 (dd, J=18,7Hz, 1H), 6.74 (d, J=8.6Hz, 1H), 7.01 (d, J=8.6Hz, 1H), 8.07 (s, 1H). 13C NMR (62.5MHz, CDCl 3) δ 14.8,19.8,25.0,25.5,27.1,28.6,30.2,31.2,36.7,49.6,66.4,80.0,87.2,108.0,109.2,111.3,113.6,126.0,129.2,140.6,148.7,165.6.LC/MS (150mm * 4.6mm, C-18,5 microns, 10mM NH 4OAc/CH 3CN, APCI+) t=7.98min, m/z=397.4 (M+1). ultimate analysis: calculated value C, 72.70; H, 8.13; N, 7.06. measured value C, 72.28; H, 8.23; N, 6.72.
Embodiment 19
2,6a, 7-trimethylammonium-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diazacyclo penta [a] anthracene-1-ethyl formate
Figure A9981647501011
Steps A:
1,6-dimethyl-1,2,3,4-tetrahydrochysene-pyridine
1,6-dimethyl-1,2,3,4-tetrahydrochysene-pyridine be according to Lipp A., Liebigs Annl.Chem., 1898; The method that 289:216 describes is synthetic.
Step B:
2,6a, 7-trimethylammonium-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diazacyclo penta [a] anthracene-1-ethyl formate
With 1,6-dimethyl-1,2,3,4-tetrahydropyridine (0.100g, 0.899mmol, embodiment 19, steps A) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.200g, 0.724mmol) De diox (0.800mL) solution is under nitrogen atmosphere, 100 ℃ of down heating 4 hours.Add the 1.0mL diox again, and continue heating 24 hours.This solution is cooled to room temperature, concentrate, and with this resistates by flash column chromatography purifying on silica gel, use the 50%-75% ethyl acetate: the hexane wash-out, and obtain 12mg (4.8%) 2,6a with re-crystallizing in ethyl acetate, 7-trimethylammonium-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diazacyclo penta [a] anthracene-1-ethyl formate is white powder; Mp169-173 ℃;
1H NMR (400MHz, CDCl 3) δ 1.34 (m, 2H), 1.36 (t, J=7.08Hz, 3H, CH 2CH 3), 1.45 (s, 3H, CH 3C (O) N), 1.56 (m, 2H), 1.66 (m, 1H), 1.93 (m, 1H), 2.56 (s, 3H, CH 3), 2.58 (s, 3H, CH 3), 2.87 (bd, J=17.58Hz, 2H), 3.50 (dd, J=18.19,6.72Hz, 1H), 4.31 (q, J=7.08Hz, 2H, CH 2CH 3), 6.68 (d, J=8.79Hz, 1H, ArH), 7.01 (d, J=8.30Hz, 1H, ArH), 8.03 (bs, 1H, NH); MS (APCI +) m/z343.2 (MH +) .C 20H 26N 2O 30.17H 2O computational analysis value: C, 69.53; H, 7.68; N, 8.11. measured value: C, 69.52; H, 7.33; N, 7.84.
Embodiment 20
7-ethyl-2,6a-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diazacyclo penta [a] anthracene-1-ethyl formate
Figure A9981647501021
Steps A: 1-ethyl-6-methyl-2,3,4,5-tetrahydropyridine perchlorate
1-ethyl-6-methyl-2,3,4,5-tetrahydropyridine perchlorate be according to LadenburgA., Liebigs Ann.Chem., 1899; The 304:54 disclosed method is synthetic.
Step B:7-ethyl-2,6a-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate
1-ethyl-6-methyl-2,3,4,5-tetrahydrochysene-pyridine perchlorate (embodiment 20, steps A for 0.245g, 1.08mmol) is dissolved in the minimum water, and handles to strong basicity with 50% aqueous sodium hydroxide solution.This aqueous solution with 4 * 10mL extracted with diethyl ether, and is washed the extract that merges with 1 * 10mL saturated sodium-chloride water solution, use dried over mgso, filter, and be concentrated to the 1-ethyl-6-methyl isophthalic acid that obtains 90mg (0.724mmol) in this reaction flask, 2,3,4-tetrahydrochysene-pyridine.Be dissolved in this resistates in the diox (0.750mL) and add 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.200g, 0.724mmol).Gained solution reflux 4 hours under nitrogen atmosphere is cooled to room temperature, and concentrates.With this thick resistates by flash column chromatography purifying on silica gel, with 100% eluent ethyl acetate and obtain the 7-ethyl-2 of 98mg (38%) with re-crystallizing in ethyl acetate, 6a-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate is white powder: mp173-174 ℃;
IR (KBr) 3298,2930,2856,1669,1433,1238,1094cm -1 1H NMR (300MHz, CDCl 3) δ 1.16 (m, 3H, CH 3CH 2N), 1.37 (m, 1H), 1.40 (m, 1H), 1.48 (s, 2H), 1.56 (s, 2H), 1.64 (m, 2H), 1.97 (m, 1H), 2.61 (s, 3H, CH 3), 2.72 (m, 1H), 2.84 (m, 1H), 2.90 (bd, J=19.04Hz, 2H), 3.16 (m, 1H), 3.54 (dd, J=18.31,6.78Hz, 1H), 4.35 (qd, J=7.14,1.65Hz, 2H, OCH 2CH 3), 6.70 (d, J=8.61Hz, 1H, ArH), 7.03 (d, J=8.61Hz, ArH), 8.06 (bs, 1H, NH); MS (APCI +) m/z357.1 (MH +) .C 21H 28N 2O 3Computational analysis value: C, 70.76; H, 7.92; N, 7.86. measured value: C, 70.49; H, 7.80; N, 7.66.
Embodiment 21
Figure A9981647501031
Isomer A:
6a-ethyl-2,7-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diazacyclo penta [a] anthracene-1-ethyl formate
Steps A: 6-ethyl-1-methyl-2,3,4,5-tetrahydropyridine perchlorate
6-ethyl-1-methyl-2,3,4,5-tetrahydrochysene-pyridine perchlorate is according to Leonard N.J.; Hauck, Jr., F.P., J.Am.Chem.Soc., 1957; The method that 79:5279 describes is synthetic.
Step B:6a-ethyl-2,7-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate
6-ethyl-1-methyl-2,3,4,5-tetrahydrochysene-pyridine perchlorate (embodiment 21, steps A for 0.712g, 3.16mmol) are dissolved in the minimum water and handle to strong basicity with 50% aqueous sodium hydroxide solution.With this aqueous solution with 4 * 15mL extracted with diethyl ether, and with the extract that merges with the washing of 1 * 15mL saturated sodium-chloride water solution, use dried over mgso, filtration, and be concentrated to and obtain 6-ethyl-1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-pyridine in this reaction flask.This resistates is dissolved in the diox (2.1mL), and adding 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.581g, 2.10mmol).Stirred 2 hours under room temperature under its nitrogen atmosphere, 50 ℃ of heating 24 hours, 60 ℃ of heating 3 hours, heating was in the time of 4.5 hours down in heating 17 hours under 70 ℃ and at 89-90 ℃, and gained solution is by TLC and MS monitoring.This dark solution is cooled to room temperature, and concentrates.With this thick resistates by flash column chromatography purifying on silica gel, use the 20-60% ethyl acetate: the hexane wash-out obtains the 6a-ethyl-2 of 56mg (7.5%), 7-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate individual isomer A, it has bigger Rf value, is white powder: mp144-147 ℃;
IR (KBr) 3375,2975,2937,2858,1671,1470,1432,1245,1202cm -1 1H NMR (400MHz, CDCl 3) δ 0.91 (m, 3H, CH 3CH 2C (O) N), 1.34 (m, 2H), 1.36 (m, 3H, OCH 2CH 3), 1.54 (bs, 1H), 1.63 (m, 1H), 1.76 (m, 1H), 1.84 (m, 1H), 2.06 (m, 1H), 2.46 (s, 3H, CH 3), 2.52 (m, 1H), 2.57 (2,3H, CH 3), 2.79 (d, J=18.07Hz, 1H), 2.88 (m, 1H), 3.37 (dd, J=18.07,6.59Hz, 1H), 4.31 (m, 2H, OCH 2CH 3), 6.67 (d, J=8.79Hz, 1H, ArH), 6.99 (d, J=8.55Hz, 1H, ArH), 8.03 (bs, 1H, NH); MS (APCI +) m/z357.2 (MH +) .C 21H 28N 2O 30.04H 2O computational analysis value: C, 70.61; H, 7.92; N, 7.84; Water, 0.22. measured value: C, 70.27; H, 7.92; N, 7.58; Water, 0.22.
Embodiment 22
Isomer B:
6a-ethyl-2,7-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate
6-ethyl-1-methyl-2,3,4,5-tetrahydrochysene-pyridine perchlorate (embodiment 21, steps A for 0.712g, 3.16mmol) are dissolved in minimum water and handle to strong basicity with 50% aqueous sodium hydroxide solution.With this aqueous solution with 4 * 15mL extracted with diethyl ether, and with the extract that merges with saturated sodium-chloride water solution 1 * 15mL washing, use dried over mgso, filtration, and be concentrated to and obtain 6-ethyl-1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-pyridine in this reaction flask.This resistates is dissolved in diox (2.1mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.581g, 2.10mmol) adding.Stirred 2 hours under room temperature under its nitrogen atmosphere, 50 ℃ of heating 24 hours, 60 ℃ of heating 3 hours, heating was in the time of 4.5 hours down in heating 17 hours under 70 ℃ and at 89-90 ℃, and gained solution is by TLC and MS monitoring.This dark solution is cooled to room temperature, and concentrates.With this thick resistates by flash column chromatography purifying on silica gel, use the 20-60% ethyl acetate: the hexane wash-out obtains the 6a-ethyl-2 of 37mg (4.9%), 7-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3, the individual isomer B of 7-diaza-ring penta [a] anthracene-1-ethyl formate, it has less Rf value, is thin pale powder: mp158-161 ℃;
IR (KBr) 3310,2957,2928,2862,1654,1436,1419,1204cm -1 1H NMR (400MHz) δ 1.08 (m, 3H, CH 3CH 2C (O) N), 1.20 (m, 1H), 1.37 (m, 3H, OCH 2C 2H 3), 1.41 (m, 1H), 1.52 (s, 3H, CH 3), 1.59 (m, 2H), 1.85 (bd, J=13.18Hz, 1H), 2.30 (m, 1H), 2.35 (m, 2H), 2.58 (s, 3H, CH 3), 2.91 (m, 1H), 3.11 (m, 2H), 4.32 (m, 2H, OCH 2CH 3), 6.72 (d, J=8.55Hz, 1H, ArH), 7.00 (d, J=8.79Hz, 1H, ArH), 8.03 (bs, 1H, NH); MS (APCI +) m/z357.2 (MH +) .C 21H 28N 2O 3Computational analysis value: C, 70.76; H, 7.92; N, 7.86. measured value: C, 71.45; H, 8.44; N, 6.65.HPLC (1: 1 H of ALLTECH/ALLTIMAC-18 2O/CH 3CN+0.05%TFA): retention time=4.940min, 99.40% purity.
Embodiment 23
6a, 7-diethyl-2-methyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diazacyclo penta [a] anthracene-1-ethyl formate
Figure A9981647501061
Steps A: 1,6-diethyl-2,3,4,5-tetrahydrochysene-pyridine perchlorate
1,6-diethyl-2,3,4,5-tetrahydrochysene-pyridine perchlorate is according to Leonard N.J., Hauck, Jr., F.P., J.Am.Chem.Soc., 1957; 79:5279 is synthetic.
Step B:6a, 7-diethyl-2-methyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa-
3,7-diaza-ring penta [a] anthracene-1-ethyl formate
1,6-diethyl-2,3,4,5-tetrahydrochysene-pyridine perchlorate (embodiment 23, steps A for 0.485g, 2.02mmol) are dissolved in minimum water and handle to strong basicity with 50% aqueous sodium hydroxide solution.This aqueous solution with 4 * 15mL extracted with diethyl ether, and is washed the extract that merges with 1 * 15mL saturated sodium-chloride water solution, use dried over mgso, filter, and be concentrated to and obtain 1 of 207mg (1.49mmol), 6-diethyl-1 in this reaction flask, 2,3,4-tetrahydrochysene-pyridine.This resistates is dissolved in diox (1.3mL) and add 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.373g, 1.35mmol).Gained solution was heated 7 hours under nitrogen atmosphere at 100 ℃, be cooled to room temperature, and concentrate.With this thick resistates by flash column chromatography purifying on silica gel, use the 20-100% ethyl acetate: the hexane wash-out, and obtain the 6a of 123mg (25%), 7-diethyl-2-methyl-7 with re-crystallizing in ethyl acetate, 8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diazacyclo penta [a] anthracene-1-ethyl formate is white crystalline solid: mp162-163 ℃;
IR (KBr) 3390,2972,2929,2859,1654,1432,1201,1097cm -1 1H NMR (400MHz, CDCl 3) δ 0.900 (m, 2H, CH 3CH 2C (O) N), 1.11 (m, 2H, CH 3CH 2N), 1.34 (m, 2H), 1.36 (m, 3H, CH 3CH 2O), 1.57 (m, 2H), 1.85 (m, 2H), 2.06 (m, 1H), 2.57 (s, 3H, CH 3), 2.70 (m, 2H), 2.79 (bd, J=18.31Hz, 1H), 2.84 (m, 1H), 3.00 (m, 1H), 3.37 (m, 1H), 4.31 (m, 2H, CH 3CH 2O), 6.64 (d, J=8.55Hz, 1H, ArH), 6.98 (d, J=8.55Hz, 1H, ArH), 8.00 (bs, 1H, NH); MS (APCI +) m/z371.1 (MH +) .C 22H 30N 2O 3Computational analysis value: C, 71.32; H, 8.16; N, 7.56. measured value: C, 71.28; H, 7.77; N, 7.32.
Embodiment 24
7-benzyl-2,6a-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate
Steps A: 1-benzyl-6-methyl-2,3,4,5-tetrahydrochysene-pyridine perchlorate
1-benzyl-6-methyl-2,3,4,5-tetrahydrochysene-pyridine perchlorate is according to M hrle H.; Dwuletzki H.Z., Naturforsch., B:Anorg.Chem., Org.Chem., 1986; The method that 41b:1323 describes is carried out.
Step B:7-benzyl-2,6a-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa-
3,7-diaza-ring penta [a] anthracene-1-ethyl formate
With excessive 1-benzyl-6-first-2,3,4,5-tetrahydrochysene-pyridine perchlorate (embodiment 24, steps A) is dissolved in minimum water and handles to strong basicity with 50% aqueous sodium hydroxide solution.With this aqueous solution with 4 * 20mL extracted with diethyl ether, and with the extract that merges with the washing of 1 * 20mL saturated sodium-chloride water solution, use dried over mgso, filtration, and concentrated this enamine that obtains.With 1-benzyl-2-methyl isophthalic acid, 2,3,4-tetrahydrochysene-pyridine (0.447g, 2.39mmol) be dissolved in diox (2.4mL) and add 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.330g, 1.20mmol).Gained solution heating 20 hours under 80-90 ℃, is cooled to room temperature under nitrogen atmosphere, and concentrates.With this thick resistates by flash column chromatography purifying on silica gel, use the 10-20% ethyl acetate: the hexane wash-out also obtains the 7-benzyl-2 of 208mg (42%) with re-crystallizing in ethyl acetate, 6a-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3, the pale powder of 7-diaza-ring penta [a] anthracene 1-ethyl formate: mp196-198 ℃;
IR (KBr) 3397,2983,2923,2897,2854,1668,1432,1200,1097cm -1 1H NMR (400MHz, CDCl 3) δ 1.36 (m, 1H), 1.37 (m, 3H, OCH 2CH 3), 1.50 (s, 3H, CH 3C (O) N), 1.53 (m, 3H), 2.03 (m, 1H), 2.56 (m, 1H), 2.58 (s, 3H, CH 3), 2.71 (m, 1H), 2.94 (d, J=18.07Hz, 1H), 3.53 (dd, J=18.07,6.84Hz, 1H), 3.58 (d, J=15.14Hz, 1H, NCH (H) Ph), 4.32 (m, 2H, OCH 2CH 3), 4.47 (d, J=14.89Hz, 1H, NCH (H) Ph), 6.71 (d, J=8.55Hz, 1H, ArH), 7.01 (d, J=8.55Hz, 1H, ArH), 7.18 (t, J=7.08Hz, 1H, PhH), 7.28 (m, 2H, PhH), 7.35 (d, J=7.33Hz, 2H, PhH), 8.06 (bs, 1 H, NH); MS (APCI +) m/z419.2 (MH +) .C 26H 30N 2O 3H 2O computational analysis value: C, 74.39; H, 7.24; N, 6.67; Water, 0.30. measured value: C, 74.27; H, 7.25; N, 6.54; Water, 0.31.
Embodiment 25
Figure A9981647501081
Isomer A:
2,7-dimethyl-6a-phenyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate
Steps A: 1-methyl-6-phenyl-2,3,4,5-tetrahydrochysene-pyridine perchlorate
Synthetic 1-methyl-6-phenyl-2,3,4, the method for 5-tetrahydrochysene-pyridine perchlorate is described in Leonard N.J.; Hauck Jr.F.P., J.Am.Chem.Soc., 1957; 79:5279.
Step B:2,7-dimethyl-6a-phenyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate
With excessive 1-methyl-6-phenyl-2,3,4,5-tetrahydrochysene-pyridine perchlorate (embodiment 25, steps A) is dissolved in minimum water and handles to strong basicity with 50% aqueous sodium hydroxide solution.With this aqueous solution with 4 * 20mL extracted with diethyl ether, and with the extract that merges with the washing of 1 * 20mL saturated sodium-chloride water solution, use dried over mgso, filtration, and concentrated this enamine that obtains.1-methyl-6-phenyl-1,2,3,4 ,-tetrahydrochysene-pyridine (0.428g, 2.47mmol) be dissolved in diox (1.8mL) and add 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.342g, 1.24mmol).This reaction mixture was being heated 16 hours under nitrogen atmosphere under 75-80 ℃, and the 1.0mL diox adds and continues heating 5 hours at 90 ℃.Exsiccant toluene (1.0mL) is joined in this mixture and with it to descend to heat 26 hours at 100 ℃, be cooled to room temperature, and concentrate.This thick resistates by flash column chromatography purifying on silica gel, is used the 10-50% ethyl acetate: the hexane wash-out obtains individual isomer A, and it has less Rf value, it is used ether: the hexane recrystallization obtains 2 of 73mg (15%), 7-dimethyl-6a-phenyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate is pale powder; Mp176-177 ℃;
IR (KBr) 3400,2942,2930,2859,1647,1434,1206,1099,1079cm -1 1H NMR (400MHz, CDCl 3) δ 1.20 (m, 3H, OCH 2CH 3), 1.48 (m, 2H), 1.67 (d, J=13.18Hz, 1H), 1.84 (m, 1H), 2.13 (s, 3H, CH 3), 2.35 (m, 1H), 2.52 (s, 3H, CH 3), 2.58 (m, 1H), 2.68 (m, 1H), 2.81 (d, J=17.33Hz, 1H), 2.90 (m, 1H), 4.17 (q, J=7.08Hz, 2H, OCH 2CH 3), 6.89 (d, J=8.79Hz, 1H, ArH), 7.06 (d, J=8.79Hz, 1H, ArH), 7.15 (m, 3H, PhH), 7.35 (m, 2H, PhH), 8.07 (bs, 1H, NH); MS (APCI +) m/z405.2 (MH +) .C 25H 28N 2O 3Computational analysis value: C, 74.23; H, 6.98; N, 6.93. measured value: C, 73.93; H, 7.11; N.6.66.
Embodiment 26
Figure A9981647501101
Isomer B:
2,7-dimethyl-6a-phenyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diazacyclo penta [a] anthracene-1-ethyl formate
With excessive 1-methyl-6-phenyl-2,3,4,5-tetrahydrochysene-pyridine perchlorate (embodiment 25, steps A) is dissolved in minimum water and handles to strong basicity with 50% aqueous sodium hydroxide solution.With this aqueous solution with 4 * 20mL extracted with diethyl ether, and with the extract that merges with the washing of 1 * 20mL saturated sodium-chloride water solution, use dried over mgso, filtration, and concentrated this enamine that obtains.1-methyl-6-phenyl-1,2,3,4 ,-tetrahydrochysene-pyridine (0.428g, 2.47mmol) be dissolved in the diox (1.8mL) and add 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.342g, 1.24mmol).This reaction mixture was being heated 16 hours under nitrogen atmosphere under 75-80 ℃, adding the 1.0mL diox and continue heating 5 hours at 90 ℃.Exsiccant toluene (1.0mL) is joined this mixture and it is descended heating 26 hours at 100 ℃, be cooled to room temperature, and concentrate.This thick resistates by flash column chromatography purifying on silica gel, is used the 10-50% ethyl acetate: the hexane wash-out, use ether: the hexane recrystallization and with this filtrate further by the silica gel chromatography purifying, use the 1-10% ethyl acetate: the hexane wash-out obtains 2 of 70mg (14%), 7-dimethyl-6a-phenyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate individual isomer B, it has bigger Rf value and is peachiness powder: mp184-186 ℃;
IR (KBr) 3380,2926,1698,1684,1436,1073cm -11H NMR (400MHz, CDCl 3) δ 1.37 (t, J=7.08Hz, 3H, OCH 2CH 3), 1.49 (m, 2H), 1.64 (m, 1H), 1.76 (m, 1H), 2.29 (m, 1H), 2.31 (s, 3H, CH 3), 2.59 (s, 3H, CH 3), 2.97 (d, J=17.58Hz, 1H), 3.52 (m, 1H), 3.77 (m, 1H), 4.32 (m, 2H, OCH 2CH 3), 4.89 (bs, 1H), 6.74 (d, J=8.55Hz, 1H, ArH), 7.02 (d, J=8.55Hz, 1H, ArH), 7.33 (m, 5H, PhH), 8.06 (bs, 1H, NH); MS (APCI +) m/z405.2 (MH +) .C 25H 28N 2O 3Computational analysis value: C, 74.23; H, 6.98; N, 6.93. measured value: C, 74.18; H, 6.90; N, 6.72
Embodiment 27
1H, 7H-indolizine be [8 ', 8a ': 5,6] pyrans [3,2-e] indoles-1-formic acid also also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-, ethyl ester
Figure A9981647501111
Steps A: 2,3,5,6,7,8-six hydrogen-1H-indolizine perchlorate
2,3,5,6,7,8-six hydrogen-1H-indolizine perchlorate is according to Reinecke M.G.; Kray L.R., J.Org.Chem., 1964; The method that 29:1736 describes is synthetic.
Step B:1H, 7H-indolizine be [8 ', 8a ': 5,6] pyrans [3,2-e] indoles-1-formic acid also also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-, ethyl ester
With 2,3,5,6,7,8-six hydrogen-1H-indolizine perchlorate (embodiment 27, steps A for 0.330g, 1.48mmol) are dissolved in minimum water and handle to strong basicity with 50% aqueous sodium hydroxide solution.With this aqueous solution with 4 * 15mL extracted with diethyl ether, and with the extract that merges with the washing of 1 * 15mL saturated sodium-chloride water solution, use dried over mgso, filtration, and be concentrated to the enamine that obtains 143mg (1.16mmol) in this reaction flask.With 1,2,3,5,6,7-six hydrogen-indolizine be dissolved in the diox (1.5mL) and add 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.321g, 1.16mmol).Gained solution reflux 5 hours under nitrogen atmosphere is cooled to room temperature, and concentrates.This thick resistates by flash column chromatography purifying on silica gel, is obtained the 1H of 129mg (31%) with 100% acetone wash-out and with re-crystallizing in ethyl acetate, 7H-indolizine also [8 ', 8a ': 5,6] pyrans [3,2-e] indoles-1-formic acid also, 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-, ethyl ester is pale powder: mp170-172 ℃;
IR (KBr) 3396,3353,2929,2853,1668,1434,1156,1096,1075cm -1 1H NMR (300MHz, CDCl 3) δ 1.38 (m, 2H), 1.40 (t, J=7.14Hz, 3H, OCH 2CH 3), 1.68 (m, 3H), 1.90 (m, 3H), 2.05 (m, 1H), 2.61 (s, 3H, CH 3), 2.74 (m, 1H), 2.84 (m, 1H), 2.97 (d, J=17.40Hz, 1H), 3.09 (m, 2H), 3.47 (dd, J=17.76,6.78Hz, 1H), 4.36 (m, 2H, OCH 2CH 3), 6.67 (d, J=8.61Hz, 1H, ArH), 7.03 (d, J=8.61Hz, 1H, ArH), 8.06 (bs, 1H, NH); MS (APCI +) m/z355.2 (MH +) .C 21H 26N 2O 30.23H 2O computational analysis value: C, 70.34; H, 7.44; N, 7.81. measured value: C, 70.35; H, 7.48; N, 7.61.
Embodiment 28 3H, 7H-pyrroles's piperazine are (Pyrrolizino) [1 ', 8 ': 5,6] pyrans [3,2-e] indoles-1-acetate also also, and 8,9,11,12,12a, 13 6 hydrogen-2-methyl-, ethyl ester
Steps A: 1,2,3,5,6,7-six hydrogen-pyrroles's piperazine perchlorate
1,2,3,5,6,7-six hydrogen-pyrroles's piperazine perchlorate is according to Miyano S. etc., Synthesis, 1978; The method of describing among the 9:701 is synthetic.
Step B:3H, 7H-pyrroles's piperazine be [1 ', 8 ': 5,6] pyrans [3,2-e] indoles-1-acetate also also, and 8,9,11,12,12a, 13-six hydrogen-2-methyl-, ethyl ester
With 1,2,3,5,6,7-six hydrogen-pyrroles's piperazine perchlorate (embodiment 28, steps A for 0.904g, 4.31mmol) are dissolved in minimum water and handle to strong basicity with 50% aqueous sodium hydroxide solution.With this aqueous solution with 4 * 15mL extracted with diethyl ether, and with the extract of this merging with the washing of 1 * 15ml saturated sodium-chloride water solution, use dried over mgso, filter, and be concentrated to the enamine that obtains 325mg (2.98mmol) in this reaction flask, 2,3,5,6-tetrahydro-1 H-pyrrolo piperazine (pyrrolizine).This resistates be dissolved in the diox (2.8mL) and add 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.794g, 2.88mmol).Gained solution was heated 17 hours under 80 ℃ of nitrogen atmosphere, be cooled to room temperature, and concentrate.This thick resistates by flash column chromatography purifying on silica gel, is used 15%MeOH:CH 2Cl 2Wash-out, and obtain the 3H of 105mg (11%) with the ether recrystallization, 7H-pyrroles's piperazine be [1 ', 8 ': 5,6] pyrans [3,2-e] indoles-1-acetate also also, and 8,9,11,12,12a, 13-six hydrogen-2-methyl-, ethyl ester is white powder; Mp206-207 ℃;
IR (KBr) 2972,2901,2864,2828,1694,1429,1196,1087cm -1 1H NMR (400MHz, CDCl 3) δ 1.37 (t, J=7.08Hz, 3H, OCH 2CH 3), 1.60 (m, 2H), 1.91 (m, 1H), 1.99 (m, 2H), 2.10 (m, 1H), 2.27 (m, 2H), 2.46 (m, 1H), 2.55 (m, 1H), 2.60 (s, 3H, CH 3), 3.22 (m, 1H), 3.35 (m, 1H), 3.36 (d, J=4.88Hz, 1H), 4.34 (m, 2H, OCH 2CH 3), 6.76 (d, J=8.55Hz, 1H, ArH), 7.00 (d, J=8.55Hz, 1H, ArH, 8.26 (m, 1H, NH); MS (APCI +) m/z341.1 (MH +) .C 20H 24N 2O 3Computational analysis value: C, 70.57; H, 7.11; N, 8.23. measured value: C, 70.40; H, 7.27; N, 7.94.
Embodiment 29
2-methyl-8,9,10,10a, 11,12,12a, 13-octahydro-3H, 6aH, 7H-6-oxa--3,6b-diaza-benzo [a] ring penta [h] anthracene-1-ethyl formate
Steps A: 1,3,4,8,9,9a-six hydrogen-2H-quinolizine
1,3,4,8,9,9a-six hydrogen-2H-quinolizine is according to Bohlmann F. etc., Chem.Ber., 1973; The method that 106:3026 describes is synthetic.
Step B:2-methyl-8,9,10,10a, 11,12,12a, 13-octahydro-3H, 6aH, 7H-6-oxa--3,6b-diaza-benzo [a] ring penta [h] anthracene-1-ethyl formate
With 1,3,4,8,9,9a-six hydrogen-2H-quinolizine (embodiment 29, steps A for 0.372g, 2.71mmol) be dissolved in the diox (2.7mL) and add 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.374g, 1.36mmol).Gained solution was heated 17 hours under 80 ℃ of nitrogen atmosphere, refluxed 24 hours, be cooled to room temperature, and concentrate.This thick resistates by flash column chromatography purifying on silica gel, is used 10-20% ethyl acetate: CH 2Cl 2Wash-out, and obtain the 2-methyl-8,9,10 of 71mg (14%) with the hexanaphthene recrystallization, 10a, 11,12,12a, 13-octahydro-3H, 6aH, 7H-6-oxa--3,6b-diaza benzo [a] ring penta [h] anthracene-1-ethyl formate is pale powder: mp178-180 ℃;
IR (KBr) 3372,2929,2859,1669,1654,1435,1198,1095,1079cm -1 1H NMR (400MHz, CDCl 3) δ 1.15 (m, 1H), 1.35 (t, J=7.08Hz, 3H, OCH 2CH 3), 1.36 (m, 4H), 1.49 (m, 2H), 1.65 (m, 3H), 2.20 (m, 1H), 2.58 (s, 3H, CH 3), 2.68 (m, 1H), 2.82 (m, 1H), 2.89 (d, J=17.58Hz, 1H), 3.05 (m, 1H), 3.45 (m, 1H), 4.31 (m, 2H, OCH 2CH 3), 4.68 (s, 1H, CH (O) N), 6.68 (d, J=8.79Hz, 1H, ArH), 6.99 (d, J=8.55Hz, 1H, ArH), 8.03 (bs, 1H, NH); Less important diastereomer diagnostic peak 1H NMR (400MHz, CDCl 3) δ 6.75 (d, J=8.55Hz, 1H, ArH); MS (APCI +) m/z369.1 (MH +) .C 22H 28N 2O 3Computational analysis value: C, 71.71; H, 7.66; N, 7.60. measured value: C, 71.96; H, 7.92; N, 7.09.HPLC (ALLTECH/ALLTIMA C-18 150mm * 4.6mm post, 1: 1 H 2O/CH 3CN+0.5%TFA): retention time=3.526min (11.26%), 3.882min (85.82%) (diastereomer), 97.08% purity .HPLC (Alltima Silica5 micron, 150mm * 4.5mm post, 95: 5 hexane+0.05%Et 2NH, ethanol+0.05%Et 2NH): retention time=5.19min (84.08%), 5.87min (8.63%) (diastereomer), 92.71% purity.
Embodiment 30
3H-pyrido [1 ", 2 ": 1 ' 2 '] azepines is [3 ' 2 ': 5,6] pyrans [3,2-e] indoles-1-acetate also also, and 7,8,9,10,12,13,14,15,15a, 16-decahydro-2-methyl-, ethyl ester, or the 7H-azepines also [1 "; 2 ": 1 " 2 '] pyrido [3 ', 2 ': 5,6] pyrans [3,2-e] indoles-1-acetate also, 3; 8,9,10,11,13; 14,15,15a, 16-decahydro-2-methyl-, ethyl ester
Figure A9981647501151
Steps A: 2,3,4,6,7,8,9,10-octahydro-pyrido [1,2-a] azepines perchlorate
Synthetic 2,3,4,6,7,8,9, the method for 10-octahydro-pyrido [1,2-a] azepines perchlorate is described in McIntosh J.M. etc., Can.J.Chem., 1983; 61:2016.
Step B:
With excessive 2,3,4,6,7,8,9,10-octahydro-pyrido [1,2-a] azepines perchlorate (embodiment 30, steps A) is dissolved in minimum water and handles to strong basicity with 50% aqueous sodium hydroxide solution.With this aqueous solution with 4 * 20mL extracted with diethyl ether, and with the extract that merges with the washing of 1 * 20mL saturated sodium-chloride water solution, use dried over mgso, filtration, and the concentrated crude product enamine that obtains 582mg (3.85mmol).This resistates be dissolved in the diox (3.8mL) and add 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.797g, 2.88mmol).This reaction mixture was heated 6 hours under 80 ℃ of nitrogen atmosphere, be cooled to room temperature, and concentrate.This thick resistates by flash column chromatography purifying on silica gel, is used 10% ethyl acetate: CH 2Cl 2-100% eluent ethyl acetate, and obtain the simplification compound of 18mg (2%), 3H-pyrido [1 ", 2 ": 1 ' 2 '] azepines with the octane-iso recrystallization also [3 ' 2 ': 5,6] pyrans [3,2-e] indoles-1-acetate also, 7,8,9,10,12,13,14,15,15a, 16-decahydro-2-methyl-, ethyl ester or 7H-azepines also [1 "; 2 ": 1 ' 2 '] pyrido [3 ', 2 ': 5,6] pyrans also [3,2-e] indoles-1-acetate, 3,8,9,10,11,13,14,15,15a, 16-decahydro-2-methyl-, ethyl ester all is thin white powder: mp118-121 ℃;
IR (KBr) 3379,3306,2926,2853,1671,1435,1151,1094,1073cm -11H NMR (400MHz, CDCl3) δ 0.86 (m, 1H), 1.35 (m, 3H), 1.36 (m, 3H, OCH 2CH 3), 1.45 (m, 3H), 1.60 (m, 3H), 1.69 (dd, J=14.65,10.01Hz, 1H), 1.95 (m, 1H), 2.19 (m, 1H), 2.41 (m, 1H), 2.54 (m, 1H), 2.57 (s, 3H, CH 3), 2.80 (d, J=18.56Hz, 1H), 3.11 (m, 1H), 3.34 (m, 1H), 3.48 (m, 1H), 4.31 (m, 2H, OCH 2CH 3), 6.70 (d, J=8.55Hz, 1H, ArH), 6.98 (d, J=8.55Hz, 1H, ArH), 8.01 (bs, 1H, NH); MS (APCI +) m/z383.1 (MH +) .rC 23H 30N 2O 3Computational analysis value: C, 72.22; H, 7.91; N, 7.32. measured value: C, 72.14; H, 7.95; N, 6.97.
Total method of method J:Mannich reaction:
This solution heat simultaneously with this acid amides (1.1mmol) by stirring, 1eq) be dissolved in EtOH.With this solution cooling.Add the HCHO aqueous solution (37%, 1.32mmol, 1.2eq) and dimethylamine (40%, 2.42mmol, 2.2eq), and with this reaction stirring.After several hours, begin to form white precipitate in this solution; This reaction can be heated to 5 ℃ to quicken this reaction.When reaction finishes, exist seldom or do not have an initiator.Water is joined in this solution, again this mixture is cooled off in ice bath.The gained white solid is collected and vacuum-drying by filtering.
Method K: total method of condensation reaction:
As follows with 1,2,3,4,6,7,8,9-octahydro-quinolizine perchlorate (17.8mmol, 1.2eq) change enamine into: imines is dissolved among the 1N NaOH (10mL) and with this solution with 2 * 20mL extracted with diethyl ether.Extract is merged drying, and vacuum-evaporation obtains white solid.This solid is dissolved in the diox (10mL).(14.8mmol 1eq) is dissolved in diox (10mL) and joining in this enamine with 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid methyl or benzyl acid amides.This solution refluxed 19 hours, formed white precipitate.This mixture cools off in ice bath, and filters and collect the gained solid.With a small amount of CH of this solid 3CN washing and 50 ℃ of following vacuum-dryings 24 hours.
Embodiment 31
8,9,11,12,13,13a, 14,14a-octahydro-N, 2-dimethyl-pyrrolo-[3 ', 2 ': 5,6] [1]-chromene is [3,2-i] quinolizine-1-methane amide also
Steps A:
4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid methyl nitrosourea is synthetic by intermediate W according to method J.Yield: 0.186g (63.2%); Mp:＞210 ℃ of decomposition;
IR:3319,1615,1515,1433,1218,801cm -1.1H NMR (DMSO-d 6) δ: 2.14 (s, 6H, CH 2N (CH 3) 2), 2.28 (s, 3H, ArCH 3), 2.70 (d, J=3.91Hz, 3H, CONHCH 3), 3.69 (s, 2H, CH 2N (CH 3) 2), 6.48 (d, J=8.55Hz, 1H, ArH), 6.97 (d, J=8.55Hz, 1H, ArH), 8.06 (s, 1H, CONHCH 3), 10.88 (s, 1H, indoles NH) .MS (APCI+): m/z262.1 (MH +); C 14H 19N 3O 2Computational analysis value: C, 64.35, H, 7.33, N, 16.08. measured value: C, 64.26, H, 7.44, N, 15.87.
Step B:
8,9,11,12,13,13a, 14,14a-octahydro-N, 2-dimethyl pyrrole also [3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-methane amide is synthetic according to method K.Yield: 0.057g (9.8%); Mp:＞210 ℃ of decomposition;
IR:3392,3057,2935,2857,1625,1429,1215cm -1 1H NMR (DMSO-d 6) δ 1.08-1.54 (m, 9H, fatty CH 2And CH), 1.63-1.69 (m, 1H, fatty CH), 1.81-1.93 (m, 1H, fatty CH), 2.27 (s, 3H, ArCH 3), 2.31-2.45 (m, 3H are blured by the DMSO peak, fatty CH), 2.63-2.69 (m, 1H, fatty CH), 2.68 (d, J=3.91Hz, 3H, CONHCH 3), 2.87-2.95 (m, 1H, fatty CH), 3.05 (dd, J=18.3,5.37Hz, 1H, fatty CH), 6.49 (d, J=8.79Hz, 1H, ArH), 6.94 (d, J=8.79Hz, 1H, ArH), 7.70-7.75 (m, 1H, CONHCH 3), 10.9 (s, 1H, NH); MS (APCI+): m/z354.2 (MH +); C 21H 27N 3O 20.5C 4H 8O 2(CH 3CO 2Et)
Computational analysis value: C, 69.49, H, 7.86, N, 10.57. measured value: C, 69.64, H, 7.75, N, 10.54.
Embodiment 32
8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-N-(phenyl methyl)-pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-methane amide also
Steps A:
4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl acid amides is synthetic by intermediate X according to method J.
Yield: 0.582g (69.2%); Mp:208-210 ℃;
IR:3312,1610,1510,1437,1207,747,697 (cm -1). 1H NMR (DMSO-d 6) δ: 2.05 (s, 6H, CH 2N (CH 3) 2), 2.31 (s, 3H, ArCH 3), 3.67 (s, 2H, CH 2N (CH 3) 2), 4.40 (d, J=5.86Hz, 2H, CONHCH 2), 6.46 (d, J=8.55,1H, ArH), 6.98 (d, J=8.55,1H, ArH), 7.18-7.34 (m, 5H, ArH), 8.63 (t, J=5.86,1H, CONHCH 2), 10.76 (s, 1H, aromatics OH), 10.91 (s, 1H, indoles NH) .MS (APCI+): m/z338.2 (MH +); C 20H 23N 3O 2The computational analysis value; C, 71.19, H, 6.87, N, 12.45. measured value: C, 70.82, H, 6.86, N, 12.24.
Step B:
Embodiment 32 is synthetic according to method K.Yield: 0.228g (35.9%); Mp:235-237 ℃;
IR:3177,2929,1627,1429,1089cm -1. 1H NMR (DMSO-d 6) δ 1.08-1.17 (m, 3H, fatty CH 2And CH), 1.35-1.61 (m, 7H, fatty CH 2And CH), 1.85-1.88 (m, 1H, fatty CH), 2.26-2.45 (m, 3H are blured by the DMSO peak, fatty CH), 2.29 (s, 3H, ArCH 3), 2.61-2.67 (m, 1H, fatty CH), 2.82-2.88 (m, 1H, fatty CH), 2.97 (dd, J=17.6,6.59Hz, 1H, fatty CH), 4.33-4.43 (m, 2H, CONHCH 2Ph), 6.49 (d, J=8.55Hz, 1H, ArH), 6.94 (d, J=8.55Hz, 1H, ArH), 7.17-7.31 (m, 5H, ArH), 8.36 (t, J=6.10Hz, 1H, CONHCH 2Ph), 10.9 (s, 1H, indoles NH); MS (APCI+): m/z430.2 (MH +); C 27H 31N 3O 20.1C 4H 8O 2Computational analysis value: C, 75.07, H, 7.31, N, 9.59. measured value: C, 74.99, H, 7.33, N, 9.54.
Embodiment 33
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-methane amide also, N-ethyl-8,9,11,12,13, and 13a, 14,14a-octahydro-2-methyl-
Figure A9981647501191
Steps A: 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid buserelin
Under nitrogen atmosphere, (3.28g 17.2mmol) is dissolved in exsiccant DMF (20mL) and be cooled to 0 ℃ in ice-water bath with 5-hydroxy-2-methyl-1-H-indolecarboxylic acid.In this solution, add successively triethylamine (2.39mL, 17.2mmol) and solid O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea (uronium) hexafluorophosphate (6.51g, 17.2mmol).Stirred 15 minutes under the gained reaction mixture room temperature, fed gas ethamine 10 minutes.Stirred 15 minutes and at room temperature stirred 15 minutes at 0 ℃ successively, reaction mixture mixes with 60mL EtOAc, and the gained mixture is used the 1N HCl aqueous solution successively, and (2 * 60mL), (2 * 60mL) wash salt solution, and use dried over sodium sulfate.This solution for vacuum concentration obtains solid.Crude product then obtains the pure title compound of 0.81g (18%) further by flash chromatography purifying (100%EtOAc) with re-crystallizing in ethyl acetate, be white solid: mp199-201 ℃ (decomposition);
IR3372,1609,1523,1464,1246,1216,1193cm -1 1H NMR (DMSO-d 6) δ 1.11 (t, J=7.14Hz, 3H, CH 2CH 3), 2.48 (s, 3H, ArCH 3), 3.25 (quintet, J=6.96Hz, 2H, NHCH 2CH 3), 6.54 (dd, J=8.61,2.20Hz, 1H, ArH), 7.06 (d, J=8.42Hz, 1H, ArH), 7.09 (d, J=2.01Hz, 1H, ArH), 7.23 (t, J=5.68Hz, 1H, NHEt), 8.70 (s, 1H, NH), 11.1 (bs, 1H, OH); MS (APCI +): m/z219.1 (MH +) .C 12H 14N 2O 20.13H 2O computational analysis value: C, 65.34; H, 6.52; N, 12.70. measured value: C, 65.00; H, 6.38; N, 12.64.
Step B:4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethanamide
With 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethanamide (0.708g 3.24mmol) mixes with 7mL EtOH, add dimethylamine agueous solution (40%, 0.895mL, 7.13mmol), then add the HCHO aqueous solution (37%, 0.315g, 3.89mmol).Obtain limpid reaction soln.Stirred 2 hours under the gained reaction mixture room temperature, form precipitation during this.Filter the pure title compound that also vacuum-drying obtains 0.298g (33%), be white solid: mp198-200 ℃ (decomposition);
IR3346,3189,2986,1615,1436,1215,801cm -1 1H NMR (DMSO-d 6) δ 1.11 (t, J=7.14Hz, 3H, CH 2CH 3), 2.18 (s, 6H, N (CH 3) 2), 2.32 (s, 3H, ArCH 3), 3.24 (quintet, J=6.78Hz, 2H, CH 2CH 3), 3.78 (s, 2H, ArCH 2NMe 2), 6.50 (d, J=8.42Hz, 1H, ArH), 7.01 (d, J=8.61Hz, 1H, ArH), 10.6 (bs, 1H, exchangeable protons), 10.9 (bs, 1H, exchangeable protons); MS (APCI +): m/z276.1 (MH +) .C 15H 21N 3O 2Computational analysis value: C, 65.43; H, 7.69; N, 15.26. measured value: C, 65.24; H, 7.73; N, 14.92.
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-methane amide also, N-ethyl-8,9,11,12,13, and 13a, 14,14a-octahydro-2-methyl-
In the mixture of perchlorate (embodiment 3, step B for 263mg, 1.11mmol) and 30mL ether, add 40mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layerly, water layer is with extracted with diethyl ether (2 * 40mL).With the ether layer that merges with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 20mL diox, and (234mg, 0.851mmol), the gained reaction mixture refluxed 16 hours under nitrogen atmosphere to add 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid buserelin then.This reaction mixture is cooled to room temperature and vacuum concentration obtains brown solid.Crude product acetonitrile recrystallization is further purified the pure title compound that (10%MeOH is in chloroform) obtains 0.070g (17%) by chromatogram then, is yellow solid: mp264-266 ℃ (decomposition);
IR3313,2930,1623,1604,1435,1216,872cm -1 1H NMR (DMSO-d 6) δ 1.08 (t, J=7.14Hz, 3H, CH 2CH 3), 1.18-1.58 (m, 9H, fatty CH 2And CH), 1.71-1.75 (m, 1H, fatty CH), 1.92-1.96 (m, 1H, fatty CH) 2.32 (s, 3H, ArCH 3), 2.38-2.49 (m is blured by the DMSO peak, 3H, fatty CH), 2.66-2.73 (m, 1H, fatty CH and CH 2), 2.90-2.94 (m, 1H, fatty CH), 3.10 (dd, J=18.3,6.78Hz, 1H, fatty CH), 3.23 (quintet, J=6.78Hz, NHCH 2CH 3), 6.53 (d, J=8.79Hz, 1H, ArH), 6.98 (d, J=8.61Hz, 1H, ArH), 7.87 (t, J=5.68Hz, 1H, NHEt), 10.9 (bs, 1H, exchangeable protons); MS (APCI +): m/z368.2 (MH +) .C 22H 29N 3O 2Computational analysis value: C, 71.90; H, 7.95; N, 11.43. measured value: C, 71.52; H, 7.97; N, 11.25.
Embodiment 34
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formaldehyde also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-
Figure A9981647501211
To DMF (642 μ L, CH 8.29mmol) 2Cl 2In the solution, under nitrogen atmosphere, drip POCl 3(736 μ L, 7.89mmol).Stir under the room temperature after 10 minutes, add pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-(embodiment 4,1.17g, 3.95mmol).After showing that by TLC reaction is finished, be poured into this reaction mixture in the 300mL saturated sodium bicarbonate aqueous solution and vigorous stirring 10 minutes.Gained mixture CHCl 3(4 * 100mL) extraction, the organic phase of merging wash with water (1 * 200mL) and salt solution (1 * 200mL), use dried over sodium sulfate, and vacuum concentration obtains golden solid.Crude product is further by flash chromatography purifying (25% acetone is in EtOAc).Use EtOH/Et 2The O recrystallization obtains the pure title compound of 0.63g (49%), is white solid: mp262 ℃ (decomposition);
IR3178,2931,1633,1617,1484,1474,1436,1391,1130,1085,868,772cm -1 1HNMR (DMSO-d 6) δ 1.14-1.59 (m, 9H, fatty CH 2And CH), 1.75-1.87 (m, 2H, fatty CH), 2.34-2.54 (m is blured by the DMSO peak, 2H, fatty CH), 2.56 (s, 3H, ArCH 3), 2.63-2.70 (m, 1H, fatty CH), 2.83-2.90 (m, 2H, fatty CH), 3.22-3.29 (m, 1H, blured fatty CH by the water peak), 6.60 (d, J=8.55Hz, 1H, ArH), 7.04 (d, J=8.55Hz, 1H, ArH), 10.0 (s, 1H, ArCHO), 11.9 (bs, 1H, exchangeable protons); MS (APCI +): m/z325.2 (MH +) .C 20H 24N 2O 2Computational analysis value: C, 74.05; H, 7.46; N, 8.63. measured value: C, 73.97; H, 7.48; N, 8.58.
Embodiment 35
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, methyl esters
Figure A9981647501221
Steps A: 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid methyl esters
Synthetic method sees that the Nenitzescu of 5-oxyindole is synthetic, Patrick, James B.; Saunders, Elizabeth K., Tetrahedron Lett., 1979; 42:4009-4012.
Step B:4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid methyl esters
With 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid methyl esters (10.0g, 49.0mmol) and dimethylamine agueous solution (40%, 12.0mL 107mmol) mixes with 32mL EtOH, add then the HCHO aqueous solution (37%, 4.75mL, 58mmol).Stirred 16 hours under the room temperature, this reaction mixture is mixed with 100mL water.The gained mixture with EtOAc (3 * 100) extraction, the organic phase water of merging (1 * 100mL) and salt solution (1 * 100mL) washing, with dried over sodium sulfate and the filtration.This filtrate is handled with hydrogen chloride gas, forms precipitation and passes through filtering separation.Obtain the 3.88g white solid with hot acetone (150mL) grinding.This white solid is suspended among the 150mLEtOAc, and mixes, this mixture is stirred to the acquisition clear solution with 10% wet chemical of 100mL, be divided into two-layer, with this water layer with ethyl acetate extraction (50mL).The organic phase that merges obtains the filbert crystallization of 3.22g (25%) with dried over sodium sulfate and vacuum concentration.The crude product of short run is obtained pure title compound with the acetone recrystallization, be white crystals: mp145-146 ℃;
1H NMR (CDCl 3) δ 2.33 (s, 6H, N (CH 3) 2), 2.55 (s, 3H, ArCH 3), 3.84 (s, 3H, CO 2CH 3), 4.19 (s, 2H, ArCH 2NMe 2), 6.72 (d, J=8.55Hz, 1H, ArH), 7.04 (d, J=8.55Hz, 1H, ArH); MS (APCI +): m/z263.1 (MH +) .C 14H 18N 2O 3Computational analysis value: C, 64.11; H, 6.92; N, 10.68. measured value: C, 63.77; H, 6.85; N, 10.54.
Step C:
In the mixture of perchlorate (embodiment 3, step B for 2.17g, 9.10mmol) and 50mL ether, add 50mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layer, water layer with ether (2 * 50mL) extraction.The ether layer that merges is with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 8mL diox, and (2.00g 7.60mmol), refluxes the gained reaction mixture 2.5 hours under nitrogen atmosphere, then stirs 16 hours under the room temperature to add indoles mannich alkali then.This reaction mixture vacuum concentration is obtained heavy-gravity oily matter.Obtain the pure title compound of 1.75g (63%) with the acetonitrile recrystallization, be white solid: mp205-205.5 ℃;
IR3242,2938,1696,1441,1236,1079,884cm -1 1H NMR (CDCl 3) δ 1.21-1.80 (m, 9H, fatty CH 2And CH), 1.82-1.95 (m, 1H, fatty CH), 2.09-2.13 (m, 1H, fatty CH), (m, 2H is by ArCH for 2.41-2.77 3The peak is fuzzy, fatty CH), 2.77 (s, 3H, ArCH 3), 2.82-2.86 (m, 2H, fatty CH), 3.00-3.07 (m, 1H, fatty CH), 3.44 (dd, J=18.1,6.59Hz, 1H, fatty CH), 3.83 (s, 3H, CO 2CH 3), 6.73 (d, J=8.55Hz, 1H, ArH), 7.01 (d, J=8.79Hz, 1H, ArH), 8.12 (bs, 1H, NH); MS (APCI +): m/z355.2 (MH +) .C 21H 26N 2O 3Computational analysis value: C, 71.16; H, 7.39; N, 7.90. measured value: C, 71.17; H, 7.32; N, 8.00.
Embodiment 36
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,12, the 12-trimethylammonium-, the phenyl methyl esters
And/or
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,10, the 10-trimethylammonium-, the phenyl methyl esters
Figure A9981647501241
Steps A: 4,4-dimethyl-1,2,3,4,6,7,8,9-octahydro-quinolizine perchlorate
Figure A9981647501242
Adopt Evans, D.A.; Domeier, L.A.Org Synth Coll Vol VI, the method for describing among the p819 is by 1-chloro-3-iodo propane and 2,3,4,5-tetrahydrochysene-2,2,6 trimethylpyridines are synthetic 4,4-dimethyl-1,2,3,4,6,7,8,9-octahydro-quinolizine perchlorate. 1H NMR (400MHz, CDCl 3) δ 1.52 (s, 6H, ℃ (CH 3) 2), 1.75-1.86 (m, 4H, aliphatic CH), 1.88-2.00 (m, 4H, aliphatic CH), 2.80-2.87 (m, 4H, aliphatic CH), 2.65-2.75 (m, 2H, NCH 2); MS (APCI +) m/z166.1 (female MH +).
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,12, the 12-trimethylammonium-, the phenyl methyl esters
And/or
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,10, the 10-trimethylammonium-, the phenyl methyl esters
4 of monovalent, 4-dimethyl-1,2,3,4,6,7,8, (1.45mmol 0.385g) is dissolved in minimum water and also handles to strong basicity with 50% aqueous sodium hydroxide solution 9-octahydro-quinolizine perchlorate.With this aqueous solution with 4 * 20mL Et 2O extracts and the extract that merges is washed with 1 * 20mL saturated sodium-chloride water solution, uses dried over mgso, filter, and concentrated this enamine that obtains.This resistates be dissolved in diox (14mL) and add 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (1.45mmol, 0.490g).This reaction mixture was heated 18 hours under 90 ℃ of nitrogen atmosphere, be cooled to room temperature, and concentrate.With this thick resistates by flash column chromatography purifying on silica gel, with 100% eluent ethyl acetate and with ether grind the pyrrolo-obtain 90mg (14%) [3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,12, the 12-trimethylammonium-, phenyl methyl esters and/or pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,10, the 10-trimethylammonium-, the phenyl methyl esters is yellow foam:
IR (KBr) 3383,2932,2857,1675,1432,1090,1072cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.07 (s, 3H, CH 3), 1.23 (s, 3H, CH 3), 1.09-1.26 (m, 5H, fatty CH), 1.42-1.61 (m, 6H, fatty CH), 1.90 (d, J=12.70Hz, 1H, fat CH), 2.58 (d, J=18.56Hz, 1H, fatty CH), (2.64-2.75 m, 3H, fatty CH), 3.11-3.19 (m, 2H, fatty CH), 3.24-3.30 (m, 1H, fat CH), 5.15-5.25 (m, 2H, OCH 2Ar), 6.52 (d, J=8.79Hz, 1H, ArH), 6.99 (d, J=8.55Hz, 1H, ArH), 7.30-7.42 (m, 5H, ArH), 11.50 (s, 1H, NH); MS (APCI +) m/z459.3 (MH +) .C 29H 34N 2O 30.19H 2O computational analysis value: C, 75.39; H, 7.50; N, 6.06; H 2O, 0.74. measured value: C, 75.00; H, 7.73; N, 5.79; H 2O, 0.36.
Embodiment 37
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester Steps A: 6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester
Figure A9981647501262
6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester is according to Littell, R.; Allen, G.R., Jr.J.Org.Chem.1968; The 33:2064 disclosed method is synthetic.
Step B:4-dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (4.51mmol 1.07g) prepares 4-dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester by 6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester according to method G.From then on be settled out this product in the reaction soln by volume is reduced 1/3rd, and obtain orange solid (0.510g, 38%): mp174-176 ℃ (decomposition) with the acetonitrile recrystallization;
IR (KBr) 3278,2975,1692,1443,1124,1078cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.32 (t, J=7.08Hz, 3H, OCH 2CH 3), 2.26 (s, 6H, N (CH 3) 2), 2.50 (s, 3H, ArCH 3), 4.17 (s, 2H, NCH 2Ar), 4.24 (q, J=7.08Hz, 2H, OCH 2CH 3), 7.05 (d, J=10.50Hz, 1H, ArH), 11.56 (bs, 1H, NH); 19F NMR (DMSO-d 6) δ-141.69 (d, J=10.68Hz); MS (APCI +) m/z295.1 (MH +) .C 15H 19F 1N 2O 3Computational analysis value: C, 61.21; H, 6.51; N, 9.52; F, 6.45. measured value: C, 61.32; H, 6.55; N, 9.51; F, 6.61.
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1.66mmol 0.488g) synthesizes ethyl ester by 4-dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester according to method I.With this compound by silica gel flash column chromatography purifying (50: 50 ethyl acetate: hexane) and with re-crystallizing in ethyl acetate obtain white solid (32%): mp184-186 ℃;
IR (KBr) 3367,2932,2858,1670,1456,1437,1135cm -1 1H NMR (400MHz, CDCl 3) δ 1.37 (t, J=7.08Hz, 3H, OCH 2CH 3), 1.25-1.47 (m, 4H, fatty CH), 1.60-1.78 (m, 5H, fatty CH), 1.85-1.95 (m, 1H, fatty CH), 2.09 (bd, J=13.43Hz, 1H, fatty CH), 2.43-2.49 (m, 2H, fatty CH), 2.57 (s, 3H, ArCH 3), 2.87-2.92 (m, 2H, fatty CH), 3.05-3.18 (m, 1H, fatty CH), 3.43-3.50 (m, 1H, fatty CH), 4.32 (q, J=7.08Hz, 2H, OCH 2CH 3), 6.86 (d, J=10.01Hz, 1H, ArH), 8.09 (bs, 1H, NH); 19F NMR (CDCl 3) δ-140.62 (d, J=10.68Hz); MS (APCI +) m/z387.1 (MH +) .C 22H 27F 1N 2O 3Computational analysis value: C, 68.37; H, 7.04; N, 7.25; F, 4.92. measured value: C, 68.30; H, 7.11; N, 7.09; F, 4.97.
Embodiment 38
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters Steps A: 6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid
With 6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (embodiment 37, steps A, 9.02mmol 2.14g) was dissolved in 40mL 2N sodium hydroxide and reflux 1 hour.This solution is cooled to 0 ℃ and also is acidified to pH9 with concentrated hydrochloric acid carefully.This solution dichloromethane extraction is removed extract and under 0 ℃ water layer further is acidified to pH4 with concentrated hydrochloric acid.Leach precipitation and vacuum-drying and obtained dark pink solid (1.16g, 62%) in 18 hours: mp202-204 ℃ (decomposition);
IR(KBr)3584，3358，1649，1471，1109cm -1； 1H?NMR(400MHz，DMSO-d 6)δ2.53(s，3H，ArCH 3)，7.04(d，J＝11.23Hz，1H，ArH)，7.46(d，J＝9.03Hz，1H，ArH)，9.17(s，1H，ArOH)，11.46(s，1H，NH?or?COOH)，11.76(s，1H，COOH?or?NH)； 19F?NMR(DMSO-d 6)δ-141.60(t，J＝10.68Hz)；MS(APCI-)m/z208.0(M-1).
Step B:6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester
Figure A9981647501291
Under the room temperature nitrogen atmosphere, to 6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (4.92mmol, 1.03g) in the suspension of 10.0mL DMF, drip 1 by syringe, 8-diazabicylo [5.4.0] 11 carbon-7-alkene (4.92mmol, 0.736mL), then add bromotoluene (5.42mmol, 0.644mL).After 48 hours, add entry (10mL), and leach precipitation, drying, and obtain white, cotton shape solid (0.677g, 46%) with the chloroform recrystallization: mp191-193 ℃; IR (KBr) 3384,3254,1662,1475,1327,1129,1098cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.59 (s, 3H, ArCH 3), 5.32 (s, 2H, OCH 2C 6H 5), 7.12 (d, J=10.99Hz, 1H, ArH), 7.31-7.49 (m, 6H, ArH), 9.29 (s, 1H, ArOH), 11.67 (s, 1H, NH); 19F NMR (DMSO-d 6) δ-140.96-141.01 (m); MS (APCI-) m/z298.1 (M-1) .C 17H 14F 1N 1O 30.04H 2O computational analysis value: C, 68.06; H, 4.73; N, 4.67; F, 6.33; H 2O, 0.24. measured value: C, 67.69; H, 4.63; N, 4.57; F, 6.61; H 2O, 0.10.
Step C:4-dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester
With 6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (2.26mmol, 0.677g) and N, N, N ', N '-tetramethyl-diamino methane (2.49mmol, 5mL dioxane solution 0.34mL) reflux 21 hours under nitrogen atmosphere.The N that adds another equal portions, N, N ', (2.49mmol 0.34mL), and with this reaction continuation backflow 24 hours, is cooled to room temperature, and concentrates N '-tetramethyl-diamino methane.This resistates obtains faint yellow solid (0.260g, 32%) with re-crystallizing in ethyl acetate: mp167-169 ℃;
IR(KBr)3280，2951，1692，1443，1123，1081cm -1； 1H?NMR(400MHz，DMSO-d 6)δ2.12(s，6H，N(CH 3) 2)，2.44(s，3H，ArCH 3)，4.04(s，2H，NCH 2Ar)，5.23(s，2H，OCH 2C 6H 5)，7.01(d，J＝10.50Hz，1H，ArH)，7.31-7.44(m，5H，ArH)，11.57(s，1H，NH)； 19F?NMR(DMSO-d 6)δ-141.55(d，J＝10.68Hz)；MS(APCI +)m/z357.1(MH +).C 20H 21F 1N 2O 3·0.07C 4H 8O 2
Computational analysis value: C, 67.18; H, 5.99; N, 7.73; F, 5.24. measured value: C, 66.81; H, 6.20; N, 7.74; F, 5.49.
Step D: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters according to method I by 4-dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.601mmol, 0.214g), synthesized in 40 hours 80 ℃ of heating.This product is by silica gel flash column chromatography purifying (30-50% ethyl acetate/hexane) and obtain white solid (0.169g, 63%) with the ether recrystallization: mp179-181 ℃;
IR (KBr) 2932,2857,1699,1453,1131,1075cm -1 1H NMR (400MHz, CDCl 3) δ 1.17-1.38 (m, 3H, fatty CH), 1.41-1.48 (m, 1H, fatty CH), 1.55-1.85 (m, 6H, fatty CH), 2.03 (bd, J=12.94Hz, 1H, fatty CH), 2.42-2.48 (m, 2H, fatty CH), 2.55 (s, 3H, ArCH 3), 2.79 (d, J=17.58Hz, 1H, fatty CH), 2.85-2.92 (m, 1H, fatty CH), 3.04-3.17 (m, 1H, fatty CH), 3.35 (dd, J=18.31,6.51Hz, 1H, fatty CH), 5.25-5.37 (m, 2H, OCH 2C 6H 5), 6.86 (d, J=10.25Hz, 1H, ArH), 7.28-7.38 (m, 3H, ArH), 7.40-7.44 (m, 2H, ArH), 8.07 (bs, 1H, NH); 19F NMR (CDCl 3) δ-142.0 (m); MS (APCI +) m/z449.1 (MH +) .C 27H 29F 1N 2O 3Computational analysis value: C, 72.30; H, 6.52; N, 6.25; F, 4.24. measured value: C, 72.28; H, 6.45; N, 6.09; F, 4.50.
Embodiment 39
The 12H-furo [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluorine 7,8,9,10,13,14,14a, 15-octahydro-2-methyl-, ethyl ester
Figure A9981647501311
Steps A: 6-fluoro-5-hydroxy-2-methyl-cumarone-3-ethyl formate
Figure A9981647501312
To 2-fluoro-[1,4] benzoquinones (38.3mmol, in 300mL glacial acetic acid solution 4.82g), add 3-amino-but-2-ene acetoacetic ester (31.9mmol, 4.12g).This vlil 1.5 hours is cooled to room temperature, and concentrates.This product separates (30-50% ethyl acetate/hexane) by the silica gel flash column chromatography and obtains yellow solid (0.456g, 6%): mp138-139 ℃;
IR (KBr) 3284,2991,1680,1469,1422,1326,1110cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.36 (t, J=7.08Hz, 3H, OCH 2CH 3), 2.68 (s, 3H, ArCH 3), 4.32 (q, J=7.08Hz, 2H, OCH 2CH 3), 7.43 (d, J=8.79Hz, 1H, ArH), 7.55 (d, J=10.74Hz, 1H, ArH), 9.82 (s, 1H, ArOH); 19FNMR (DMSO-d 6) δ-137.42 (t, J=9.16Hz); MS (APCI-) m/z237.1 (M-1) .C 12H 11F 1O 4Computational analysis value: C, 60.50; H, 4.65; F, 7.98. measured value: C, 60.50; H, 4.46; F, 8.20
Step B:4-dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-cumarone-3-ethyl formate
With 6-fluoro-5-hydroxy-2-methyl-cumarone-3-ethyl formate (1.90mmol, 0.452g) and N, N, N ', N '-tetramethyl-diamino methane (2.09mmol, 4mL dioxane solution 0.285mL) reflux 4.5 hours under nitrogen atmosphere, be cooled to room temperature, and concentrate.(10mL) joins in this resistates with water, and leaches gained precipitation, drying, and obtain faint yellow solid (0.225g, 40%) with the t-butyl methyl ether recrystallization: mp120-122 ℃; IR (KBr) 2989,1706,1446,1384,1322,1120cm -1 1HNMR (400MHz, DMSO-d 6) δ 1.34 (t, J=7.08Hz, 3H, OCH 2CH 3), 2.21 (s, 6H, N (CH 3) 2), 2.57 (s, 3H, ArCH 3), 4.03 (s, 2H, NCH 2Ar), 4.32 (q, J=7.08Hz, 2H, OCH 2CH 3), 7.48 (d, J=10.25 Hz, 1H, ArH); 19F NMR (DMSO-d 6) δ-137.69 (d, J=10.68Hz); MS (APCI +) m/z296.1 (MH +) .C 15H 18F 1N 1O 4Computational analysis value: C, 61.01; H, 6.14; N, 4.74; F, 6.43. measured value: C, 61.06; H, 6.07; N, 4.61; F, 6.47.
Step C:12H-furo [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluoro-7,8,9,10,13,14,14a, 15-octahydro-2-methyl-, ethyl ester
The 12H-furo [3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 5-fluoro-7,8,9,10,13,14,14a, 15-octahydro-2-methyl-, ethyl ester is according to (90 ℃ of method I, 21 hours) (0.603mmol 0.178g) synthesizes by 4-dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-cumarone-3-ethyl formate.This product is by silica gel flash column chromatography purifying (30% ethyl acetate/hexane) and obtain white solid (0.210g, 90%) with the ether recrystallization: mp147-149 ℃;
IR (KBr) 2936,2848,1717,1453,1242,1125cm -1 1H NMR (400MHz, CDCl 3) δ 1.25-1.37 (m, 2H, fatty CH), 1.38 (t, J=7.08Hz, 3H, OCH 2CH 3), 1.40-1.52 (m, 2H, fatty CH), 1.57-1.80 (m, 5H, fatty CH), 1.84-1.96 (m, 1H, fatty CH), 2.02 (d, J=13.43Hz, 1H, fatty CH), 2.42-2.58 (m, 2H, fatty CH), 2.61 (s, 3H, ArCH 3), 2.83-2.91 (m, 1H, fatty CH), 2.90 (d, J=17.82Hz, 1H, fatty CH), 3.06-3.16 (m, 1H, fatty CH), 3.34-3.40 (m, 1H, fatty CH), 4.34 (q, J=7.08Hz, 2H, OCH 2CH 3), 7.03 (d, J=9.77Hz, 1H, ArH); 19F NMR (CDCl 3) δ-137.90 (d, J=9.16Hz); MS (APCI +) m/z388.2 (MH +) .C 22H 26F 1N 1O 4Computational analysis value: C, 68.20; H, 6.76; N, 3.62; F, 4.90. measured value: C, 68.12; H, 6.84; N, 3.56; F, 4.96.
Embodiment 40
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 4,5-two fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters Steps A: 2,3-two fluoro-benzene-1,4-glycol
2, (Aldrich, 183.2mmol 24.32g) use the nitric acid Potassium Persulphate according to following method: Feiring, A.E. to the 3-difluorophenol; Sheppard, W.A.J.Org.Chem.1975; The 40:2543 oxidation.Crude product is by silica gel flash column chromatography purifying (10% acetonitrile/chloroform) and obtain faint yellow solid (7.32g, 27%) with the chloroform recrystallization: mp156-158 ℃; IR (KBr) 3343 (br), 1514,1505,1259,1199,1041cm -1 1H NMR (400MHz, DMSO-d 6) δ 6.52 (d, J=5.37Hz, 2H, ArH), 9.45 (s, 2H, ArOH); 19F NMR (DMSO-d 6) δ-159.78 (d, J=4.58Hz); MS (APCI-) m/z145.0 (M-1) .C 6H 4F 2O 2Computational analysis value: C, 49.33; H, 2.76; F, 26.01. measured value: C, 49.09; H, 2.73; F, 26.37.
Step B:2,3-two fluoro-[1,4] benzoquinones
Figure A9981647501341
With 2,3-two fluoro-benzene-1, (49.1mmol is 7.17g) with cerous nitrate (IV) ammonium, according to following method: Feiring, A.E. for the 4-glycol; Sheppard, W.A.J.Org.Chem.1975; The 40:2543 oxidation obtains glassy yellow solid (6.63g, 94%): mp97.0-98.5 ℃; IR (KBr) 3352,1684,1333cm -1 1H NMR (400MHz, DMSOd6) δ 6.98 (s, 2H, ArH); 19F NMR (DMSO-d 6) δ-144.85 (s); MS (APCI-) m/z144.0 (M-).Analysis theories value C 6H 2F 2O 2: C, 50.02; H, 1.40; F, 26.37.Measured value: C, 49.89; H, 1.31; F, 26.19.
Step C:6,7-two fluoro-5-hydroxy-2-methyls-1H-indole-3-carboxylic acid benzyl ester
Figure A9981647501342
To 2, and 3-two fluoro-[1,4] benzoquinones (1.26mmol, in 3.4mL glacial acetic acid solution 0.180g), adding 3-amino-but-2-ene acid benzyl ester (1.05mmol, 0.200g).This mixture 50 ℃ of heating 18 hours, is cooled to room temperature, and leaches precipitation.This beige solid is obtained clean product with Glacial acetic acid washing and vacuum-drying.This filtrate that neutralizes adds entry (20mL), and this solution is with ethyl acetate extraction (4 * 20mL).With this resistates dried over mgso, filter, concentrate and with this resistates by silica gel flash column chromatography purifying (20% ethyl acetate/hexane).Merge pure product part and obtain 0.174 mg (52%) pale solid, it uses acetonitrile recrystallization: mp215-217 ℃; IR (KBr) 3457,3243,1658,1480,1338,1150cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.58 (s, 3H, ArCH 3), 5.31 (s, 2H, OCH 2C 6H 5), 7.29-7.45 (m, 6H, ArH), 9.75 (s, 1H, ArOH), 12.13 (s, 1H, NH); MS (APCI +) m/z318.0 (MH +) .C 17H 13F 2N 1O 30.04C 2H 4O 2Computational analysis value: C, 64.17; H, 4.15; N, 4.38; F, 11.89. measured value: C, 63.80; H, 4.15; N, 4.05; F, 12.18.
Step D:4-dimethylaminomethyl-6,7-two fluoro-5-hydroxy-2-methyls-1H-indole-3-carboxylic acid benzyl ester
Figure A9981647501351
By 6, (8.08mmol 2.56g) prepares 7-two fluoro-5-hydroxy-2-methyls-1H-indole-3-carboxylic acid benzyl ester according to method G for 4-dimethylaminomethyl-6,7-two fluoro-5-hydroxy-2-methyls-1H-indoles 3-benzyl formate.Heating was 21 hours under this was reflected at 50 ℃, leached precipitation, use washing with alcohol, and drying obtained faint yellow solid (1.49g, 49%): mp159-160 ℃ (decomposition);
IR (KBr) 3235,1688,1438,1365,1301,1123,1083cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.13 (s, 6H, N (CH 3) 2), 2.46 (s, 3H, ArCH 3), 4.00 (s, 2H, ArCH 2N), 5.24 (s, 2H, OCH 2C 6H 5), 7.27-7.38 (m, 3H, ArH), 7.41-7.44 (m, 2H, ArH), 12.08 (s, 1H, NH); 19F NMR (DMSO-d 6) δ-168.26 (d, J=21.4Hz) ,-159.68 (d, J=21.4Hz); MS (APCI +) m/z375.0 (MH +) .C 20H 20F 2N 2O 3Computational analysis value: C, 64.16; H, 5.38; N, 7.48; F, 10.15. measured value: C, 64.00; H, 5.44; N, 7.36; F, 10.15.
Step e: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 4,5-two fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 4,5-two fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters is according to (90 ℃ of method I, 18 hours) by 4-dimethylaminomethyl-6,7-two fluoro-5-hydroxy-2-methyls-1H-indole-3-carboxylic acid benzyl ester (3.82mmol, 1.43g) synthetic.This product obtains the cream-colored solid of 1.37g (77%) by silica gel flash column chromatography purifying (5-10% ethyl acetate/dichloromethane).A part obtains white solid with t-butyl methyl ether/hexane recrystallization: mp159-160 ℃; IR (KBr) 3297,2933,2857,1704,1455,1141,1124cm -1 1H NMR (400MHz, CDCl 3) δ 1.17-1.36 (m, 3H, fatty CH), 1.43-1.49 (m, 1H, fatty CH), 1.57-1.78 (m, 6H, fat CH), 2.00 (d, J=13.7Hz, 1H, fatty CH), 2.46 (d, J=9.77Hz, 1H, fat CH), 2.53-2.57 (m, 1H, fatty CH), 2.57 (s, 3H, ArCH 3), 2.71 (d, J=18.31Hz, 1H, fatty CH), 2.83-2.88 (m, 1H, fatty CH), 3.06-3.16 (m, 1H, fatty CH), 3.24-3.30 (m, 1H, fatty CH), 5.24-5.36 (m, 2H, OCH 2C 6H 5), 7.32-7.38 (m, 3H, ArH), 7.42 (d, J=6.84Hz, 2H, ArH), 8.21 (s, 1H, NH); 19F NMR (CDCl 3) δ-166.80 (d, J=19.84Hz) ,-162.52 (d, J=21.36Hz); MS (APCI +) m/z467.1 (MH +) .C 27H 28F 2N 2O 3Computational analysis value: C, 69.51; H, 6.05; N, 6.00; F, 8.14. measured value: C, 69.36; H, 5.99; N, 5.88; F, 8.37.
Embodiment 41
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 4,5-two chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters
Figure A9981647501371
Steps A: 6,7-two chloro-5-hydroxy-2-methyls-1H-indole-3-carboxylic acid benzyl ester
Figure A9981647501372
6,7-two chloro-5-hydroxy-2-methyls-1H-indole-3-carboxylic acid benzyl ester is by 2,3-two chloro-[1,4] benzoquinones (16.8mmol, 2.98g) and 3-amino-but-2-ene acid benzyl ester (25.3mmol, 4.83g) according to Grinev, A.N.; Zaitsev, I.A.; Shvedov, V.I.; Terent ' ev, A.P.J.Org.Chem.USSR (English); The method preparation of the corresponding ethyl ester of 28:439 report.Yield 0.649g (11%): mp235-236 ℃;
IR (KBr) 3421,3281,1651,1098cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.59 (s, 3H, ArCH 3), 5.29 (s, 2H, OCH 2C 6H 5), 7.30 (t, J=7.08Hz, 1H, ArH), 7.34-7.38 (m, 2H, ArH), 7.42 (d, J=7.32Hz, 2H, ArH), 7.51 (s, 1H, ArH); MS (APCI-) m/z348.0 (M-1) .HPLC (ALLTECH/ALLTIMAC-18,1: 1-2: 98 H 2O/CH 3CN+0.05%TFA): retention time :=6.573min, 98.41% purity.
Step B:4-dimethylaminomethyl-6,7-two chloro-5-hydroxy-2-methyls-1H-indole-3-carboxylic acid benzyl ester
By 6, (3.06mmol 1.07g) prepares 7-two chloro-5-hydroxy-2-methyls-1H-indole-3-carboxylic acid benzyl ester according to method G for 4-dimethylaminomethyl-6,7-two chloro-5-hydroxy-2-methyls-1H-indole-3-carboxylic acid benzyl ester.This is reflected at 50 ℃ of down heating 22.5 hours, concentrates and obtains golden yellow solid (0.830g, 67%) by silica gel flash column chromatography purifying (30-50% acetone/hexane): mp167-170 ℃;
IR (KBr) 3328,1695,1438,1409,1330,1281,1107cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.18 (s, 6H, N (CH 3) 2), 2.52 (s, 3H, ArCH 3), 4.06 (s, 2H, ArCH 2N), 5.27 (s, 2H, OCH 2C 6H 5), 7.30-7.39 (m, 3H, ArH), 7.41-7.47 (m, 2H, ArH), 11.84 (s, 1H, NH); MS (APCI +) m/z407.1 (M +) .C 20H 20Cl 2N 2O 3Computational analysis value: C, 58.98; H, 4.95; N, 6.88; Cl, 17.41. measured value: C, 58.87; H, 4.96; N, 6.68; Cl, 17.23.
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 4,5-two chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 4,5-two chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters according to method I (80 ℃ 18 hours) by 4-dimethylaminomethyl-6,7-two chloro-5-hydroxy-2-methyls-1H-indole-3-carboxylic acid benzyl ester (1.82mmol, 0.742g) synthetic.This product obtains 0.684g (75%) peachiness foam by silica gel flash column chromatography purifying (10% acetone/hexane): mp100-105 ℃;
IR (KBr) 3424,2932,2853,1685,1430,1125,1076cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.00-1.30 (m, 3H, fatty CH), 1.37-1.76 (m, 8H, fatty CH), 2.37-2.40 (m, 1H, fatty CH), 2.46-2.49 (m, 1H, fatty CH), 2.50 (s, 3H, ArCH 3), 2.63-2.69 (m, 2H, fatty CH), 2.95-2.99 (m, 1H, fatty CH), 3.17 (dd, J=18.31,6.74Hz, 1H, fatty CH), 5.23 (dd, J=28.08,12.21Hz, 2H, OCH 2C 6H 5), 7.31-7.39 (m, 3H, ArH), 7.42-7.44 (m, 2H, ArH), 11.85 (s, 1H, NH); MS (APCI +) m/z499.1 (MH +) .C 27H 28Cl 2N 2O 30.07H 2O computational analysis value: C, 64.77; H, 5.66; N, 5.59; Cl, 14.16; H 2O, 0.25. measured value: C, 64.37; H, 5.64; N, 5.51; Cl, 13.96; H 2O, 0.32.
Embodiment 42
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-4,5-dimethoxy-2-methyl-, the phenyl methyl esters Steps A: 6,7-dimethoxy-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester
With 2, (10.4mmol, (8.62mmol is in ethanol 1.65g) (25mL) solution 1.74g) to join 3-amino-but-2-ene acid benzyl ester under 0 ℃ for 3-dimethoxy-[1,4] benzoquinones.This reaction is heated to room temperature, and reflux is 18 hours then.Except that desolvating and this product also being obtained peachiness solid (0.621g, 21%) with the toluene recrystallization by silica gel flash column chromatography purifying (30-50% ethyl acetate/hexane): mp154-156 ℃;
IR (KBr) 3336,3267,1660,1468,1327,1146,1081cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.56 (s, 3H, ArCH 3), 3.73 (s, 3H, OCH 3), 3.89 (s, 3H, OCH 3), 5.29 (s, 2H, OCH 2C 6H 5), 7.11 (s, 1H, ArH), 7.29-7.43 (m, 5H, ArH), 8.79 (s, 1H, ArOH), 11.59 (s, 1H, NH); MS (APCI-) m/z340.0 (M-1) .C 19H 19N 1O 5Computational analysis value: C, 66.85; H, 5.61; N, 4.10 measured values: C, 66.69; H, 5.55; N, 3.79.
Step B:4-dimethylaminomethyl-6,7-dimethoxy-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester
By 6, (1.69mmol 0.577g) prepares 7-dimethoxy-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester according to method G for 4-dimethylaminomethyl-6,7-methoxyl group-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester.This is reflected at 50 ℃ of down heating 18 hours, concentrates and also obtains lemon yellow solid (0.274g, 41%) with the hexanaphthene recrystallization by silica gel flash column chromatography purifying (0-3% triethylamine/ethyl acetate): mp132-134 ℃;
IR (KBr) 3312,1698,1440,1415,1290,1129cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.10 (s, 6H, N (CH 3) 2), 2.44 (s, 3H, ArCH 3), 3.73 (s, 3H, ArOCH 3), 3.86 (s, 3H, ArOCH 3), 3.94 (s, 2H, ArCH 2N), 5.21 (s, 2H, OCH 2C 6H 5), 7.29-7.38 (m, 3H, ArH), 7.41-7.43 (m, 2H, ArH), 11.48 (s, 1H, NH); MS (APCI +) m/z399.0 (MH +) .C 22H 26N 2O 5Computational analysis value: C, 66.32; H, 6.58; N, 7.03. measured value: C, 66.47; H, 6.58; N, 6.73.
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-4,5-dimethoxy-2-methyl-, the phenyl methyl esters
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-4,5-dimethoxy-2-methyl-, the phenyl methyl esters is according to (90 ℃ of method I, 21 hours) by 4-dimethylaminomethyl-6,7-dimethoxy-5-hydroxy-2-methyl-1H-indoles 3-benzyl formate (0.595mmol, 0.237g) synthetic.This product is by silica gel flash column chromatography purifying (50% ethyl acetate/hexane) and obtain white solid: mp130-136 ℃ of 0.089g (30%) with the pure isooctane recrystallization;
IR (KBr) 3307,2931,2856,1833,1700,1684,1448,1418,1282,1137,1123cm -1 1H NMR (400MHz, CDCl 3) δ 1.24-1.38 (m, 4H, fatty CH), 1.44-1.55 (m, 1H, fatty CH), 1.59-1.80 (m, 6H, fatty CH), 2.09 (d, J=13.98Hz, 1H, fatty CH), 2.51 (d, J=10.37Hz, 1H, fatty CH), 2.58 (s, 3H, ArCH 3), 2.78 (d, J=18.08Hz, 1H, fatty CH), 2.85-2.91 (m, 1H, fatty CH), 3.08-3.14 (m, 1H, fatty CH), 3.29-3.36 (m, 1H, fatty CH), 3.96 (s, 3H, OCH 3), 4.05 (s, 3H, OCH 3), 5.26-5.37 (m, 2H, OCH 2C 6H 5), 7.31-7.40 (m, 3H, ArH), 7.44 (d, J=6.99Hz, 2H, ArH), 8.29 (s, 1H, NH); MS (APCI +) m/z491.1 (MH +) .HPLC (ALLTECH/ALLTIMA C-18,1: 1-2: 98 H 2O/CH 3CN+0.05%TFA): retention time=4.527min, 100.00% purity.
Embodiment 43
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 5-dimethyl-, the phenyl methyl esters
Figure A9981647501411
Steps A: 6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester
Figure A9981647501421
6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (2.42g, 10%) derives from methyl-[1,4] benzoquinones (Aldrich, 81.9mmol, 10.0g) and 3-amino-but-2-ene acid benzyl ester (79.5mmol, 15.2g), reaction method is according to Allen, G.R., Jr.; Pidacks, C.; Weiss, M.J.J.Am.Chem.Soc.1966; The method of the corresponding ethyl ester of reporting among the 88:2536.The crude product reaction product is made up of the mixture of required 6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester and regional isomer 7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester.These regional isomerism body and functions Poletto, J.F.; Allen, G.R., Jr.; Sloboda, A.E.; Weiss, M.J.J.Med.Chem.1973; The method of the corresponding ethyl ester of reporting among the 16:757 is separated.Every kind of isomer with acetone respectively recrystallization obtain the crystallization of X-x ray level.List-crystal x-ray analysis has pointed out that higher Rf isomer (silica gel, 50% ethyl acetate/hexane) is 6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester: mp196-197 ℃;
IR (KBr) 3399,3314,1655,1469,1438,1086cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.14 (s, 3H, ArCH 3), 2.53 (s, 3H, ArCH 3), 5.28 (s, 2H, OCH 2C 6H 5), 6.99 (s, 1H, ArH), 7.28-7.42 (m, 6H, ArH), 8.81 (s, 1H, ArOH), 11.42 (s, 1H, NH); MS (APCI +) m/z296.0 (MH +) .C 18H 17N 1O 30.25H 2O computational analysis value: C, 72.10; H, 5.88; N, 4.67. measured value: C, 71.72; H, 5.54; N, 4.74.
Step B:4-dimethylaminomethyl-6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester
Figure A9981647501431
(7.48mmol 2.21g) adds dimethylamine and the 26.9mmol prepared formaldehyde of 49.4mmol to 4-dimethylaminomethyl-6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester by 6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester according to method G.This is reflected at 50 ℃ of down heating 70 hours, concentrates and obtains tawny solid (1.67g, 63%) by silica gel flash column chromatography purifying (0-5% triethylamine/ethyl acetate).A part obtains faint yellow solid with re-crystallizing in ethyl acetate: mp162-164 ℃;
IR (KBr) 3313,1688,1432,1227,1119,1075cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.13 (s, 9H, N (CH 3) 2And ArCH 3), 2.44 (s, 3H, ArCH 3), 4.01 (s, 2H, ArCH 2N), 5.22 (s, 2H, OCH 2C 6H 5), 6.95 (s, 1H, ArH), 7.29-7.44 (m, 5H, ArH), 11.40 (s, 1H, NH); MS (APCI +) m/z353.1 (MH +) .C 21H 24N 2O 3Computational analysis value: C, 71.57; H, 6.86; N, 7.95. measured value: C, 71.30; H, 6.92; N, 7.87.
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 5-dimethyl-, the phenyl methyl esters
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 5-dimethyl-, (4.45mmol 1.57g) synthesizes the phenyl methyl esters by 4-dimethylaminomethyl-6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester according to method I (90 ℃, 24 hours).This product obtains yellow solid: mp110-115 ℃ of 0.953g (48%) by silica gel flash column chromatography purifying (the 20-50% acetone/hexane is the 20-40% ethyl acetate/dichloromethane then); IR (KBr) 3379,2931,2857,1673,1425,1123,1071cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.05-1.16 (m, 2H, fatty CH), 1.21-1.25 (m, 1H, fatty CH), 1.33-1.42 (m, 2H, fatty CH), 1.45-1.66 (m, 5H, fatty CH), 1.78 (d, J=13.67Hz, 1H, fatty CH), 2.18 (s, 3H, ArCH 3), 2.34 (d, J=9.28Hz, 1H, fatty CH), 2.44 (s, 3H, ArCH 3), 2.41-2.46 (m, 1H, fatty CH), 2.62-2.70 (m, 2H, fatty CH), 2.87-2.95 (m, 1H, fatty CH), 3.16 (dd, J=18.07,6.59Hz, 1H, fatty CH), 5.19 (dd, J=25.15,12.21Hz, 2H, OCH 2C 6H 5), 6.90 (s, 1H, ArH), 7.28-7.37 (m, 3H, ArH), 7.41 (d, J=6.84Hz, 2H, ArH), 11.37 (s, 1H, NH); MS (APCI +) m/z445.3 (MH +) .C 28H 32N 2O 30.16H 2O
Computational analysis value: C, 75.16; H, 7.28; N, 6.26; H 2O, 0.64. measured value: C, 74.76; H, 7.35; N, 6.07; H 2O, 0.34.
Embodiment 44
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 4-dimethyl-, the phenyl methyl esters
Figure A9981647501441
Steps A: 7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester
Figure A9981647501442
As embodiment 43, in the steps A, by methyl [1,4] benzoquinones (81.9mmol, 10.0g) and 3-amino-but-2-ene acid benzyl ester (79.5mmol, 15.2g) making 7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (2.04g, 8.7% yield) is pale powder.The single crystal x-ray analysis shows that low Rf isomer (silica gel, 50% ethyl acetate/hexane) is 7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester: mp188-189 ℃;
IR (KBr) 3430,3286,1641,1446,1294,1153,1098cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.32 (s, 3H, ArCH 3), 2.58 (s, 3H, ArCH 3), 5.27 (s, 2H, OCH 2C 6H 5), 6.39 (d, J=1.22Hz, 1H, ArH), 7.10 (d, J=1.71Hz, 1H, ArH), 7.26-7.31 (m, 1H, ArH), 7.34-7.38 (m, 2H, ArH), 7.42 (d, J=7.81Hz, 1H, ArH), 8.71 (s, 1H, ArOH), 11.42 (s, 1H, NH); MS (APCI +) m/z296.0 (MH +) .C 18H 17N 1O 3Computational analysis value: C, 73.20; H, 5.80; N, 4.74. measured value: C, 73.02; H, 5.70; N, 4.40.
Step B:4-dimethylaminomethyl-7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester
Figure A9981647501451
4-dimethylaminomethyl-7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester according to method G by 7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (6.62mmol, 1.85g), dimethylamine and the 22.5mmol prepared formaldehyde of 41.3mmol.Heating was 46 hours under this was reflected at 50 ℃, concentrated, and obtained khaki solid (0.900g, 41%) by silica gel flash column chromatography purifying (0-5% triethylamine/ethyl acetate) and with re-crystallizing in ethyl acetate: mp161-164 ℃;
IR (KBr) 3307,1684,1292,1220,1070cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.08 (s, 6H, N (CH 3) 2), 2.30 (s, 3H, ArCH 3), 2.47 (s, 3H, ArCH 3), 3.89 (s, 2H, ArCH 2N), 5.22 (s, 2H, OCH 2C 6H 5), 6.37 (s, 1H, ArH), 7.28-7.38 (m, 3H, ArH), 7.43 (d, J=7.08Hz, 2H, ArH), 11.28 (s, 1H, NH); MS (APCI +) m/z353.2 (MH +) .C 21H 24N 2O 3Computational analysis value: C, 71.57; H, 6.86; N, 7.95. measured value: C, 71.20; H, 6.82; N, 7.79.
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 4-dimethyl-, the phenyl methyl esters
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 4-. dimethyl-, the phenyl methyl esters according to method I (80 ℃ 39 hours) by 4-dimethylaminomethyl-7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (2.55mmol, 0.900g) synthetic.This product obtains pale solid: mp183-187 ℃ of 0.569g (50%) by silica gel flash column chromatography purifying (30% ethyl acetate/hexane, 20-50% ethyl acetate/dichloromethane then); IR (KBr) 3325,2929,1664,1431,1279,1221,1107,1075cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.06-1.15 (m, 2H, fatty CH), 1.19-1.22 (m, 1H, fatty CH), 1.31-1.62 (m, 8H, fatty CH), 1.81 (d, J=12.94Hz, 1H, fatty CH), 2.30 (s, 3H, ArCH 3), 2.33-2.42 (m, 1H, fatty CH), 2.45 (s, 3H, ArCH 3), 2.55 (d, J=17.82Hz, 1H, fatty CH), 2.61-2.66 (m, 1H, fatty CH), 2.82-2.88 (m, 1H, fatty CH), 3.09-3.15 (m, 1H, fatty CH), 5.20 (dd, J=24.90,12.21Hz, 2H, OCH 2C 6H 5), 6.41 (s, 1H, ArH), 7.28-7.43 (m, 5H, ArH), 11.31 (s, 1H, NH); MS (APCI +) m/z445.3 (MH +) .C 28H 32N 2O 3Computational analysis value: C, 75.65; H, 7.26; N, 6.30. measured value: C, 75.62; H, 7.34; N, 6.31.
Embodiment 45
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 5-dimethyl-, 1-(4-fluorophenyl) ethyl ester
Figure A9981647501461
Steps A: with benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 5-dimethyl-, acid anhydrides
Figure A9981647501471
To pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 5-dimethyl-, phenyl methyl esters (1.88mmol, 0.837g) and triethylamine (1.88mmol, in 18mL tetrahydrofuran solution 0.262mL), the Pd (OH) of adding 20% 2/ C (0.200g, 24wt%).This mixture was stirred 20 minutes and by diatomite filtration, cleaned with tetrahydrofuran (THF) under the room temperature down in nitrogen atmosphere (balloon), obtain this carboxylic acid: MS (APCI+) m/z355.2 (MH +).In this filtrate, under nitrogen atmosphere, drip under the room temperature Benzoyl chloride (1.88mmol, 0.218mL).After following 60 hours of the room temperature, leach precipitation, concentrated filtrate, and this resistates ground with ether obtain light pink solid (0.517g, 60%): 1H NMR (400MHz, DMSO-d 6) selected diagnostic peak δ 2.23 (s, 3H, ArCH 3), 2.48 (s, 3H, ArCH 3), 7.00 (s, 1H, ArH), 7.57 (t, J=7.81Hz, 2H, ArH), 7.73 (t, J=7.57Hz, 1H, ArH), 8.06 (d, J=7.32Hz, 2H, ArH), 11.94 (s, 1H, NH); MS (APCI +) m/z459.2 (MH +).
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 5-dimethyl-, 1-(4-fluorophenyl) ethyl ester
With benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 5-dimethyl-, acid anhydrides (1.13mmol, 0.517g) join 4-fluoro-α-Jia Jibianchun (3.38mmol, 0.427mL) in, and 150 ℃ of following heated and stirred 2 minutes.Form homogeneous solution, be cooled to room temperature, be dissolved in the ethyl acetate (10mL), and stir with saturated sodium bicarbonate aqueous solution.Layering, and with 3 batches of (10mL) ethyl acetate extraction waters.The extract that merges concentrates, and this product is obtained glossiness cream-coloured powder (0.256g, 48%) by silica gel flash column chromatography purifying (10-15% acetone/hexane): mp124-128 ℃;
IR (KBr) 3378,2933,1675,1425,1228,1127,1059cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.07-1.28 (m, 3H, fatty CH), 1.42-1.65 (m, 6H, fatty CH), 1.57 (d, J=6.75Hz, 3H, OCH (CH 3) Ar), 1.71-1.74 (m, 1H, fatty CH), 1.79-1.87 (m, 1H, fatty CH), 2.21﹠amp; 2.22 (s, 3H, ArCH 3, diastereomer) and 2.38 (d, J=11.09Hz, 1H, fatty CH), 2.46-2.49 (m, 1H, fatty CH), 2.50﹠amp; 2.52 (s, 3H, ArCH 3, diastereomer), 2.64-2.72 (m, 2H, fatty CH), 2.92-2.98 (m, 1H, fatty CH), 3.10-3.29 (m, 1H, fatty CH), 5.94-6.00 (m, 1H, OCH (CH 3) Ar), 6.92﹠amp; (6.93 s, 1H, ArH, diastereomer), 7.16-7.22 (m, 2H, ArH), 745-7.51 (m, 2H, ArH), 11.40 (s, 1H, NH); 19F NMR (DMSO-d 6)-115.13﹠amp;-114.94 (s, diastereomers), MS (APCI +) m/z477.3 (MH +) .C 29H 33F 1N 2O 3Computational analysis value: C, 73.09; H, 6.98; N, 5.88; F, 3.99. measured value: C, 72.84; H, 7.02; N, 5.78; F, 3.89.
Embodiment 46
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 4-dimethyl-, 1-(4-fluorophenyl) ethyl ester
Steps A: with benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 4-dimethyl-, acid anhydrides
According to embodiment 45, the method for steps A, pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 4-dimethyl-, phenyl methyl esters (1.10mmol, 0.491g) change mixed acid anhydride intermediate (cream-colored solid, 0.512 g, 100%) into: MS (APCI +) m/z459.3 (MH +).
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 4-dimethyl-, 1-(4-fluorophenyl) ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 4-dimethyl-, 1-(4-fluorophenyl) ethyl ester is according to embodiment 45, the method for step B by with benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 4-dimethyl-, acid anhydrides (1.12mmol, 0.512g) preparation.This product obtains fluffy pale solid (0.227g, 43%) by silica gel flash column chromatography purifying (10-20% acetone/hexane): mp105-108 ℃;
IR (KBr) 3325,2931,1674,1512,1433,1222,1109,1059cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.12-1.26 (m, 3H, fatty CH), 1.39-1.72 (m, 7H, fatty CH), 1.57 (d, J=6.51Hz, 3H, OCH (CH 3) Ar), 1.82-1.91 (m, 1H, fatty CH), 2.31-2.36 (m, 1H, fatty CH), 2.33﹠amp; 2.34 (s, 3H, ArCH 3, diastereomer), 2.43-2.47 (m, 1H, fatty CH), 2.54﹠amp; 2.56 (s, 3H, ArCH 3, diastereomer), 2.58-2.70 (m, 2H, fatty CH), 2.86-2.91 (m, 1H, fatty CH), 3.06-3.25 (m, 1H, fatty CH), 5.94-6.01 (m, 1H, OCH (CH 3) Ar), 6.43﹠amp; (6.45 s, 1H, ArH, diastereomer), and 7.16-7.22 (m, 2H, ArH), 7.45-7.51 (m, 2H, ArH), 11.31﹠amp; (11.32 s, 1H, NH, diastereomer); 19F NMR (DMSO-d 6The ﹠amp of)-(115.13-115.08);-(114.92-114.91) (m, diastereomer); MS (APCI +) m/z477.3 (MH +) .C 29H 33F 1N 2O 30.12H 2O computational analysis value: C, 72.75; H, 7.00; N, 5.85; F, 3.97; H 2O, 0.45. measured value: C, 72.38; H, 7.13; N, 5.73; F, 3.61; H 2O, 0.31.
Embodiment 47
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[3-(methoxycarbonyl) phenyl] and ethyl ester
Figure A9981647501501
Steps A: 3-(1-hydroxyethyl) methyl benzoate
Charge into nitrogen in the 500mL stainless steel reactor and charge into successively 1-(3-bromophenyl) ethanol (0.126mol, 25.4g), DMSO (150mL), methyl alcohol (3.70mol, 150mL), triethylamine (0.143mol, 20.0mL), Pd (OAc) 2(2.78mmol, 0.625g) with 1, two (diphenylphosphine) propane of 3-(2.62mmol, 1.08g).With this reactor sealing, charge into nitrogen, charge into CO then, be forced into 663psi with CO, shake and be heated to 80 ℃, kept 12 hours.With CO this reactor is forced into 724psi again, shakes and be heated to 100 ℃, kept 70 hours.This reaction is cooled to room temperature,, concentrates, and between water and methylene dichloride, distribute by diatomite filtration.Water with dichloromethane extraction (3 * 100mL), and extract wash with water (3 * 100mL), use dried over mgso, and simmer down to oily matter.This product obtains 3-(1-hydroxyethyl) methyl benzoate (15.1g, 66%) by silica gel flash column chromatography purifying (10-25% ethyl acetate/hexane):
1H?NMR(400MHz，CDCl 3)δ1.50(d，J＝6.59Hz，3H，CH(CH 3)OH)，1.86(d，J＝3.66Hz，1H，CH(CH 3)OH)，3.90(s，3H，CO 2CH 3)，4.92-4.97(m，1H，CH(CH 3)OH)，7.39-7.43(m，1H，ArH)，7.57(d，J＝7.57Hz，1H，ArH)，7.92(d，J＝7.57Hz，1H，ArH)，8.02(s，1H，ArH).
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[3-(methoxycarbonyl) phenyl] and ethyl ester
In the 100ml reaction flask, add 3-(1-hydroxyethyl) methyl benzoate (18.0mmol, 3.24g), then add with benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, acid anhydrides (embodiment 86,4.50mmol, 2.00g) and 150 ℃ of heated and stirred to obtaining homogeneous solution (4.5 minutes).This solution is cooled to room temperature, is dissolved in ethyl acetate and stirs with saturated sodium bicarbonate aqueous solution.Be settled out white solid and filter.With this filtrate layering, with ethyl acetate (3 * 25ml) aqueous layer extracted, and the extract that merges is dry and concentrate and obtain thickness oily matter.This product is obtained white solid (0.776g, 34%): mp100-103,155-156 ℃ (diastereomer) by silica gel flash column chromatography purifying (20% acetone/hexane);
IR (KBr) 3375,2931,2855,1725,1704,1432,1200,1078,1065cm -1 1H NMR (400MHz, CDCl 3) δ 1.20-1.29 (m, 1H, fatty CH), 1.32-1.34 (m, 2H, fatty CH), 1.38-1.47 (m, 1H, fatty CH), 1.53-1.58 (m, 2H, fatty CH), 1.62-1.82 (m, 4H, fatty CH), 1.68 (d, J=6.59Hz, 3H, OCH (CH 3) Ar), 2.01-2.12 (m, 1H, fatty CH), 2.41-2.45 (m, 1H, fatty CH), 2.50-2.53 (m, 1H, fatty CH), 2.60﹠amp; 2.62 (s, 3H, ArCH 3, diastereomer), 2.69-2.85 (m, 2H, fatty CH), 2.98-3.04 (m, 1H, fatty CH), 3.29-3.43 (m, 1H, fatty CH), 3.89 (s, 3H, CO 2CH 3), 6.09-6.17 (m, 1H, OCH (CH 3) Ar), 6.73﹠amp; (6.74 d, J=8.55Hz, 1H, ArH, diastereomer), 7.01﹠amp; 7.02 (d, J=8.79﹠amp; 8.55Hz, 1H, ArH, diastereomer), 7.41﹠amp; 7.42 (t, J=7.81﹠amp; 7.57Hz, 1H, ArH, diastereomer), 7.61﹠amp; (7.63 d, J=7.57Hz, 1H, ArH, diastereomer), 7.93-7.95﹠amp; (7.95-7.97 m, 1H, ArH, diastereomer), 8.06 (bs, 1H, NH), 8.10﹠amp; 8.13 (s, 1H, ArH, diastereomer; MS (APCI +) m/z503.1 (MH +) .C 30H 34N 2O 5Computational analysis value: C, 71.69; H, 6.82; N, 5.57. measured value: C, 71.58; H, 6.95; N, 5.42.
Embodiment 48
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(3-carboxyl phenyl) ethyl ester
Figure A9981647501521
With pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[3-(methoxycarbonyl) phenyl] and ethyl ester (1.43mmol, 0.717g) methyl alcohol (18mL) and 1N NaOH (5.71mmol, 5.71mL) solution 55-60 ℃ the heating 1 hour.This solution is cooled to room temperature, removes methyl alcohol by rotary evaporation, and with among the 1N HCl and water.The formation precipitation also leaches, by silica gel flash column chromatography purifying (10-15%MeOH/CHCl 3) obtain cream-colored powder (0.522g, 75%): mp244-250 ℃ (decomposition);
IR (KBr) 3413-3229 (b), 2931,1685,1432,1195,1150,1078,1063cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.03-1.22 (m, 3H, fatty CH), 1.38-1.72 (m, 7H, fatty CH), 1.57 (d, J=6.35Hz, 3H, OCH (CH 3) Ar), 1.78-1.88 (m, 1H, fatty CH), 2.28-2.38 (m, 1H, fatty CH), 240-2.47 (m, 1H, fatty CH), 2.51﹠amp; 2.55 (s, 3H, ArCH 3, diastereomer), 2.56-2.69 (m, 2H, fatty CH), 2.81-2.92 (m, 1H, fatty CH), 3.06-3.23 (m, 1H, fatty CH), 5.96-6.04 (m, 1H, OCH (CH 3) Ar), 6.57﹠amp; 6.58 (d, J=8.55﹠amp; 8.30Hz, 1H, ArH, diastereomer), 7.01﹠amp; (7.02 d, J=8.30Hz, 1H, ArH, diastereomer), 7.45-7.50 (m, 1H, ArH, diastereomer, 7.64﹠amp; 7.67 (d, J=10.25﹠amp; 8.55Hz, 1H, ArH, diastereomer), 7.83﹠amp; 7.85 (d, J=6.10﹠amp; 7.32Hz, 1H, ArH, diastereomer), 7.96﹠amp; (7.98 s, 1H, ArH, diastereomer), 11.54 (s, 1H, NH), 13.00 (s, 1H, CO 2H); MS (APCI +) m/z489.1 (MH +) .C 29H 32N 2O 50.50H 2O0.20SiO 2Computational analysis value: C, 68.35; H, 6.53; N, 5.50; H 2O, 1.77. measured value: C, 67.96; H, 6.81; N, 5.22; H 2O, 1.81.HPLC (ALLTECH/ALLTIMA C-18,60: 40-20: 80 H 2O/CH 3CN+0.05%TFA): retention time=4.843﹠amp; (4.970min diastereomer), 95.53% purity.
Embodiment 49
1-third ammonium, N, N, the N-trimethylammonium-, with 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole be [3 ', 2 ': 5,6] [1]-chromene salt (1: 1) of [3,2-i] quinolizine-1-carboxylic acid 1-(3-carboxyl phenyl) ethyl ester also also
With Choline Bicarbonate (0.935mmol, 0.165mL, aqueous solution 5.66M) join pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (0.935mmol is in ethanol 0.457g) (23mL) suspension for 1-(3-carboxyl phenyl) ethyl ester, and with this mixture 75-80 ℃ of heating 30 minutes, be cooled to room temperature, and filter.This filtrate concentrates.This resistates obtains faint yellow solid with ether vigorous stirring and filtration.This solid is dissolved in hot CHCl 3, filter, concentrate, and obtain yellow powder (0.233g, 42%): mp210-216 ℃ 60 ℃ of following vacuum-dryings;
IR (KBr) 3428-3211 (b), 2930,1684,1566,1432,1878,1870,1079,1063cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.03-1.26 (m, 3H, fatty CH), 1.36-1.72 (m, 6H, fatty CH), 1.55 (d, J=6.35Hz, 3H, OCH (CH 3) Ar), 1.80-1.88 (m, 1H, fatty CH), 2.30-2.42 (m, 2H, fatty CH), 2.51﹠amp; 2.52 (s, 3H, ArCH 3, diastereomer), 2.61-2.70 (m, 2H, fatty CH), 2.81-2.92 (m, 1H, fatty CH), 3.07 (s, 9H, N (CH 3) 3), 3.11-3.23 (m, 1H, fatty CH), 3.26-3.35 (m, 2H, CH 2OH﹠amp; Fat CH), 3.36 (t, J=4.88Hz, 2H, OCH 2CH 2N (CH 3) 3), 3.77-3.83 (m, 2H, OCH 2CH 2N (CH 3) 3), 5.91-5.99 (m, 1H, OCH (CH 3) Ar), 6.54-6.58 (m, 1H, ArH), 7.01-7.04 (m, 1H, ArH), 7.21-7.28 (m, 1H, ArH), 7.32-7.38 (m, 1H, ArH), 7.71-7.79 (m, 1H, ArH), 7.91﹠amp; (7.93 s, 1H, ArH, diastereomer), 11.70 (s, 1H, NH); MS (APCI-) m/z487.1 (female M-1) .C 29H 31N 2O 50.88C 5H 14NO0.50H 2O0.50CHCl 3Computational analysis value: C, 62.84; H, 6.97; N, 6.23; H 2O, 1.39. measured value: C, 62.92; H, 6.17; N, 6.93; H 2O, 1.72.
Embodiment 50
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-nitrophenyl) methyl esters
Figure A9981647501541
According to embodiment 47, the method for step B, the 3-nitrobenzyl alcohol (18.0mmol, 2.81g) and with benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (embodiment 86,4.50mmol for acid anhydrides, 2.00g) change into pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-nitrophenyl) methyl esters.This product obtains pale yellow powder (1.10g, 51%) by silica gel flash column chromatography purifying (25-50% ethyl acetate/hexane) and with re-crystallizing in ethyl acetate: mp203-205 ℃;
IR (KBr) 3383,3181,2929,2855,1709,1532,1430,1351,1236,1075,886cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.02-1.16 (m, 2H, fatty CH), 1.19-1.24 (m, 1H, fatty CH), 1.32-1.62 (m, 7H, fat CH), 1.82 (d, J=13.18Hz, 1H, fatty CH), 2.33 (d, J=9.76Hz, 1H, fat CH), 2.41 (d, J=11.23Hz, 1H, fatty CH), 2.48 (s, 3H, ArCH 3), 2.60-2.67 (m, 2H, fatty CH), 2.84-2.89 (m, 1H, fatty CH), 3.15-3.21 (m, 1H, fatty CH), 5.32-5.40 (m, 2H, OCH 2Ar), 6.59 (d, J=8.79Hz, 1H, ArH), 7.03 (d, J=8.55Hz, 1H, ArH), 7.65-7.69 (m, 1H, ArH), 7.89 (d, J=7.57Hz, 1H, ArH), 8.18 (d, J=8.06Hz, 1H, ArH), 8.29 (s, 1H, ArH), 11.58 (s, 1H, NH); MS (APCI +) m/z476.1 (MH +) .C 27H 29N 3O 5Computational analysis value: C, 68.20; H, 6.15; N, 8.84. measured value: C, 67.89; H, 6.20; N, 8.74.
Embodiment 51
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(3-cyano-phenyl) ethyl ester
Figure A9981647501551
Steps A: 3-(1-hydroxyethyl) benzonitrile
(68.9mmol is adding NaBH in MeOH 10.0g) (230mL) solution in batches under nitrogen atmosphere under 0 ℃ to 3-ethanoyl benzonitrile 4(68.9mmol, 2.61g).After progressively being warming up to room temperature in 2 hours, add 1N HCl and removal of solvent under reduced pressure.Methylene dichloride (50mL) adds, layering, and extract with three batches of methylene dichloride (50mL).The extract that merges with sodium bicarbonate (1 * 50mL), saturated sodium-chloride (dried over mgso is used in 1 * 50mL) washing, and vacuum concentration obtains pure product, is yellow oil (10.0g, 98%): 1H NMR (400MHz, CDCl 3) δ 1.47 (d, J=6.35Hz, 3H, ArCH (CH 3) OH), 1.99 (bs, 1H, OH), 4.92 (q, J=6.35Hz, 1H, ArCH (CH 3) OH), 7.43 (t, J=7.81Hz, 1H, ArH), 7.53 (d, J=7.57Hz, 1H, ArH), 7.59 (d, J=7.81Hz, 1H, ArH), 7.66 (s, 1H, ArH).
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(3-cyano-phenyl) ethyl ester
According to embodiment 47, the method for step B, 3-(1-hydroxyethyl)-benzonitrile (13.5mmol, 1.98g) and with benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (embodiment 86,3.37mmol for acid anhydrides, 1.50g) change into pyrrolo-[3 ', 2 ': 5,6] [1]-chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(3-cyano-phenyl) ethyl ester.This product obtains cream-colored powder (0.614g, 39%) by silica gel flash column chromatography purifying (20-30% acetone/hexane): mp131-134 and 171-173 ℃ (diastereomer);
IR (KBr) 3377,2931,2856,2230,1702,1432,1148,1077,1066cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.02-1.25 (m, 3H, fatty CH), 1.31-1.72 (m, 7H, fatty CH), 1.57 (d, J=6.35Hz, 3H, OCH (CH 3) Ar), 1.79-1.88 (m, 1H, fatty CH), 2.32-2.44 (m, 2H, fatty CH), 2.46 (s, 3H, ArCH 3), 2.56-2.69 (m, 2H, fatty CH), 2.80-2.91 (m, 1H, fatty CH), 3.02-3.28 (m, 1H, fatty CH), 5.93-6.01 (m, 1H, OCH (CH 3) Ar), 6.56-6.60 (m, 1H, ArH), 7.00-7.04 (m, 1H, ArH), 7.51-7.59 (m, 1H, ArH), 7.71-7.80 (m, 2H, ArH), 7.86﹠amp; (7.90 s, 1H, ArH, diastereomer), 11.56 (s, 1H, NH); MS (APCI +) m/z470.1 (MH +) .C 29H 31N 3O 30.25H 2O computational analysis value: C, 73.47; H, 6.70; N, 8.86; H 2O, 0.95. measured value: C, 73.18; H, 6.73; N, 8.56, H 2O, 0.58
Embodiment 52
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-[3-[(dimethylamino) and carbonyl] phenyl] ethyl ester Steps A: 3-(1-hydroxyethyl) phenylformic acid
With 3-(1-hydroxyethyl) benzonitrile (embodiment 51, steps A, 6.79mmol, 1.00g) mixture heating up in 10% aqueous sodium hydroxide solution (68mL) refluxed 4.5 hours, was cooled to room temperature, and with extracted with diethyl ether (2 * 50mL).Discard extract.Water concentrated hydrochloric acid acidifying, the usefulness extracted with diethyl ether (3 * 50mL), and, use dried over mgso with the extract salt water washing that merges, and the concentrated white solid (0.98g, 87%) that obtains: mp107-110 ℃;
1H?NMR(400MHz，DMSO-d 6)δ1.29(d，J＝6.35Hz，3H，ArCH(CH 3)OH)，4.71-4.78(m，1H，ArCH(CH 3)OH)，5.25(d，J＝4.40Hz，1H，OH)，7.39(t，J＝7.57Hz，1H，ArH)，7.53(d，J＝7.57Hz，1H，ArH)，7.76(d，J＝7.57Hz，1H，ArH)，7.91(s，1H，ArH)，12.87(s，1H，COOH)；MS(APCI-)m/z165.1(M-1).
Step B:3-(1-hydroxyethyl)-N, the N-dimethyl benzamide
Figure A9981647501581
To 3-(1-hydroxyethyl) phenylformic acid (54.8mmol, 9.10g), dimethylamine (54.8mmol, 27.4mL 2.0M THF solution) and iPr 2NEt (109mmol, in 55mL DMF solution 19.1mL), under nitrogen atmosphere, add in two batches under 0 ℃ HBTU (54.8mmol, 20.8g).After 45 minutes, add 1N HCl (50mL) and ether (50mL), and layering.Water is further also used extracted with diethyl ether (4 * 50mL) with 1N HCl acidifying.With this extract merging and concentrated.Water also concentrates.Merge enriched material, be dissolved in CH 2Cl 2, with 10%HCl (1 * 20mL), saturated sodium bicarbonate (1 * 20mL), (1 * 20mL) washing is with dried over mgso and concentrate for salt solution.This resistates obtains 3-(1-hydroxyethyl)-N, N-dimethyl benzamide, iPr by silica gel flash column chromatography purifying (50-100% ethyl acetate/hexane) 2NEt and N, N, N ', the mixture of N '-tetramethyl-urea.Based on 1The yield of H NMR is 6.56g (62%).One carries out chromatogram purification in small batches again obtains pure product, is limpid, anhydrous oily matter: 1H NMR (400MHz, DMSO-d 6) δ 1.28 (d, J=6.59Hz, 3H, ArCH (CH 3) OH), 2.86 (s, 3H, NCH 3), 2.93 (s, 3H, NCH 3), 4.67-4.73 (m, 1H, ArCH (CH 3) OH), 5.20 (d, J=4.15Hz, 1H, OH), 7.18-7.20 (m, 1H, ArH), 7.31-7.37 (m, 3H, ArH); MS (APCI +) m/z194.0 (MH +).
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-[3-[(dimethylamino) and carbonyl] phenyl] ethyl ester
According to embodiment 47, the method for step B, 3-(1-hydroxyethyl)-N, N-dimethyl benzamide (14.9mmol, 2.88g) and with benzoic pyrrolo-[3 ', 2 ': 5,6] [1]-chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (embodiment 86,3.73mmol for acid anhydrides, 1.66g) with dimethylbenzene (10mL) mix be incorporated in 150 ℃ of heating formed in 5 minutes pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-[3-[(dimethylamino)-carbonyl] phenyl] ethyl ester.This product is by silica gel flash column chromatography purifying (0-5% Et 3The N/ ethyl acetate), be dissolved in ether/ethyl acetate and wash that (15 * 20mL) remove unreacted 3-(1-hydroxyethyl)-N, N-dimethyl benzamide with water.Organic phase concentrates and this resistates is obtained white powder (1.65g, 86%) with the acetonitrile recrystallization: mp199-202 ℃;
IR (KBr) 3416 (br), 3219 (br), 2930,2855,1684,1622,1432,1188,1146,1091,1062cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.02-1.28 (m, 3H, fatty CH), 1.32-1.70 (m, 7H, fatty CH), 1.57 (d, J=6.84Hz, 3H, OCH (CH 3) Ar), 1.76-1.88 (m, 1H, fatty CH), 2.32-2.43 (m, 2H, fatty CH), 2.50﹠amp; 2.51 (s, 3H, ArCH 3, diastereomer), 2.52-2.689 (m, 2H, fatty CH), 2.84 (s, 3H, NCH 3), 2.84-2.89 (m, 1H, fatty CH), 2.92 (s, 3H, NCH 3), 3.06-3.30 (m, 1H, fatty CH), 5.94-6.01 (m, 1H, OCH (CH 3) Ar), 6.57﹠amp; (6.58 d, J=8.55Hz, 1H, ArH, diastereomer), 7.01﹠amp; (7.02 d, J=8.55Hz, 1H, ArH, diastereomer), 7.29 (t, J=7.33Hz, 1H, ArH), 7.37-7.50 (m, 3H, ArH), 11.53 (s, 1H, NH); MS (APCI +) m/z516.3 (MH +) .C 31H 37N 3O 4Computational analysis value: C, 72.21; H, 7.23; N, 8.15. measured value: C, 71.96; H, 7.25; N, 8.22.
Embodiment 53
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-[3-[(dimethylamino) and methyl] phenyl] ethyl ester Steps A: 1-(3-dimethylaminomethyl phenyl) ethanol
Figure A9981647501592
To LiAIH 4(23.3mmol in THF 0.931g/95%) (40mL) suspension, is adding 3-(1-hydroxyethyl)-N under nitrogen atmosphere under 0 ℃, (embodiment 52, step B, 15.5mmol, 10mL THF solution 3.00g) for the N dimethyl benzamide.Stop to emit H 2After, this reaction is heated to room temperature.Room temperature was placed after 4 hours, this mixture is cooled to 0 ℃ also adds ethyl acetate (0.74mL) and 10% aqueous sodium hydroxide solution successively.This mixture is heated to room temperature placement 30 minutes, stir adding MgSO down 4And diatomite, and with this mixture by diatomite filtration, with 20mL THF washing.This filtrate concentrating obtains pure 1-(the 3-dimethylaminomethyl phenyl) ethanol of 2.73g (99%):
1H?NMR(400MHz，DMSO-d 6)δ1.26(d，J＝6.59Hz，3H，ArCH(CH 3)OH)，2.09(s，6H，N(CH 3) 2)，3.31(s，2H，ArCH 2N)，4.64-4.67(m，1H，ArCH(CH 3)OH)，5.08(d，J＝4.15Hz，1H，OH)，7.07(d，J＝7.08Hz，1H，ArH)，7.15-7.25(m，3H，ArH)；MS(APCI +)m/z180.0(MH +).
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-[3-[(dimethylamino) and methyl] phenyl] ethyl ester
According to embodiment 47, the method for step B, 1-(3-dimethylaminomethyl phenyl) ethanol (15.2mmol, 2.73g) and with benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (embodiment 86,3.81mmol for acid anhydrides, 1.69g) with dimethylbenzene (10mL) mix be incorporated in 150 ℃ down heating formed in 5 minutes pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-[3-[(dimethylamino) and methyl] phenyl] ethyl ester.Then carry out conventional extraction aftertreatment (ethyl acetate).Water 100mL acetone diluted, and leach inorganic salt.This filtrate concentrates.This organic phase and aqueous residue are merged, mixes with 15mL under the nitrogen atmosphere under the room temperature and with pyridine (68.5mmol, 5.54mL) and acetic anhydride (34.3mmol, 3.23mL) processing successively.After 48 hours, leach white precipitate, and with this filtrate water washing (3 * 20mL).This water washings concentrated and with this product by silica gel flash column chromatography purifying (0-5%Et 3The N/ ethyl acetate) obtains yellow solid (0.160g, 8.4%): mp95-100 ℃;
IR (KBr) 2931,2857,1678,1430,1237,1195,1147,1062cm -1. 1H NMR (400MHz, DMSO-d 6) δ 1.09-1.27 (m, 3H, fatty CH), 1.32-1.68 (m, 7H, fatty CH), 1.54 (d, J=6.35Hz, 3H, OCH (CH 3) Ar), 1.79-1.84 (m, 1H, fatty CH), 2.07﹠amp; 2.08 (s, 6H, N (CH 3) 2, diastereomer), 2.29-2.43 (m, 2H, fatty CH), 2.49﹠amp; 2.50 (s, 3H, ArCH 3, diastereomer), 2.59-2.69 (m, 2H, fatty CH), 2.81-2.92 (m, 1H, fatty CH), 3.02-3.17 (m, 1H, fatty CH), 3.33﹠amp; 3.34 (s, 2H, ArCH 2N, diastereomer), 5.90-5.98 (m, 1H, OCH (CH 3) Ar), 6.56-6.59 (m, 1H, ArH), 7.00-7.03 (m, 1H, ArH), 7.12-7.21 (m, 1H, ArH), 7.26-7.33 (m, 3H, ArH), 11.50﹠amp; (11.51 s, 1H, NH, diastereomer); MS (APCI +) m/z502.2 (MH +) .C 31H 39N 3O 30.27C 4H 8O 2
Computational analysis value: C, 73.33; H, 7.90; N, 8.00. measured value: C, 72.94; H, 7.90; N, 8.10.
Total method J
In 1 hour, (Aldrich 1eq.) is added drop-wise in the THF mixture of 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (1eq.), triphenylphosphine (1eq.) and selected alcohol (1.5eq.) diethylazodicarboxylate.Stirred 24 hours under the room temperature, this mixture concentrates.This product is purifying (45% ethyl acetate: hexane) obtain corresponding ester on silica gel by recrystallization purifying or flash column chromatography.
Total method K
By injection technique, under nitrogen atmosphere, (Aldrich 1eq.) joins in the DMF solution of 5-acetoxyl group-2-Methyl-1H-indole-3-formic acid (1eq.) with DBU.In this reaction mixture, add selected alkyl halide (Aldrich, DMF solution 1.1eq.).Stirred 24 hours under the room temperature, this reaction mixture is diluted with methylene dichloride, cause the precipitation of required product.This solid product is leached and washes with water.
Total method L
Dimethylamine (2.2eq.) and formaldehyde (1.2eq.) are joined in the 10mL Denatured alcohol solution of selected ester (1.0eq.).With this mixture stirring and refluxing 24 hours under nitrogen atmosphere.After judging that according to MS and TLC this reaction is finished, this mixture is concentrated.This product is by flash column chromatography purifying (30%MeOH: CH on silica gel 2Cl 2).
Total method M
1,2,3,4,6,7,8,9-octahydro quinolizine perchlorate (1.7eq.) is dissolved in 2NNaOH (excessive).This solution extracted with diethyl ether.The organic layer that merges obtains limpid oily matter through concentrating.This oily matter is dissolved in diox and joins required Mannich alkali (in the 1eq.) De dioxane solution.110 ℃ of heating after 24 hours, this reaction is cooled to room temperature and removes diox obtain brown oil.This product is by flash column chromatography purifying (40% hexane: ethyl acetate) on silica gel.
Total method N
The mixture of mixed acid anhydride (4eq.) and selected alcohol (4eq.) is reacted evenly 150 ℃ of heating 5 minutes or up to this.After being cooled to room temperature, this oily matter is washed with the ethyl acetate dilution and with saturated sodium bicarbonate.Separate organic layer and concentrate and obtain brown oil.This product is by flash column chromatography purifying on silica gel.
Total method O.
In the methanol solution of ester (1eq.), add 2N NaOH (4eq.).After 1 hour, this reaction becomes limpid 55 ℃ of heating.This reaction mixture is cooled to 0 ℃ and neutralize with concentrated hydrochloric acid.This product precipitates from solution, for white solid and leach.This mother liquor is obtained other product with ethyl acetate extraction and except that desolvating.
Total method P
In the anhydrous THF suspension of selected Mannich alkali (1eq.), slowly add solid LiBH 4(5eq.).Drip MeOH (5eq.) immediately by syringe.The gained mixture heating up refluxed 1 hour.After being cooled to 0 ℃, add 1N HCl this reaction that neutralizes.This product precipitates from solution, is white solid.Mother liquor CH 2Cl 2Extraction.The organic layer dried over mgso that merges, and obtain more product except that desolvating.
Embodiment 54
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,1,13,14,14a, 15-decahydro-2-methyl-, the 2-phenyl chlorocarbonate
Figure A9981647501631
Steps A: 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid phenyl chlorocarbonate
5-hydroxy-2-methyl-1H-indole-3-carboxylic acid phenyl chlorocarbonate according to method J by 2-phenyl-ethanol (6.39g, 52.3mmol) synthetic and obtain fine powder: mp186-188 ℃ of 2.40g (31.1%) with the hexane/ethyl acetate recrystallization;
IR (KBr) 3231,2978,1644,1463,1173,1101cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.49 (s, 3H, CCH 3), 3.03 (t, J=6.99Hz, 2H, OCH 2CH 2), 4.40 (t, J=6.75Hz, 2H, OCH 2CH 2), 6.57 (dd, J=8.60,2.29Hz, 1H, ArH), 7.09 (d, J=8.68Hz, 1H, ArH), 7.20 (d, J=6.99Hz, 1H, ArH), 7.26-7.33 (m, 5H, ArH), 8.81 (s, 1H, OH), 11.49 (s, 1H, NH); MS (APCI+): m/z326.1 (MH +) .C 18H 17N 1O 3Computational analysis value: C, 73.20; H, 5.80; N, 4.74. measured value: C, 73.23; H, 5.74; N, 4.67.
Step B:4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid phenyl chlorocarbonate
Figure A9981647501641
4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid phenethyl ester according to method L by 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid phenyl chlorocarbonate (2.89g, 9.78mmol) synthetic and obtain the white solid of 0.250g (15.0%) with re-crystallizing in ethyl acetate: mp200-201 ℃;
IR (KBr) 3138,2971,1673,1585,1437,1279,1099cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.34 (s, 3H, CCH 3) 2.68 (s, 6H, N (CH 3) 2), 3.00 (t, J=6.59Hz, 2H, OCH 2CH 2), 4.43 (t, J=6.59Hz, 2H, OCH 2CH 2), 4.67 (s, 2H, NCH 2Ar), 6.81 (d, J=8.79Hz, 1H, ArH), 7.17-7.20 (m, 1H, ArH), 7.23-7.28 (m, 5H, ArH), 11.93 (s, 1H, NH); MS (APCI+): m/z353.2 (MH +) .C 21H 24N 2O 3Computational analysis value: C, 61.35; H, 7.48; N, 6.81. measured value: C, 60.96; H, 6.66; N, 6.42.
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,1,13,14,14a, 15-decahydro-2-methyl-, the 2-phenyl chlorocarbonate
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,1,13,14,14a, 15-decahydro-2-methyl-, the 2-phenyl chlorocarbonate according to method M by 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid phenethyl ester (0.250g, 0.709mmol) synthesize, and obtain the white solid of 0.170g (54.0%) with the ethyl acetate/hexane recrystallization: mp185-186 ℃;
IR (KBr) 3297,2931,2856,1673,1432,1199,1080cm -1 1HNMR (400MHz, CDCl 3) δ 1.20-1.81 (m, 10H, fatty CH), 2.07 (d, J=13.92Hz, 1H, fatty CH), 2.41 (s, 3H, CCH 3), 2.44-2.53 (m, 2H, fatty CH), 2.73-2.84 (m, 2H, fatty CH), 2.98-3.04 (m, 1H, fatty CH), 3.05-3.08 (m, 2H, OCH 2CH 2), 3.38 (dd, J=17.95,6.71Hz, 1H, fatty CH), 4.50-4.53 (m, 2H, OCH 2CH 2), 6.72 (d, J=8.79Hz, 1H, ArH), 6.99 (d, J=8.79Hz, 1H, ArH), 7.17-7.29 (m, 5H, ArH), 7.99 (s, 1H, NH); MS (APCI+): m/z445.3 (MH +) .C 28H 32N 2O 3Computational analysis value: C, 75.56; H, 7.26; N, 6.30. measured value: C, 75.36; H, 7.28; N, 6.13.
Embodiment 55
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(methoxycarbonyl) phenyl] methyl esters
Figure A9981647501651
Steps A: 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl benzyl ester
Figure A9981647501652
(6.64g 29.0mmol) synthesizes, and be settled out the lavender powder that obtains 4.88g (55.0%) from ether: mp232-234 ℃ 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester by the 4-bromomethyl-benzoic acid methyl ester according to method K;
IR (KBr) 3322,2950,1696,1654,1465,1288,1093cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.57 (s, 3H, CCH 3), 3.80 (s, 3H, OCH 3), 5.34 (s, 2H, OCH 2Ar), 6.55 (dd, J=8.67,2.32Hz, 1H, ArH), 7.09 (d, J=8.55Hz, 1H, ArH), 7.24 (d, J=2.20Hz, 1H, ArH), 7.54 (d, J=8.06Hz, 2H, ArH), 7.94 (d, J=8.30Hz, 2H, ArH), 8.83 (s, 1H, OH), 11.59 (s, 1H, NH); MS (APCI+): m/z340.1 (MH +) .C 19H 17N 1O 5Computational analysis value: C, 67.25; H, 5.05; N, 4.13. measured value: C, 66.88; H, 5.06; N, 4.05.
Step B:4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester
4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester according to method L by 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester (17.2g, 50.7mmol) synthesize, and obtain white solid: mp125-126 ℃ of 8.50g (43.0%) with the ethyl acetate grinding;
IR (KBr) 3142,2959,1672,1585,1434,1285,1095cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.12 (s, 6H, N (CH 3) 2), 2.49 (s, 3H, CCH 3), 3.84 (s, 3H, OCH 3), 4.02 (s, 2H, NCH 2Ar), 5.34 (s, 2H, OCH 2Ar), 6.58 (d, J=8.44Hz, 1H, ArH), 7.09 (d, J=8.44Hz, 1H, ArH), 7.60 (d, J=8.20Hz, 2H, ArH), 7.98 (d, J=8.20Hz, 2H, ArH), 11.56 (s, 1H, NH); MS (APCI+): m/z397.2 (MH +) .C 22H 24N 2O 5Computational analysis value: C, 66.41; H, 6.12; N, 7.04. measured value: C, 66.41; H, 6.01; N, 6.97.
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(methoxycarbonyl) phenyl] methyl esters
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(methoxycarbonyl) phenyl] methyl esters according to method M by 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester (0.200g, 0.505mmol) synthesize, and obtain the granular ash white solid of 0.090g (23.0%) with the t-butyl methyl ether recrystallization: mp179-180 ℃;
IR (KBr) 3173,2930,2856,1725,1615,1433,1275,1079cm -1 1H NMR (400MHz, CDCl 3) δ 1.21-1.81 (m, 10H, fatty CH), 2.06 (d, J=8.79Hz, 1H, fatty CH), 2.43 (d, J=12.70Hz, 1H, fatty CH), 2.50-2.53 (m, 1H, fatty CH), 2.55 (s, 3H, CCH 3), 2.73-2.84 (m, 2H, fatty CH), 2.96-3.05 (m, 1H, fatty CH), 3.38 (dd, J=17.70,7.20Hz, 1H, fatty CH), 3.89 (s, 3H, OCH 3), 5.34 (dd, J=16.36,12.70Hz, 2H, OCH 2Ar), 6.73 (d, J=8.79Hz, 1H, ArH), 7.01 (d, J=8.79Hz, 1H, ArH), 7.47 (d, J=8.06Hz, 2H, ArH), 8.01 (d, J=8.30Hz, 2H, ArH), 8.06 (s, 1H, NH); MS (APCI+): m/z489.3 (MH +). C 29H 32N 2O 5Computational analysis value: C, 71.29; H, 6.60; N, 5.73. measured value: C, 70.94; H, 6.26; N, 5.57.
Embodiment 56
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2 ,-methyl-, (4-carboxyl phenyl) methyl esters
Figure A9981647501671
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-carboxyl phenyl) methyl esters is synthetic according to method O, and obtains thin pale powder: mp243-244 ℃ of 0.030g (11.0%) with the methyl alcohol grinding;
IR (KBr) 2932,2863,1698,1592,1432,1077cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.05-1.26 (m, 3H, fatty CH) 1.39-1.66 (m, 6H, fatty CH), 1.85 (d, J=13.67Hz, 1H, fatty CH), 2.44 (d, J=11.23Hz, 1H, fatty CH), 2.47-2.48 (m, 1H, fatty CH), 2.48 (s, 3H, CCH 3), 2.63-2.69 (m, 2H, fatty CH), 2.85-2.91 (m, 1H, fatty CH), 3.19 (dd, J=18.07,6.84Hz, 1H, fatty CH), 3.41-3.43 (m, 1H, fatty CH), 5.31 (dd, J=20.02,12.94Hz, 2H, OCH 2Ar), 6.60 (d, J=8.55Hz, 1H, ArH), 7.04 (d, J=8.55Hz, 1H, ArH), 7.54 (d, J=8.30Hz, 2H, ArH), 7.94 (d, J=8.30Hz, 2H, ArH), 11.57 (s, 1H, NH), 12.98 (s, 1H, CO 2H); MS (APCI+): m/z475.3 (MH +) .C 28H 30N 2O 5Computational analysis value: C, 70.1 7; H, 6.42; N, 5.85. measured value: C, 69.78; H, 6.50; N, 5.62.
Embodiment 57
1-[3-(4-carboxyl-benzyloxycarbonyl)-5-hydroxy-2-methyl-1H-indoles-4-ylmethyl]-1,2,3,4,6,7,8,9-octahydro-quinolizine; Muriate
Figure A9981647501681
To pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1 formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(methoxycarbonyl) phenyl] (embodiment 56, step C, 1.00g for methyl esters, 2.05mmol) the 25.6mL methanol solution in, add 2N NaOH (4.09mL, 8.19mmol).Heating is after 1 hour down at 55 ℃, and this mixture changes clear solution into.This reaction mixture is cooled to 0 ℃ also slowly adds concentrated hydrochloric acid up to pH3.With this water layer with ethyl acetate extraction (5 * 50mL), and with the organic layer dried over mgso that merges, and except that desolvating.This resistates grinds with methylene dichloride and obtains fine white powder: mp230-231 ℃ of 0.967g (92.0%);
IR (KBr) 3361,2941,2360,1709,1589,1428,1227,1083cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.20-1.30 (m, 1H, fatty CH) 1.43-1.51 (m, 4H, fatty CH), 1.69-2.30 (m, 5H, fatty CH), 2.48﹠amp; 2.49 (s, 3H, CCH 3, open loop and closed loop), 2.48-2.55 (m, 2H, fatty CH), 2.85-3.30 (m, 2H, fatty CH), 3.40-3.80 (m, 3H, fatty CH), 5.33-5.36 (m, 2H, OCH 2Ar), 6.79﹠amp; 6.82 (d, J=8.55﹠amp; 8.06Hz, 1H, ArH, open loop and closed loop), 7.11﹠amp; 7.20 (d, J=8.55﹠amp; 8.55Hz, 1H, ArH, open loop and closed loop), and 7.54-7.56 (m, 2H, ArH), 7.94-7.96 (m, 2H, ArH), 9.19 (s, 1H, OH, open loops), 11.79﹠amp; (11.85 s, 1H, NH, open loop and closed loop), 13.00 (s, 1H, CO 2H); MS (APCI+): m/z475.3 (MH +) .C 28H 31N 2O 5Cl 1Computational analysis value: C, 65.35; H, 6.12; N, 5.44. measured value: C, 65.06; H, 6.17; N, 5.15.
Embodiment 58
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(hydroxymethyl) phenyl] methyl esters
Figure A9981647501691
Steps A: 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-hydroxymethyl-benzyl ester
Figure A9981647501692
4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-hydroxymethyl-benzyl ester according to method P by 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-(embodiment 56 for the benzyl ester, step B, 2.32g, 5.84mmol) synthetic and grind the white solid that obtains 0.993g (47.0%) with acetone: mp140-143 ℃; IR (KBr) 3140,2777,1686,1583,1435,1092cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.51 (s, 3H, CH 3), 2.71 (s, 6H, N (CH 3) 2), 4.47 (d, J=5.13Hz, 2H, ArCH 2OH), 4.73 (s, 2H, NCH 2Ar), 5.18 (t, J=5.62Hz, 1H, ArCH 2OH), 5.25 (s, 2H, OCH 2Ar), 6.84 (d, J=8.55Hz, 1H, ArH), 7.28 (d, J=8.55Hz, 1H, ArH), 7.31 (d, J=7.81Hz, 2H, ArH), 7.40 (d, J=7.81Hz, 2H, ArH), 8.60 (s, 1H, OH), 11.97 (s, 1H, NH); MS (APCI+): m/z369.2 (MH +) (ALLTCH/ALLTIMAC-18 1: 1-2: 98 H for .HPLC 2O/CH 3CN+0.05%TFA): retention time=4.57min, 95.23% purity.
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(hydroxymethyl) phenyl] methyl esters
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(hydroxymethyl) phenyl] methyl esters according to method M by 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-hydroxymethyl-benzyl ester (0.969g, 2.63mmol) synthetic and grind the white solid that obtains 0.890g (49.0%) with acetone: mp198-200 ℃;
IR (KBr) 3405,3237,2931,1660,1424,1237,1081cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.11-1.27 (m, 3H, fatty CH), 1.39-1.70 (m, 7H, fatty CH), 1.85 (d, J=13.50Hz, 1H, fatty CH), 2.36 (d, J=10.37Hz, 1H, fatty CH), 2.41-2.43 (m, 1H, fatty CH), 2.47 (s, 3H, CCH 3), 2.65-2.69 (m, 2H, fatty CH), 2.86-2.92 (m, 1H, fatty CH), 3.23 (dd, J=16.64,9.64Hz, 1H, fatty CH), 4.48 (d, J=5.78Hz, 2H, ArCH 2OH), 5.17 (t, J=5.55Hz, 1H, ArCH 2OH), 5.21 (dd, J=22.42,12.06, Hz, 2H, OCH 2Ar), 6.59 (d, J=8.44Hz, 1H, ArH), 7.03 (d, J=8.68Hz, 1H, ArH), 7.31 (d, J=7.72Hz, 2H, ArH), 7.39 (d, J=7.96Hz, 2H, ArH), 11.52 (s, 1H, NH); MS (APCI+): m/z 461.2 (MH +) .C 28H 32N 2O 4Computational analysis value: C, 73.02; H, 7.00; N, 6.08. measured value: C, 72.62; H, 6.84; N, 5.83.
Embodiment 59
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-2-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-naphthyl methyl esters Steps A: 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalene-2-base methyl esters
Figure A9981647501712
5-hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalene-2-base methyl esters according to method K by 2-brooethyl-naphthalene (7.63g, 34.5mmol) synthetic and: mp243-245 ℃ by being settled out the lavender powder that obtains 5.01g (48.1%) in the methylene dichloride;
IR (KBr) 3408,3306,3058,1665,1596,1465,1172,1093cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.59 (s, 3H, CCH 3), 5.46 (s, 2H, OCH 2Ar), 6.59 (dd, J=8.44,2.41Hz, 1H, ArH), 7.12 (d, J=8.44Hz, 1H, ArH), 7.30 (d, J=2.41Hz, 1H, ArH), 7.51 (dd, J=6.03,3.38Hz, 1H, ArH), 7.59 (d, J=1.69Hz, 1H, ArH), 7.61 (d, J=1.69Hz, 1H, ArH), 7.90-7.96 (m, 4H, ArH), 8.83 (s, 1H, OH), 11.58 (s, 1H, NH); MS (APCI+): m/z332.2 (MH +) .HPLC (ALLTCH/ALLTIMA C-18 35: 65-2: 98 H 2O/CH 3CN+0.05%TFA): retention time=3.70min, 95.81% purity.
Step B:4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalene-2-base methyl esters
Figure A9981647501721
(embodiment 57 by the basic methyl esters of 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalene-2-according to method L for 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalene-2-base methyl esters, steps A, 3.38g, 10.2mmol) synthesize, and obtain the white solid of 0.750g (19.0%) by the methylene dichloride recrystallization: mp170-171 ℃;
IR (KBr) 3120,2964,2853,1675,1592,1431,1257,1088cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.11 (s, 6H, N (CH 3) 2), 2.49 (s, 3H, CCH 3), 4.03 (s, 2H, NCH 2Ar), 5.43 (s, 2H, OCH 2Ar), 6.57 (d, J=8.68Hz, 1H, ArH), 7.08 (d, J=8.44Hz, 1H, ArH), 7.51-7.53 (m, 2H, ArH), 7.60 (d, J=8.44Hz, 1H, ArH), 7.91-7.99 (m, 4H, ArH), 11.55 (s, 1H, NH); MS (APCI+): m/z389.2 (MH +) (ALLTCH/ALLTIMAC-18 55: 45-15: 85 H for .HPLC 2O/CH 3CN+0.05%TFA): retention time=4.80min, 94.36% purity.
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-2-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-naphthyl methyl esters
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-2-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-naphthyl methyl esters according to method M by 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalene-2-base methyl esters (0.620g, 1.62mmol) synthesize, and obtain the granular, white solid of 0.690g (59.0%) with the ethyl acetate/hexane recrystallization: mp141-143 ℃;
IR (KBr) 3177,3056,2929,1702,1430,1146,1079cm -1 1H NMR (400MHz, CDCl 3) δ 1.19-1.45 (m, 4H, fatty CH) 1.55-1.78 (m, 6H, fatty CH), 2.07 (d, J=13.99Hz, 1H, fatty CH), 2.43-2.46 (m, 1H, fatty CH), 2.52-2.55 (m, 1H, fatty CH), 2.58 (s, 3H, CCH 3), 2.77-2.86 (m, 2H, fatty CH), 3.01-3.07 (m, 1H, fatty CH), 3.41 (dd, J=18.08,6.75Hz, 1H, fatty CH), 5.48 (dd, J=19.53,10.61Hz, 2H, OCH 2Ar), 6.75 (d, J=8.68Hz, 1H, ArH), 7.03 (d, J=8.68Hz, 1H, ArH), 7.48-7.50 (m, 2H, ArH), 7.55-7.57 (m, 1H, ArH), 7.82-7.86 (m, 3H, ArH), 8.11 (s, 1H, NH); MS (APCI+): m/z481.3 (MH +) .C 31H 32N 2O 3Computational analysis value: C, 77.47; H, 6.71; N, 5.83. measured value: C, 77.13; H, 6.84; N, 5.51.
Embodiment 60
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(methoxycarbonyl) phenyl] methyl esters
Figure A9981647501731
Steps A: 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester
Figure A9981647501741
(5.49g 24.0mmol) synthesizes 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl benzyl ester, and grinds the light gray powder that obtains 2.01g (27.0%) with ethyl acetate: mp160-162 ℃ by the 3-bromomethyl-benzoic acid methyl ester according to method K;
IR (KBr) 3383,3310,1721,1666,1465,1289,1095cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.56 (s, 3H, CCH 3), 3.81 (s, 3H, OCH 3), 5.35 (s, 2H, OCH 2Ar), 6.57 (dd, J=8.55,2.20Hz, 1H, ArH), 7.10 (d, J=8.55Hz, 1H, ArH), 7.25 (d, J=2.20Hz, 1H, ArH), 7.53 (t, J=7.81Hz, 1H, ArH), 7.70 (d, J=7.81Hz, 1H, ArH), 7.89 (d, J=7.57Hz, 1H, ArH), 8.01 (s, 1H, ArH), 8.82 (s, 1H, OH), 11.58 (s, 1H, NH); MS (APCI+): m/z340.1 (MH +) .C 19H 17N 1O 5Computational analysis value: C, 67.25; H, 5.05; N, 4.13. measured value: C, 67.22; H, 4.75; N, 4.05.
Step B:4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester
Figure A9981647501742
4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester according to method L by 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester (7.26g, 21.4mmol) synthesize, and obtain fine white powder: mp164-167 ℃ of 4.80g (56.6%) with the ethyl acetate grinding;
IR (KBr) 3031,2951,1725,1683,1432,1285,1077cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.10 (s, 6H, N (CH 3) 2), 2.49 (s, 3H, CCH 3), 3.81 (s, 3H, OCH 3), 3.96 (s, 2H, NCH 2Ar), 5.31 (s, 2H, OCH 2Ar), 6.55 (d, J=8.55Hz, 1H, ArH), 7.06 (d, J=8.55Hz, 1H, ArH), 7.52 (t, J=7.81Hz, 1H, ArH), 7.72 (d, J=7.57Hz, 1H, ArH), 7.90 (d, J=7.81Hz, 1H, ArH), 8.03 (s, 1H, ArH), 11.54 (s, 1H, NH); MS (APCI+): m/z397.0 (MH +) .HPLC (ALLTCH/ALLTIMA C-18 65: 35-15: 85 H 2O/CH 3CN+0.05%TFA): retention time=4.91min, 92.97% purity.
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(methoxycarbonyl) phenyl] methyl esters
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(methoxycarbonyl) phenyl] methyl esters according to method M by 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester (2.09g, 5.27mmol) synthesize, and obtain fine white powder: mp169-170 ℃ of 1.21g (47.1%) with the t-butyl methyl ether recrystallization; IR (KBr) 3380,2931,2855,1721,1433,1289,1076cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.03-1.21 (m, 3H, fatty CH) 1.36-1.63 (m, 7H, fatty CH), 1.81 (d, J=13.43Hz, 1H, fatty CH), 2.33 (d, J=10.50Hz, 1H, fatty CH), 2.40-2.42 (m, 1H, fatty CH), 2.46 (s, 3H, CCH 3), 2.56-2.67 (m, 2H, fatty CH), 2.82-2.88 (m, 1H, fatty CH), 3.14 (dd, J=18.07,6.84Hz, 1H, fatty CH), 3.81 (s, 3H, OCH 3), 5.29 (dd, J=25.15,12.45Hz, 2H, OCH 2Ar), 6.57 (d, J=8.79Hz, 1H, ArH), 7.02 (d, J=8.79Hz, 1H, ArH), 7.52 (t, J=7.57Hz, 1H, ArH), 7.71 (d, J=7.57Hz, 1H, ArH), 7.90 (d, J=7.81Hz, 1H, ArH), 8.02 (s, 1H, ArH), 11.55 (s, 1H, NH); MS (APCI+): m/z489.2 (MH +) .C 29H 32N 2O 5Computational analysis value: C, 71.29; H, 6.60; N, 5.73. measured value: C, 71.22; H, 6.91; N, 5.43.
Embodiment 61
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(hydroxymethyl) phenyl] methyl esters
Steps A: 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-hydroxymethyl-benzyl ester
Figure A9981647501762
4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-hydroxymethyl-benzyl ester according to method P by 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-(embodiment 60 for the benzyl ester, step B, 2.21g, 5.58mmol) synthesize, and grind the white powder that obtains 1.11g (54.0%) with methylene dichloride: mp199-201 ℃; IR (KBr) 3065,2884,1681,1586,1432,1090cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.25 (s, 3H, CCH 3) 2.72 (s, 6H, N (CH 3) 2), 4.48 (d, J=5.37Hz, 2H, ArCH 2OH), 4.75 (s, 2H, NCH 2Ar), 5.22 (t, J=5.62Hz, 1H, ArCH 2OH), 5.28 (s, 2H, OCH 2Ar), 6.87 (d, J=8.55Hz, 1H, ArH), 7.25-7.34 (m, 4H, ArH), 7.40 (s, 1H, ArH), 8.59 (s, 1H, ArOH), 12.06 (s, 1H, NH); MS (APCI+): m/z369.2 (MH +) .HPLC (ALLTCH/ALLTIMA C-18 98: 2-75: 25 H 2O/CH 3CN+0.05%TFA): retention time=2.11min, 98.74% purity
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(hydroxymethyl) phenyl] methyl esters
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(hydroxymethyl) phenyl] methyl esters according to method M by 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-hydroxymethyl-benzyl ester (0.980g, 2.66mmol) synthetic and grind the pistac crystallization that obtains 0.420g (44.2%) with t-butyl methyl ether: mp183-185 ℃;
IR (KBr) 3381,3197,2931,1682,1430,1249,1076cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.06-1.37 (m, 3H, fatty CH) 1.40-1.65 (m, 6H, fatty CH), 1.82 (d, J=13.43Hz, 1H, fatty CH), 2.33 (d, J=10.01Hz, 1H, fatty CH), 2.40-2.43 (m, 1H, fatty CH), 2.46 (s, 3H, CCH 3), 2.61-2.68 (m, 2H, fatty CH), 2.83-2.89 (m, 1H, fatty CH), 3.12-3.16 (m, 1H, fatty CH), 3.18 (dd, J=18.31,6.84Hz, 1H, fatty CH), 4.46 (d, J=5.62Hz, 2H, ArCH 2OH), 5.18 (t, J=6.10Hz, 1H, ArCH 2OH), 5.21 (dd, J=20.27,12.21Hz, 2H, OCH 2Ar), 6.58 (d, J=8.79Hz, 1H, ArH), 7.01 (d, J=8.55Hz, 1H, ArH), 7.23-7.32 (m, 3H, ArH), 7.36 (s, 1H, ArH), 11.51 (s, 1H, NH); MS (APCI+): m/z461.1 (MH +) .C 28H 32N 2O 4Computational analysis value: C, 73.02; H, 7.00; N, 6.08. measured value: C, 72.84; H, 7.07; N, 5.91.
Embodiment 62
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-carboxyl phenyl) methyl esters)
Figure A9981647501771
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-carboxyl phenyl) methyl esters according to method O by pyrrolo-[3 ', 2 ': 5,6] [1]-chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(methoxycarbonyl) phenyl] (embodiment 60, step C for methyl esters, 0.923g, 1.89mmol) synthesize, and grind the white powder that obtains 0.456g (50.7%): mp205-208 ℃ with ethyl acetate;
IR (KBr) 2932,2859,1693,1563,1432,1076cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.08-1.36 (m, 3H, fatty CH) 1.39-1.63 (m, 7H, fatty CH), 1.81 (d, J=13.18Hz, 1H, fatty CH), 2.33 (d, J=11.23Hz, 1H, fatty CH), 2.40-2.43 (m, 1H, fatty CH), 2.47 (s, 3H, CCH 3), 2.56-2.67 (m, 2H, fatty CH), 2.84-2.88 (m, 1H, fatty CH), 3.15 (dd, J=17.82,6.35Hz, 1H, fatty CH), 5.28 (dd, J=24.17,12.45Hz, 2H, OCH 2Ar), 6.57 (d, J=8.79Hz, 1H, ArH), 7.02 (d, J=8.55Hz, 1H, ArH), 7.48 (t, J=7.57Hz, 1H, ArH), 7.65 (d, J=7.57Hz, 1H, ArH), 7.87 (d, J=7.81Hz, 1H, ArH), 8.00 (s, 1H, ArH), 11.55 (s, 1H, NH); MS (APCI+): m/z475.1 (MH +) .C 28H 30N 2O 5Computational analysis value: C, 69.18; H, 6.50; N, 5.75. measured value: C, 68.83; H, 6.40; N, 5.63.
Embodiment 63
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole be [3 ', 2 ': 5,6] [1]-chromene salt (1: 1) of [3,2-i] quinolizine-1-carboxylic acid (3-carboxyl phenyl) methyl esters also also
Figure A9981647501781
To pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1 formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (embodiment 62, and 0.100g is in 5mL EtOH suspension 0.211mmol) for (3-carboxyl phenyl) methyl esters, adding choline carbonate (0.037mL, 0.211mmol, 5.66M).This reaction mixture reflux was obtained clear solution in 1 hour.After being cooled to room temperature, this mixture concentrates and obtains yellow oil.Grind the beige solid that this oily matter obtains 0.097g (88.0%): mp165-170 ℃ with ether;
IR (KBr) 2930,2855,1685,1566,1436,1077cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.09-1.28 (m, 3H, fatty CH) 1.39-1.70 (m, 7H, fatty CH), 1.86 (d, J=13.50Hz, 1H, fatty CH), 2.35 (d, J=10.37Hz, 1H, fatty CH), 2.42-2.45 (m, 1H, fatty CH), 2.47 (s, 3H, CCH 3), 2.65-2.72 (m, 2H, fatty CH), 2.87-2.91 (m, 1H, fatty CH), 3.09 (s, 9H, N (CH 3) 3), 3.23 (dd, J=15.19,8.44Hz, 1H, fatty CH), 3.35-3.40 (m, 2H, NCH 2CH 2OH), 3.81-3.85 (m, 2H, NCH 2CH 2OH), 5.20 (dd, J=23.63,12.30Hz, 2H, OCH 2Ar), 6.55 (d, J=8.44Hz, 1H, ArH), 7.03 (d, J=8.44Hz, 1H, ArH), 7.22 (t, J=7.47Hz, 1H, ArH), 7.29 (d, J=7.23Hz, 1H, ArH), 7.75 (d, J=7.48Hz, 1H, ArH), 7.89 (s, 1H, ArH), 11.55 (s, 1H, NH); MS (APCI+): m/z475.1 (MH +) .C 33H 43N 3O 6: computational analysis value: C, 65.23; H, 7.68; N, 6.92. measured value: C, 64.95; H, 7.68; N, 6.92.
Embodiment 64
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [the 3-[(dimethylamino) methyl] phenyl] methyl esters
Figure A9981647501791
To the Ph that stirs 3P (0.161g, 0.616mmol) and pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(hydroxymethyl) phenyl]-(embodiment 61, step B for methyl esters, 0.284g, drip N-bromosuccinimide (0.110g, 2mL THF solution 0.616mmol) down at-18 ℃ in 2.93mL anhydrous THF solution 0.616mmol).After 10 minutes, remove cryostat, and a collection of adding dimethylamine.In stainless steel vessel this being reflected at 80 ℃ heated 1 hour.Remove THF, and with this product by flash column chromatography purifying (20%MeOH: CH on silica gel 2Cl 2) and obtain the crude product pale powder of 1.21g (40.3%) with the methylene dichloride recrystallization: mp87-90 ℃;
IR (KBr) 2930,2854,1700,1589,1432,1077cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.06-1.36 (m, 3H, fatty CH) 1.39-1.63 (m, 7H, fatty CH), 1.82 (d, J=13.18Hz, 1H, fatty CH), 2.11 (s, 6H, N (CH 3) 2) 2.34 (d, J=10.74Hz, 1H, fatty CH), 2.40-2.46 (m, 1H, fatty CH), 2.45 (s, 3H, CCH 3), 2.59-2.67 (m, 2H, fatty CH), 2.83-2.89 (m, 1H, fatty CH), 3.15 (dd, J=18.31,6.84Hz, 1H, fatty CH), 3.37 (s, 2H, ArCH 2N (CH 3) 2), 5.20 (dd, J=23.93,12.21Hz, 2H, OCH 2Ar), 6.57 (d, J=8.79Hz, 1H, ArH), 7.02 (d, J=8.79Hz, 1H, ArH), 7.22-7.31 (m, 3H, ArH), 7.34 (s, 1H, ArH), 11.53 (s, 1H, NH); MS (APCI+): m/z488.1 (MH +) .C 30H 37N 3O 3Computational analysis value: C, 71.89; H, 7.65; N, 8.62. measured value: C, 71.89; H, 7.65; N, 8.20.
Embodiment 65
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [the 3-[(dimethylamino) carbonyl] phenyl] methyl esters Steps A: 3-hydroxymethyl-N, N-dimethyl-benzamide
Figure A9981647501811
To 3-(hydroxymethyl) phenylformic acid (9.87g, 64.9mmol), dimethylamine (2M in THF, 32.4mL, 64.9mmol), N, (22.6mL is in 20mL DMF mixture 130mmol) for the N-diisopropyl ethyl amine, add HBTU (24.6g, 55mLDMF solution 64.9mmol) down at 0 ℃.After 5 minutes, this yellow solution becomes orange.After stirring 1 hour under 0 ℃, this reaction mixture is diluted with ether, with 10%HCl, saturated sodium bicarbonate, salt water washing, use dried over mgso, and the concentrated brown oil that obtains.This product by flash column chromatography on silica gel purifying (3%MeOH: methylene dichloride) obtain the yellow oil of 7.5g (64.5%): 1H NMR (400MHz, DMSO-d 6) δ 2.88 (s, 3H, NCH 3), 2.96 (s, 3H, NCH 3), 4.51 (d, J=5.55Hz, 2H, OCH 2Ar), 5.25 (t, J=5.79Hz, 1H, OH), 7.21-7.25 (m, 1H, ArH), 7.31-7.47 (m, 3H, ArH); MS (APCI+): m/z180.1 (MH +).
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [the 3-[(dimethylamino) carbonyl] phenyl] methyl esters
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-[(dimethylamino) carbonyl]-phenyl] methyl esters according to method N by 3-hydroxymethyl-N, (1.04g 5.81mmol) synthesizes N-dimethyl-benzamide, and grinds the fluffy white powder that obtains 0.250g (25.7%) with acetone: mp112-116 ℃; IR (KBr) 2929,2854,1698,1624,1432,1077cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.09-1.62 (m, 10H, fatty CH), 1.82 (d, J=14.16Hz, 1H, fatty CH), 2.33 (d, J=10.25Hz, 1H, fatty CH), 2.40-2.43 (m, 1H, fatty CH), 2.45 (s, 3H, CCH 3), 2.46 (s, 6H, N (CH 3) 2), 2.59-2.67 (m, 2H, fatty CH), 2.86-2.93 (m, 1H, fatty CH), 3.16 (dd, J=18.80,7.81Hz, 1H, fatty CH), 5.24 (dd, J=20.75,12.45Hz, 2H, OCH 2Ar), 6.57 (d, J=8.55Hz, 1H, ArH), 7.02 (d, J=8.55Hz, 1H, ArH), 7.33 (d, J=7.57Hz, 1H, ArH), 7.40-7.44 (m, 2H, ArH), 7.49 (d, J=7.57Hz, 1H, ArH), 11.54 (s, 1H, NH); MS (APCI+): m/z502.2 (MH +) C 30H 35N 3O 4Computational analysis value: C, 71.83; H, 7.03; N, 8.38. measured value: C, 71.44; H, 7.05; N, 8.21.
Embodiment 66
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [2-(4-morpholinyl) ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [2-(4-morpholinyl) ethyl ester according to method N by 2-morpholine-4-base-ethanol (0.300mL, 2.64mmol) synthesize, and grind the white solid that obtains 0.122g (41.0%) with methylene dichloride: mp188-190 ℃;
IR (KBr) 2931,2854,1696,1588,1432,1148cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.14-1.75 (m, 10H, fatty CH), 1.90 (d, J=13.18Hz, 1H, fatty CH), 2.34-2.46 (m, 2H, fatty CH), 2.46 (s, 4H, N (CH 2CH 2) 2O), 2.49 (s, 3H, CCH 3), 2.59 (t, J=5.62Hz, 2H, CO 2CH 2CH 2), 2.64-2.73 (m, 2H, fatty CH), 2.86-2.91 (m, 1H, fatty CH), 3.29 (dd, J=19.29,10.25Hz, 1H, fatty CH), 3.52 (s, 4H, N (CH 2CH 2) 2O), 4.18-4.30 (m, 2H, CO 2CH 2CH 2), 6.58 (d, J=8.55Hz, 1H, ArH), 7.02 (d, J=8.55Hz, 1H, ArH), 11.48 (s, 1H, NH); MS (APCI+): m/z454.1 (MH +) .C 26H 35N 3O 4Computational analysis value: C, 68.60; H, 7.79; N, 9.23. measured value: C, 68.23; H, 7.80; N, 9.02.
Embodiment 67
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[1,1 '-xenyl]-4-base ethyl ester
Figure A9981647501831
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[1,1 '-xenyl]-(2.68g 13.5mmol) synthesizes 4-base ethyl ester, and grinds the white powder that obtains 0.619g (35.4%) with ether: mp132-135 ℃ by 1-xenyl-4-base-ethanol according to method N;
IR (KBr) 2929,2855,1677,1432,1078cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.11-1.67 (m, 10H, fatty CH), 1.59 (d, J=6.59Hz, 2H, OCHCH 3), 1.79-1.89 (m, 2H, fatty CH), 2.33-2.47 (m, 1H, fatty CH), 2.53﹠amp; 2.54 (s, 3H, CCH 3, diastereomer), 2.60-2.67 (m, 2H, fatty CH), 2.79-2.95 (m, 1H, fatty CH), 3.14 (dd, J=28.08,10.12Hz, 1H, fatty CH), 5.96-6.03 (m, 1H, OCHCH 3), 6.55-6.59 (m, 1H, ArH), 7.00-7.03 (m, 1H, ArH), 7.31-7.34 (m, 1H, ArH), 7.40-7.51 (m, 4H, ArH), 7.60-7.64 (m, 4H, ArH), 11.53 (s, 1H, NH); MS (APCI+): m/z521.1 (MH +) .C 34H 36N 2O 3Computational analysis value: C, 78.25; H, 7.36; N, 5.14. measured value: C, 78.20; H, 7.76; N, 4.85.
Embodiment 68
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2, the 6-difluorophenyl) methyl esters
Figure A9981647501832
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2, the 6-difluorophenyl) methyl esters according to method N by (2,6-two fluoro-phenyl)-(1.50mL 13.5mmol) synthesizes methyl alcohol, and grinds the fluffy white powder that obtains 1.07g (68.0%) with ether: mp219-220 ℃;
IR (KBr) 3330,2928,1664,1473,1059cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.03-1.35 (m, 3H, fatty CH), 1.38-1.56 (m, 7H, the CH of ring), 1.78 (d, J=13.18Hz, 2H, fatty CH), 2.32-2.34 (m, 2H, fatty CH), 2.41 (s, 3H, CCH 3), 2.55-2.66 (m, 2H, fatty CH), 2.83-2.88 (m, 1H, fatty CH), 3.08 (dd, J=18.31,7.08Hz, 1H, fatty CH), 5.20 (d, J=11.96Hz, 1H, OCH 2Ar), 6.57 (d, J=8.55Hz, 1H, ArH), 7.01 (d, J=8.55Hz, 1H, ArH), 7.16 (t, J=7.81Hz, 2H, ArH), 7.48-7.53 (m, 1H, ArH), 11.57 (s, 1H, NH); MS (APCI+): m/z467.1 (MH +) .C 27H 28N 2O 3F 2Computational analysis value: C, 69.32; H, 6.19; N, 5.80. measured value: C, 69.51; H, 6.05; N, 6.00.
Embodiment 69
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1-phenyl-2,2,2-trifluoro) ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1-phenyl-2,2,2-trifluoro) ethyl ester according to method N by 2,2, (1.58g 9.00mmol) synthesizes 2-three fluoro-1-phenylethyl alcohols, and grinds the fluffy white powder that obtains 0.356g (31.8%) with t-butyl methyl ether: mp115-117 ℃;
IR (KBr) 3382,2931,1718,1432,1067cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.07-1.68 (m, 10H, fatty CH), 1.87-1.90 (m, 2H, fatty CH), 2.35-2.46 (m, 2H, fatty CH), 2.58-2.62 (m, 1H, fatty CH), 2.61﹠amp; 2.62 (s, 3H, CCH 3, diastereomer), 2.62-2.90 (m, 1H, fatty CH), 3.18 (dd, J=17.82,6.84Hz, 1H, fatty CH), 6.52-6.57 (m, 1H, OCHCF 3), 6.61-6.63 (m, 1H, ArH), 7.05-7.07 (m, 1H, ArH), 7.43-7.44 (m, 3H, ArH), 7.55-7.57 (m, 2H, ArH), 11.83 (s, 1H, NH); MS (APCI+): m/z499.1 (MH +) .C 28H 29N 2O 3F 3Computational analysis value: C, 67.46; H, 5.86; N, 5.62. measured value: C, 67.40; H, 6.03; N, 5.44.
Embodiment 70
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[3-(trifluoromethyl) phenyl] and ethyl ester
Figure A9981647501851
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[3-(trifluoromethyl) phenyl] ethyl ester according to method N by 1-(3-trifluoromethyl-phenyl)-ethanol (2.06mL, 13.5mmol) synthesize, and obtain white solid: mp102-105 ℃ of 0.793g (45.8%) with the ether grinding;
IR (KBr) 3380,2931,1680,1432,1075cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.05-1.59 (m, 10H, fatty CH), 1.59 (d, J=6.59Hz, 3H, OCHCH 3), 1.77-1.88 (m, 1H, fatty CH), 2.33 (d, J=9.03Hz, 1H, fatty CH), 2.41 (d, J=8.55Hz, 1H, fatty CH), 2.51﹠amp; 2.52 (s, 3H, CCH 3, diastereomer), 2.51-2.67 (m, 2H, fatty CH), 2.83-2.86 (m, 1H, fatty CH), 3.06 (dd, J=18.07,6.84Hz, 1H, fatty CH), 6.01-6.05 (m, 1H, OCHCH 3), 6.58-6.60 (m, 1H, ArH), 7.01-7.04 (m, 1H, ArH), 7.57-7.67 (m, 2H, ArH), 7.71-7.75 (m, 2H, ArH), 11.56 (s, 1H, NH); MS (APCI+): m/z513.1 (MH +) .C 29H 31N 2O 3F 3Computational analysis value: C, 67.69; H, 6.08; N, 5.44. measured value: C, 67.34; H, 6.35; N, 5.24.
Embodiment 71
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino) ethyl ester
Figure A9981647501861
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino) ethyl ester according to method N by 2-dimethylamino-ethanol (1.36mL, 13.5mmol) synthesize, and grind the granular ash white solid that obtains 0.489g (34.9%) with ether: mp190-191 ℃;
IR (KBr) 3274,2950,1653,1518,1248cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.13-1.59 (m, 10H, fatty CH), 1.71-1.76 (m, 1H, fatty CH), 1.90 (d, J=13.43Hz, 1H, fatty CH), 2.05 (s, 6H, N (CH 3) 2), 2.35 (d, J=10.25Hz, 1H, fatty CH), 2.48 (s, 3H, CCH 3), 2.52 (t, J=5.86Hz, 2H, OCH 2CH 2), 2.64-2.74 (m, 2H, fatty CH), 2.85-2.89 (m, 1H, fatty CH), 3.31 (dd, J=18.56,7.08Hz, 1H, fatty CH), 4.14-4.27 (m, 2H, OCH 2CH 2), 6.58 (d, J=8.55Hz, 1H, ArH), 7.02 (d, J=8.79Hz, 1H, ArH), 11.56 (s, 1H, NH); MS (APCI+): m/z412.2 (MH +) .C 24H 33N 3O 3Computational analysis value: C, 70.04; H, 8.08; N, 10.21. measured value: C, 70.01; H, 8.20; N, 9.98.
Embodiment 72
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(1-pyrrolidyl) ethyl ester
Figure A9981647501871
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(1-pyrrolidyl) ethyl ester according to method N by 2-tetramethyleneimine-1-base-ethanol (1.02g, 8.85mmol) synthesize, and obtain white solid: mp195-196 ℃ of 0.253g (26.0%) with the t-butyl methyl ether grinding;
IR (KBr) 3377,2930,1700,1432,1081cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.12-1.78 (m, 10H, fatty CH), 1.61-1.69 (m, 8H, the CH of ring 2), 1.92 (d, J=13.26Hz, 1H, fatty CH), 2.37 (d, J=10.61Hz, 1H, fatty CH), 2.47-2.49 (m, 1H, fatty CH), 2.50 (s, 3H, CH 3), 2.66-2.76 (m, 2H, fatty CH), 2.72 (t, J=6.51Hz, 2H, OCH 2CH 2), 2.87-2.93 (m, 1H, fatty CH), 3.32 (dd, J=19.05,13.02Hz, 1H, fatty CH), 4.19-4.30 (m, 2H, OCH 2CH 2), 6.60 (d, J=8.68Hz, 1H, ArH), 7.04 (d, J=8.68Hz, 1H, ArH), 11.49 (s, 1H, NH); MS (APCI+): m/z438.2 (MH +) .C 26H 35N 3O 3Computational analysis value: C, 71.37; H, 8.06; N, 9.60. measured value: C, 70.99; H, 8.13; N, 9.49.
Embodiment 73
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(1-naphthyl) ethyl ester
Figure A9981647501881
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(1-naphthyl) ethyl ester according to method N by 1-naphthalene-1-base-ethanol (2.32g, 13.5mmol) synthesize, and obtain fine white powder: mp140-145 ℃ of 0.707g (40.9%) with the ether grinding;
IR (KBr) 3387,2929,1682,1432,1078cm -1 1H NMR (400MHz, DMSO-d 6) δ 0.94-1.72 (m, 10H, fatty CH), 1.72 (d, J=2.69Hz, 3H, OCHCH 3), 1.83 (d, J=12.94Hz, 1H, fatty CH), 2.30-2.63 (m, 3H, fatty CH), 2.50﹠amp; 2.52 (s, 3H, CCH 3, diastereomer), 2.83-2.88 (m, 2H, fatty CH), 3.21 (dd, J=32.72,26.12Hz, 1H, fatty CH), 6.52-6.58 (m, 1H, ArH), 6.74-6.75 (m, 1H, OCHCH 3), 6.98-7.03 (m, 1H, ArH), 7.46-7.65 (m, 4H, ArH), 7.84-7.89 (m, 1H, ArH), 7.93-7.96 (m, 1H, ArH), 8.12-8.14 (m, 1H, ArH), 11.54 (s, 1H, NH); MS (APCI+): m/z513.1 (MH +) .C 32H 34N 2O 3Computational analysis value: C, 76.66; H, 6.92; N, 5.58. measured value: C, 76.29; H, 6.96; N, 5.40.
Embodiment 74
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring butyl ester
Figure A9981647501891
Steps A: 1-phenyl-cyclobutanol
Figure A9981647501892
To phenyl-magnesium-bromide (1M in THF, 148mL, in 87mL anhydrous ether solution 148mmol), 0 ℃ add down the cyclobutanone that is present in the 15mL ether (10.0g, 143mmol).This reaction mixture was stirred in ice bath 1 hour.The adding saturated ammonium chloride also stirred 10 minutes.With this reaction mixture H 2(dried over mgso is used in 2 * 250mL) washings to O, and the concentrated yellow oil that obtains.This product by flash column chromatography on silica gel purifying (10% acetone: hexane) obtain the yellow oil of 10.1g (47.7%): 1H NMR (400MHz, CDCl 3) δ 1.62-1.73 (m, 1H, CCH 2CH 2), 1.94-2.09 (m, 1H, CCH 2CH 2), 2.29-2.38 (m, 2H, CCH 2), 2.50-2.57 (m, 2H, CCH 2), 2.68 (s, 1H, OH), 7.21-7.29 (m, 1H, ArH), 7.31-7.38 (m, 2H, ArH), 7.38-7.50 (m, 2H, ArH); MS (APCI+): m/z171.5 (MH +).
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring butyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring butyl ester according to method N by 1-phenyl-cyclobutanol (1.33g, 9.00mmol) synthesize, and grind the white powder that obtains 0.201g (19.0%) with ether: mp218-220 ℃;
IR (KBr) 3328,2930,1674,1434,1080cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.09-1.84 (m, 10H, fatty CH), 1.94-2.00 (m, 1H, fatty CH), 2.33 (d, J=9.03Hz, 1H, fatty CH), 2.40-2.46 (m, 1H, fatty CH), 2.46 (s, 3H, CCH 3), 2.56 (s, 6H, the C (CH of ring 2) 3Ar), 2.52-2.64 (m, 2H, fatty CH), 2.83-2.88 (m, 1H, fat CH), 3.15 (dd, J=18.80,7.08Hz, 1H, fatty CH), 6.56 (d, J=8.55Hz, 1H, ArH), 7.00 (d, J=8.55Hz, 1H, ArH), 7.22 (t, J=7.08Hz, 1H, ArH), 7.33 (t, J=7.57Hz, 2H, ArH), 7.47 (d, J=7.32Hz, 2H, ArH), 11.48 (s, 1H, NH); MS (APCI+): m/z671.1 (MH +) .C 30H 35N 2O 3Computational analysis value: C, 74.72; H, 7.56; N, 5.81. measured value: C, 74.43; H, 7.26; N, 5.41.
Embodiment 75
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring propyl ester
Figure A9981647501901
Steps A: 1-phenyl-ring propyl alcohol
1-phenyl-ring propyl alcohol is pressed Kulinkovich, O.G.; Sviridov, S.V.; Vasilevskii, D.A.; Savchenko, A.I.; Pritytskaya, T.S.J.Org.Chem.USSR (English) 1991; The method of describing among the 27:250-253 is synthetic.
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i) quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring propyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring propyl ester according to method N by 1-phenyl-ring propyl alcohol (1.22g, 9.00mmol) synthesize, and grind the glossiness yellow powder that obtains 0.078g (7.57%) with ether: mp130-135 ℃;
IR (KBr) 3384,2929,1690,1431,1069cm -1 1HNMR (400MHz, DMSO-d 6) δ 1.06-1.69 (m, 10H, fatty CH), 1.86 (d, J=13.43Hz, 1H, fatty CH), 2.34 (d, J=10.01Hz, 1H, fatty CH), 2.41-2.44 (m, 1H, fatty CH), 2.46 (s, 3H, CCH 3), 2.52 (s, 4H, the C (CH of ring 2) 2Ar), 2.63-2.70 (m, 2H, fatty CH), 2.81-2.89 (m, 1H, fatty CH), 3.20 (dd, J=18.56,7.33Hz, 1H, fatty CH), 6.59 (d, J=8.55Hz, 1H, ArH), 7.03 (d, J=8.55Hz, 1H, ArH), 7.15-7.19 (m, 3H, ArH), 7.26-7.30 (m, 2H, ArH), 11.57 (s, 1H, NH); MS (APCI+): m/z457.1 (MH +) .C 29H 32N 2O 3: computational analysis value: C, 76.29; H, 7.06; N, 6.14. measured value: C, 76.12; H, 7.39; N, 5.83.
Embodiment 76
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-pyrazinyl ethyl ester
Figure A9981647501911
Steps A: 1-pyrazine-2-base-ethanol
Figure A9981647501912
(5.00g in 100mL MeOH solution 40.9mmol), adds NaBH at 0 ℃ in batches to 1-pyrazine-2-base-ethyl ketone 4(0.774g, 20.5mmol).Stirred 24 hours under the room temperature, this reaction mixture is also used dichloromethane extraction (3 * 100mL) with 1N HCl stopped reaction.Organic layer is with dried over sodium sulfate and concentrate the yellow oil that obtains 2.60g (51.2%): 1HNMR (400MHz, CDCl 3) δ 1.54 (d, J=6.59Hz, 3H, CHCH 3), 3.54 (s, 1H, OR), 4.97 (q, J=6.59Hz, 1H, CH 3CH), 8.49 (s, 2H, NCHCHN), 8.65 (s, 1H, CCHN); MS (APCI+): m/z125.1 (MH +).
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-pyrazinyl ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-pyrazinyl ethyl ester according to method N by 1-pyrazine-2-base-ethanol (1.12g, 9.00mmol) synthesize, and grind the crude product white powder end that obtains 0.303g (30.3%) with cold acetone: mp224-225 ℃;
IR (KBr) 3172,2930,1704,1431,1073cm -1 1HNMR (400MHz, DMSO-d 6) δ 1.06-1.63 (m, 10H, fatty CH), 1.61 (d, J=3.17Hz, 3H, OCHCH 3), 1.77-1.98 (m, 1H, fatty CH), 2.34 (d, J=10.25Hz, 1H, fatty CH), 2.40-2.43 (m, 1H, fatty CH), 2.52﹠amp; 2.53 (s, 3H, CCH 3, diastereomer), 2.62-2.68 (m, 1H, fatty CH), 2.84-2.87 (m, 1H, fatty CH), 3.12 (dd, J=19.04,6.84Hz, 1H, fatty CH), 5.99 (q, J=7.08Hz, 1H, OCHCH 3), 6.56-6.60 (m, 1H, ArH), 7.01-7.04 (m, 1H, ArH), 8.57 (s, 1H, ArH), 8.62 (s, 1H, ArH), 8.71﹠amp; (8.73 s, 1H, ArH, diastereomer), 11.56 (s, 1H, NH); MS (APCI+): m/z447.1 (MH +) .C 26H 30N 4O 3Computational analysis value: C, 69.90; H, 6.79; N, 12.50. measured value: C, 69.51; H, 6.78; N, 12.35.
Embodiment 77
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-quinolyl) ethyl ester Steps A: 1-quinolyl-4-ethanol
Figure A9981647501931
Under-40 ℃, to quinoline-4-formaldehyde (5.00g, in 127mL anhydrous THF solution 31.8mmol), add methyl-magnesium-bromide (13.8mL, 41.4mmol).Stir after 5 hours, this reaction mixture is also used ethyl acetate extraction (5 * 100mL) with the saturated ammonium chloride stopped reaction.Dried over sodium sulfate is used in organic layer salt water washing, and the concentrated purple solid that obtains.This solid grinds the lavender solid that obtains 4.52g (82.2%) with acetone:
1H?NMR(400MHz，CDCl 3)δ1.60(d，J＝6.35Hz，3H，CHCH 3)，3.70(s，1H，OH)，5.62(q，J＝6.35Hz，1H，CHCH 3)，7.50(t，J＝7.57Hz，1H，CCCHCH)，7.56(d，J＝4.40Hz，1H，NCHCH)，7.63(t，J＝7.32Hz，1H，NCCHCH)，7.97(d，J＝8.55Hz，1H，CCCHCH)，8.05(d，J＝8.30Hz，1H，NCCHCH)，8.73(d，J＝4.39Hz，1H，NCHCH)，MS(APCI+)：m/z174.1(MH +).
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-quinolyl) ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-quinolyl) ethyl ester according to method N by 1-quinolyl-4-ethanol (1.56g, 9.00mmol) synthesize, and grind the pale yellow powder that obtains 0.192g (17.1%) with acetone: mp165-168 ℃;
IR (KBr) 2930,2853,1690,1429,1074cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.00-1.46 (m, 10H, fatty CH), 1.70 (d, J=6.35Hz, 3H, OCHCH 3), 1.85 (d, J=13.18Hz, 1H, fatty CH), 2.32-2.63 (m, 3H, fatty CH), 2.57﹠amp; 2.58 (s, 3H, CCH 3, diastereomer), 2.83-2.86 (m, 2H, fatty CH), 3.20 (dd, J=18.31,6.84Hz, 1H, fatty CH), 6.55-6.58 (m, 1H, ArH), 6.65 (q, J=6.59Hz, 1H, OCHCH 3), 7.01-7.05 (m, 1H, ArH), 7.50-7.54 (m, 1H, ArH), 7.63-7.67 (m, 1H, ArH), and 7.75-7.79 (m, 1H, ArH), 8.04-8.06 (m, 1H, ArH), 8.21-8.23 (m, 1H, ArH), 8.84-8.88 (m, 1H, ArH), 11.61 (s, 1H, NH); MS (APCI+): m/z496.2 (MH +) .C 31H 33N 3O 3Computational analysis value: C, 74.12; H, 7.00; N, 7.83. measured value: C, 73.73; H, 7.09; N, 7.44.
Embodiment 78
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-pyrimidyl) ethyl ester
Figure A9981647501941
Steps A: 1-pyrimidine-2-base-ethyl ketone
1-pyrimidine-2-base-ethyl ketone is according to Naumenko, I.I.; Mikhaleva, M.A.; Mamaev, V.P.Chem.Het.Cmpds.1981; The method of describing among the 17:710-714 is synthetic.
Step B:1-pyrimidine-2-base-ethanol
(2.34g in 65mL MeOH solution 19.2mmol), adds NaBH at 0 ℃ in batches to 1-pyrimidine-2-base-ethyl ketone 4(0.726g, 19.2mmol).Stirred 4 hours under the room temperature, this reaction mixture is also used dichloromethane extraction (3 * 100mL) with 1N HCl stopped reaction.Organic layer is with dried over sodium sulfate and concentrate the yellow oil that obtains 0.984g (41.3%): 1HNMR (400MHz, DMSO-d 6) δ 1.36 (d, J=6.59Hz, 3H, CHCH 3), 4.73 (q, J=6.59Hz, 1H, CH 3CH), 5.21 (s, 1H, OH), 7.33-7.36 (m, 1H, NCHCH), 8.73-8.77 (m, 2H, NCHCH); MS (APCI+): m/z125.1 (MH +).
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-pyrimidyl) ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-pyrimidyl) ethyl ester according to method N by 1-pyrimidine-2-base-ethanol (1.01g, 8.10mmol) synthesize, and obtain thin pale powder: mp220-222 ℃ of 0.360g (29.9%) with the acetone grinding;
IR (KBr) 3176,2932,1686,1426,1078cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.06-1.54 (m, 10H, fatty CH), 1.59 (d, J=6.59Hz, 3H, OCHCH 3), 1.84 (d, J=13.92Hz, 1H, fatty CH), 2.34-2.55 (m, 2H, fatty CH), 2.58 (s, 3H, CCH 3), 2.64-2.69 (m, 2H, fatty CH), 2.81-2.86 (m, 1H, fatty CH), 3.17 (dd, J=18.31,6.59Hz, 1H, fatty CH), 5.84 (q, J=6.84Hz, 1H, OCHCH 3), 6.57 (d, J=8.79Hz, 1H, ArH), 7.02 (d, J=9.03Hz, 1H, ArH), 7.37-7.38 (m, 1H, ArH), 8.76-8.77 (m, 2H, ArH), 11.53 (s, 1H, NH); MS (APCI+): m/z447.1 (MH +) .C 26H 30N 4O 3Computational analysis value: C, 69.86; H, 7.04; N, 12.07. measured value: C, 69.50; H, 6.94; N, 11.71.
Embodiment 79
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-chloro-7,8,9,10,12,13,14, and 14a, 15-decahydro-2-methyl-, the phenyl methyl esters
Figure A9981647501951
Steps A: 6-chloro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester
Figure A9981647501961
To 3-amino-but-2-ene acid benzyl ester (10.1g in 211mL EtOH solution 52.9mmol), adds 2-chloro-1, the 4-benzoquinones (9.04g, 63.4mmol).After 24 hours, this mixture is cooled to room temperature and the concentrated brown oil that obtains 50 ℃ of heating.Hexane) and obtain the pale yellow powder of 1.02g (5.12%) with re-crystallizing in ethyl acetate this product is by flash column chromatography purifying (20% ethyl acetate:: mp 221-224 ℃ on silica gel; IR (KBr) 3409,3226,1642,1461,1181cm -1 1H NMR (400MHz, DMSO-d 6) δ 2.55 (s, 3H, CCH 3), 5.29 (s, 2H, OCH 2Ar), 7.27 (s, 1H, ArH), 7.30 (d, J=6.84Hz, 1H, ArH), 7.36 (t, J=8.30Hz, 2H, ArH), 7.42 (d, J=7.57Hz, 2H, ArH), 7.50 (s, 1H, ArH), 9.56 (s, 1H, OH), 11.67 (s, 1H, NH); MS (APCI+): m/z316.1 (MH +) .HPLC (ALLTCH/ALLTIMA C-18 50: 50-2: 98 H 2O/CH 3CN+0.05%TFA): retention time=5.47min, 95.86% purity
Step B:6-chloro-4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester
6-chloro-4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester according to method L by 6-chloro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (7.77g, 24.6mmol) synthesize, and grind the white solid that obtains 6.77g (73.8%) with cold ethanol: mp178-180 ℃;
IR (KBr) 3298,2951,1687,1425,1437,1264,1078cm -1 1HNMR (400MHz, DMSO-d 6) δ 2.14 (s, 6H, N (CH 3) 2) 4.06 (s, 2H, NCH 2Ar), 5.23 (s, 2H, OCH 2Ar), 7.22 (s, 1H, ArH), 7.31-7.39 (m, 3H, ArH), 7.44 (d, J=6.84Hz, 2H, ArH), 11.85 (s, 1H, NH); MS (APCI+): m/z373.1 (MH +) .HPLC (ALLTCH/ALLTIMA C-18 50: 50-2: 98 H 2O/CH 3CN+0.05%TFA): retention time=3.10min, 99.09% purity.
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-chloro-3,7,8,9,10,12,13,14, and 14a, 15-decahydro-2-methyl-, the phenyl methyl esters
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2 methyl-, the phenyl methyl esters according to method M by 6-chloro-4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (6.77g, 18.2mmol) synthesize, and grind the glossiness powder that obtains 6.05g (71.7%) with acetone: mp90-93 ℃;
IR (KBr) 3291,2933,2858,1673,1427,1076cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.01-1.71 (m, 10H, fatty CH), 1.75 (d, J=13.43Hz, 1H, fatty CH), 2.37 (d, J=10.50Hz, 1H, fatty CH), 2.45-2.46 (m, 1H, fatty CH), 2.46 (s, 3H, CCH 3), 2.64-2.74 (m, 2H, fatty CH), 2.94-2.99 (m, 1H, fatty CH), 3.38 (dd, J=18.56,7.08Hz, 1H, fatty CH), 5.21 (dd, J=26.12,12.21Hz, 2H, OCH 2Ar), 7.18 (s, 1H, ArH), 7.29-7.43 (m, 5H, ArH), 11.62 (s, 1H, NH); MS (APCI+): m/z465.2 (MH +) .C 27H 29N 2O 3Cl 1
Computational analysis value: C, 69.74; H, 6.29; N, 6.02. measured value: C, 69.45; H, 6.68; N, 5.82.
Embodiment 80
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-chlorine 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl, 1-(4-fluorophenyl) ethyl ester
Figure A9981647501971
Steps A: with benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl, acid anhydrides
Figure A9981647501981
In 250mL three neck round-bottomed flasks, add pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3 successively, 2-i] quinolizine-1-formic acid, 5-chlorine 3,7,8,9,10,12,13,14,14a, 15-decahydro-2 methyl-, (embodiment 79, step C for the phenyl methyl esters, 5.44g, 11.7mmol), THF (58.6mL, 0.2M), Et 3N (1.63mL, 11.7mmol) and 10%Pd (OH) 2/ C (1.26g).This mixture was stirred 1 hour down in nitrogen atmosphere (balloon).This reaction mixture is filtered by the diatomite plate, and again this yellow filtrate is carried out the next step.In this yellow filtrate, drip Benzoyl chloride (1.36mL, 11.7mmol).Obtain brown oil with stirring 48 hours under this mixture room temperature and removing to desolvate.Grind the yellow powder that obtains 3.50g (62.4%) with acetone: mp160-165 ℃;
1H NMR (400MHz, DMSO-d 6) δ 1.10-1.58 (m, 10H, fatty CH), 1.83 (d, J=12.94Hz, 1H, fatty CH), 2.41-2.46 (m, 2H, fatty CH), 2.51 (s, 3H, CCH 3), 2.66-2.71 (m, 1H, fatty CH), 2.98-3.01 (m, 2H, fatty CH), 3.38 (dd, J=17.82,6.59Hz, 1H, fatty CH), 7.29 (s, 1H, ArH), 7.58 (t, J=7.57Hz, 2H, ArH), 7.74 (t, J=7.57Hz, 1H, ArH), 8.07 (d, J=7.08Hz, 2H, ArH), 12.14 (s, 1H, NH); MS (APCI+): m/z479.1 (MH +).
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl, 1-(4-fluorophenyl) ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2 methyl-, 1-(4-fluorophenyl) ethyl ester according to method N by 1-(4-fluoro-phenyl)-ethanol (0.900g, 7.16mmol) and with benzoic pyrrolo-[3 ', 2 ': 5,6] [1]-chromene [3,2-i] quinolizine-1-formic acid also, 5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl, acid anhydrides (0.857g, 1.79mmol) synthetic.This product obtains the white powder of 0.210g (23.6%) with the t-butyl methyl ether recrystallization: mp102-107 ℃;
IR (KBr) 2934,2859,1674,1428,1055cm -1 1H NMR (400MHz, DMSO-d 6) δ 1.06-1.81 (m, 11H, fatty CH), 1.55 (d, J=6.59Hz, 3H, OCHCH 3), 2.37 (d, J=10.25Hz, 1H, fatty CH), 2.44-2.46 (m, 1H, fatty CH), 2.46 (s, 3H, CCH 3), 2.63-2.75 (m, 2H, fatty CH), 2.97-3.14 (m, 1H, fatty CH), 3.20 (dd, J=13.18,6.59Hz, 1H, fatty CH), 5.95 (q, J=6.59Hz, 1H, OCHCH 3), 7.15-7.19 (m, 3H, ArH), 7.43-7.49 (m, 2H, ArH), 11.62 (s, 1H, NH); MS (APCI+): m/z497.2 (MH +) .C 28H 30N 2O 3F 1Cl 1Computational analysis value: C, 66.82; H, 6.15; N, 5.57. measured value: C, 66.96; H, 6.39; N, 5.46.
Embodiment 81
Quinolizine, the 1-[[(4-fluorophenyl) methoxyl group] carbonyl]-5-hydroxy-2-methyl-1H-indoles-4-yl] methyl]-1,2,3,4,6,7,8, the 9-octahydro-, muriate
To pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1 formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-fluorophenyl) methyl esters (0.500g, 1.11mmol) the 125mL dichloromethane solution in, add ether HCl in batches and become muddy up to this solution.Except that after desolvating, this yellow residue is ground the white powder that obtains 0.307g (61.0%) with acetone: mp179-185 ℃;
IR (KBr) 3408,3193,2934,1697,1431,1152cm -1 1H NMR (400MHz, CDCl 3) δ 1.37-1.52 (m, 1H, fatty CH), 1.52-1.77 (m, 8H, fatty CH), 2.07-2.15 (m, 1H, fatty CH), 2.26 (d, J=14.65Hz, 1H, fatty CH), 2.40-2.54 (m, 2H, fatty CH), 2.58 (s, 3H, CCH 3), 3.10-3.18 (m, 2H, fatty CH), 3.34-3.48 (m, 2H, fatty CH), 5.28 (dd, J=14.65,12.45Hz, 2H, OCH 2Ar), 6.78 (d, J=14.65Hz, 1H, ArH), 7.05 (t, J=8.55Hz, 1H, ArH), 7.14 (d, J=8.79Hz, 1H, ArH), 7.41 (t, J=5.37Hz, 1H, ArH), 8.58 (s, 1H, OH), 12.52 (s, 1H, NH); MS (APCI+): m/z449.3 (MH +) .C 27H 30N 2O 3F 1Cl 1Computational analysis value: C, 66.87; H, 6.23; N, 5.78; Cl, 7.31; F, 3.92. measured value: C, 66.37; H, 6.27; N, 5.69; Cl, 7.64; F, 4.02.
Embodiment 82
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-1, the 2-dimethyl-, (4-fluorophenyl) methyl esters
To be present in pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3, the 2-i] quinolizine-1-formic acid also among the 20mL DMF, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (0.500g 1.11mol) joins NaH (60% dispersion in mineral oil, 0.049g to (4-fluorophenyl) methyl esters, 1.23mmol, use hexane wash), and at room temperature stirred 1 hour.(0.076mL 1.23mol) joins this reaction mixture methyl iodide.This reaction was stirred 2 hours, use 15mL H 2The O stopped reaction, and with extracted with diethyl ether (5 * 50mL).Organic layer concentrates and obtains yellow solid, and it grinds with acetone and obtains white solid: mp179-180 ℃ of 0.274g (52.7%);
IR (KBr) 3466,2932,2854,1673,1482,1155cm -1 1H NMR (400MHz, CDCl 3) δ 1.06-1.21 (m, 3H, fatty CH), 1.36-1.58 (m, 7H, fatty CH), 1.79 (d, J=14.20 Hz, 1H, fatty CH), 2.34 (d, J=10.74 Hz, 1H, fatty CH), 2.42-2.49 (m, 2H, fatty CH), 2.49 (s, 3H, CCH 3), 2.64 (t, J=10.74Hz, 1H, fatty CH), 2.86 (t, J=11.48Hz, 1H, fatty CH), 3.10 (dd, J=18.31,6.84Hz, 1H, fatty CH), 3.59 (s, 3H, NCH 3), 5.21 (dd, J=29.05,11.96 Hz, 2H, OCH 2Ar), 6.64 (d, J=8.79 Hz, 1H, ArH), 7.16-7.22 (m, 3H, ArH), 7.48 (t, J=7.81Hz, 1H, ArH); MS (APCI+): m/z463.1 (MH +) .C 28H 31N 2O 3F 1Computational analysis value: C, 72.71; H, 6.76; N, 6.06. measured value: C, 72.89; H, 6.72; N, 5.92.
Embodiment 83
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-phenyl propyl ester
Figure A9981647502011
Steps A: 5-acetoxyl group-2-Methyl-1H-indole-3-formic acid-1-phenyl-propyl ester
This mixture prepares according to method A.White solid, mp144-145.5 ℃; MS (APCI-): m/z 350.1 (M-H).
Step B:5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 1-phenyl-propyl ester
Figure A9981647502021
5-acetoxyl group-2-Methyl-1H-indole-3-formic acid, (1.36g 3.86mmol) with the 10mL methanol mixed, adds NaOCH to 1-phenyl-propyl ester then 3(0.834g, 15.4mmol).With gained reaction mixture stirring and refluxing 1 minute, be cooled to room temperature then.This reaction mixture is mixed with 10mL water again, and the gained reaction mixture is handled to pH=1 with 5%HCl and is obtained white precipitate.This mixture ethyl acetate extraction (2 * 60mL).The organic mixture that merges obtains black thickness oily matter with dried over sodium sulfate and vacuum concentration, and it is further by chromatogram purification, obtains the required product of 1.13g (98%) with the 10%MeOH that is present in the trichloromethane as eluent, is brown solid: 1H NMR (DMSO-d 6) δ 0.917 (t, J=7.33Hz, 3H, CHCH 2CH 3), 1.84-2.03 (m, 2H, CHCH 2CH 3), 2.59 (s, 3H, ArCH 3), 5.84 (t, J=5.68Hz, 2H, CHCH 2CH 3), 6.59 (dd, J=8.61,2.38Hz, 1H, ArH), 7.12 (d, J=8.61Hz, 1H, ArH), 7.23-7.41 (m, 6H, ArH), 8.87 (s, 1H, exchangeable protons), 11.6 (bs, 1H, exchangeable protons).
Step C:4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid, 1-phenyl-propyl ester
Figure A9981647502022
5-hydroxy-2-methyl-1H-indole-3-carboxylic acid, 1-phenyl-propyl ester (1.07g, 3.60mmol) and dimethylamine agueous solution (40%, 0.99mL 7.92mmol) mixes with 2.4mL EtOH, this mixture with heating gun heating up to obtaining clear solution.After being cooled to room temperature, and the adding HCHO aqueous solution (37%, 0.35g, 4.3mmol).The gained reaction mixture stirred 4 hours down at 50 ℃, at room temperature stirred then 12 hours.This reaction mixture is diluted with EtOAc (30mL), wash with water (2 * 30mL), and use dried over sodium sulfate.Vacuum concentration then carries out chromatogram purification, uses 100%EtOAc, and the 10%MeOH that is present in then in the trichloromethane obtains the pure title compound of 0.50g (38%) as eluent, is yellow foam: mp50-62 ℃ (decomposition); MS (APCI +): m/z367.2 (MH +).
Step D: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-phenyl propyl ester
In the mixture of perchlorate (embodiment 3, step B for 0.38g, 1.6mmol) and 30mL ether, add 30mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layerly, water layer is with extracted with diethyl ether (2 * 30mL).The ether layer that merges is with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 10mL diox, and (0.45g, 1.2mmol), the gained reaction mixture refluxed 18 hours under nitrogen atmosphere to add indoles mannich alkali then.This reaction mixture is cooled to room temperature and vacuum concentration obtains thickness oily matter.Crude product further obtains the title compound of 0.40g (71%) by chromatogram purification (50%EtOAc is in hexane), be white foam: mp90-115 ℃; MS (APCI +): m/z459.3 (MH +).
Embodiment 84
Quinoline, 1,2,3,4,6,7,8,9-octahydro-1-[[5-hydroxy-2-methyl-3-[(phenyl methoxyl group) carbonyl]-1H-indoles-4-yl] methyl]-, muriate
Figure A9981647502041
To pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1 formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (0.209g in dichloromethane solution 0.485mmol), adds ether HCl to the phenyl methyl esters.Stirred 1 minute under the room temperature, with this reaction mixture vacuum concentration.This resistates grinds with 2-butanone.Filter, then vacuum-drying obtains the required product of 0.18g (79%), is white solid: MS (APCI+): m/z431.3 (MH +).Analysis theories value C 27H 30N 2O 31.0HCl0.3H 2O:C, 68.65; H, 6.74; N, 5.93; Cl, 7.50; H 2O, 1.14.Measured value: C, 68.62; H, 6.80; N, 6.00; Cl, 7.54; H 2O, 0.93.
Embodiment 85
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-nitrophenyl) methyl esters
Figure A9981647502042
With pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenyl methyl esters (0.149g, 0.341mmol) be dissolved in 15mL THF, in this solution, add N,N-dimethylacetamide dimethylacetal (0.5mL) and Pd (OH) 2/ C (20%, 0.125g).The gained reaction soln stirs up to this benzyl ester under room temperature, nitrogen atmosphere and thoroughly reacts.Remove by filter catalyzer, and with vacuum concentration under this filtrate room temperature, the not purified the next step that is directly used in.
In the DMF solution of the crude product of debenzylation, add nitrobenzyl bromine and DBU.To stir 16 hours under the gained reaction soln room temperature.With this reaction mixture with 50mLEtOAc dilution and with saturated sodium bicarbonate aqueous solution (3 * 50mL) and water (3 * 50mL) wash successively.After dried over sodium sulfate, this solution for vacuum concentration and by chromatogram purification twice with being present in 10%MeOH in the trichloromethane and the 50%EtOAc wash-out in hexane, obtains the required product of 28mg (17%), is yellow solid: mp240-242 ℃; MS (APCI +): m/z476.3 (MH +).
Embodiment 86
With benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, acid anhydrides
Figure A9981647502051
With pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenyl methyl esters (10.15g, 23.58mmol) be dissolved in 110mL THF, and this solution is transferred in the round-bottomed flask that has stirring rod and the three-pointswitch that is connected with balloon envelope.(3.287mL 23.58mmol), then adds Pd (OH) to add triethylamine in this solution 2/ C (20%, 2.7g).This reaction flask is charged into hydrogen several times.Stir under the gained reaction soln room temperature nitrogen atmosphere and thoroughly react (being 2 hours) herein up to this benzyl ester.Remove by filter catalyzer, and this filtrate is used for the next step.
In this filtrate, add Benzoyl chloride (2.737mL, 23.58mmol).The gained reaction soln stirred 16 hours under the room temperature under nitrogen atmosphere.Formed white precipitate is shifted out in filtration.This filtrate vacuum concentration obtains thickness oily matter; Obtain the required product of 9.18g (two step total recoverys 88%) with the ether grinding, be white solid: mp 159-160 ℃; MS (APCI+): m/z443.3 (MH +).
Total method Q: by the synthetic ester of mixed acid anhydride
With mixed acid anhydride (1eq.) and corresponding alcohol (＞2eq.) mixes, the gained slurries 120-150 ℃ of heating up to the acquisition clear solution.After being cooled to room temperature, this solution dilutes with ethyl acetate, mixes with sodium bicarbonate aqueous solution (saturated) then.This mixture was placed 5 minutes.Be divided into two-layer, and with organic layer with salt solution and water washing, use dried over mgso then.Obtain required product by flash chromatography or recrystallization purifying.
Embodiment 87
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-the 1-phenyl chlorocarbonate
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-the 1-phenyl chlorocarbonate is synthetic by (R)-(+)-1-phenylethyl alcohol according to method Q.Crude product obtains 25mg required product with 100% acetonitrile as eluent at the enterprising circumstances in which people get things ready for a trip spectrum of preparation silica-gel plate purifying, is white solid: mp100-112 ℃; MS (APCI +): m/z445.3 (MH +).
Embodiment 88
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) ethyl ester
Figure A9981647502062
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) ethyl ester is synthetic by 1-(to fluorophenyl) ethanol according to method Q.Crude product is earlier at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying (30% EtOAc in hexane as eluent), obtain the required product of 54.5mg (37%) then at the preparation enterprising circumstances in which people get things ready for a trip spectrum purifying of silica-gel plate (100% acetonitrile is as eluent), be yellow foam: mp98-110 ℃; MS (APCI +): m/z463.1 (MH +).
Total method R: by parallel synthetic 6 esters of mixed acid anhydride
Mixed acid anhydride (1eq.) and corresponding alcohol (2eq.) mix in the VWR60826-202 pipe.This pipe covered loosely and immerse in 120 ℃ of oil baths heating 7 minutes.After being cooled to room temperature, 10mL ether and 10mL saturated aqueous sodium sulfate are joined in this pipe.This mixture was stirred 1 minute, then this ether layer is transferred in the new pipe that sal epsom is housed.After 10 minutes, remove by filter sal epsom.This filtrate blows out with nitrogen gas stream and this resistates is dissolved in the 0.2mL ether again, and transfers on the SPE tube that 1g silica gel is housed.With the hexane solution wash-out of this short column with the 10%EtOAc of 20mL.Collection mainly contains the fraction of corresponding alcohol and discards.Then this post is used 5mL 10%EtOAc hexane solution wash-out.The fraction of collecting is concentrated (blowing out with nitrogen gas stream) obtain crude product.
Embodiment 89
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenyl ester
Figure A9981647502071
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenyl ester is synthetic by phenol according to method R.Not repurity of crude product: white solid; MS (APCI +): m/z417.1 (MH +).
Embodiment 90
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three fluoro-1-phenyl-1-(trifluoromethyl) ethyl esters
Figure A9981647502081
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2, by 1,1,1,3,3,3-hexafluoro-2-phenyl-2-propyl alcohol is synthetic according to method R for 2-three fluoro-1-phenyl-1-(trifluoromethyl) ethyls.Not repurity of crude product: white solid; MS (APCI-): m/z565.1 (M-H).
Embodiment 91
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, two ring [2.2.1] heptane-2-base ester
Figure A9981647502082
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, two ring [2.2.1] heptane-2-base ester is synthetic by external form-norborneol according to method R.Not repurity of crude product: white solid; MS (APCI-): m/z433.2 (M-H).
Embodiment 92
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl)-1-methyl ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl)-1-methyl ethyl ester is synthetic by 2-(4-fluorophenyl)-2-propyl alcohol according to method Q.Crude product obtains the required product of 0.15g (9%) at the enterprising circumstances in which people get things ready for a trip of silicagel column spectrum purifying (50-70% ether in hexane as eluent), is white solid mp110-112 ℃; MS (APCI +): m/z477.1 (MH +).
Embodiment 93
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring pentyl ester
Figure A9981647502092
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring pentyl ester is synthetic by 1-phenyl-1-cyclopentanol according to method Q.Crude product obtains the required product of 0.15g (6%) at the enterprising circumstances in which people get things ready for a trip of silicagel column spectrum purifying (50% ether in hexane as eluent), is white solid: mp205-206 ℃; MS (APCI +): m/z483.1 (MH +).
Embodiment 94
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-phenyl cyclohexyl
Figure A9981647502101
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-phenyl cyclohexyl is synthetic by the 1-phenylcyclohexanol according to method Q.Crude product obtains the required product of 0.13g (5%) at the enterprising circumstances in which people get things ready for a trip of silicagel column spectrum purifying (50-70% ether in hexane as eluent), is yellow solid: mp217-219 ℃; MS (APCI-): m/z497 (M-H).
Embodiment 95
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(hydroxymethyl) phenyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(hydroxymethyl) phenyl ester is synthetic by 3-hydroxybenzyl alcohol according to method Q.Crude product obtains the required product of 0.196g (16%) at the enterprising circumstances in which people get things ready for a trip of silicagel column spectrum purifying (EtOAc of 50-100% in hexane as eluent), is white foam: mp138-140 ℃; MS (APCI +): m/z447.2 (MH +).
Embodiment 96
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-hydroxy phenyl) methyl esters
Figure A9981647502111
Pyrrolo-[3 ', 2 ': 5,6] [the 1j chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-hydroxy phenyl) methyl esters is synthetic by 3-hydroxybenzyl alcohol according to method Q.Crude product obtains the required product of 0.4818g (39%) at the enterprising circumstances in which people get things ready for a trip of silicagel column spectrum purifying (EtOAc of 50-100% in hexane as eluent), is white solid: mp231-233 ℃; MS (APCI +): m/z447.1 (MH +).
Embodiment 97
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(4-pyridyl) ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(4-pyridyl) ethyl ester is synthetic by (S)-(-)-1-(4-pyridyl) ethanol according to method Q.It is yellow foam: mp105-115 ℃ that crude product obtains the required product of 0.09g at the enterprising circumstances in which people get things ready for a trip spectrum purifying of silicagel column (100%EtOAc is as eluent); MS (APCI +): m/z447.2 (MH +).
Embodiment 98
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [6-(methoxycarbonyl)-2-pyridyl] methyl esters
Figure A9981647502121
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [6-(methoxycarbonyl)-2-pyridyl] methyl esters is synthetic by 6-(hydroxymethyl)-pyridine carboxylic acid ethyl ester according to method Q.The EtOAc solution (40mL) of crude product is mixed in separating funnel with 40mL 0.5N HCl solution and fully shake, then water is alkalized to pH=1 with 2N NaOH solution, fully shake.Be divided into two-layer then.The organic layer dried over sodium sulfate.Obtain the required product of 0.87g (53%) at the enterprising circumstances in which people get things ready for a trip of silicagel column spectrum purifying (EtOAc of 50-100% in hexane as eluent), be white foam: mp90-100 ℃; MS (APCI +): m/z490.1 (MH +).
Embodiment 99
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 2-pyridyl methyl ester Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 2-pyridyl methyl ester is synthetic by 2-pyridyl methyl alcohol according to method Q.The EtOAc solution (40mL) of crude product mixes with 40mL 0.5N HCl solution in separating funnel and fully shakes, and then water is alkalized to pH=1 with the 2N sodium hydroxide solution, fully shakes.Be divided into two-layer then.After this method repeats 3 times, separate organic layer and use dried over sodium sulfate.Obtain the required product of 1.39g (72%) at the enterprising circumstances in which people get things ready for a trip of silicagel column spectrum purifying (EtOAc of 60-100% in hexane as eluent), be white foam: mp85-95 ℃; MS (APCI +): m/z432.2 (MH +).
Embodiment 100
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (6-carboxyl-2-pyridyl) methyl esters
To pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [6-(methoxycarbonyl)-2-pyridyl] methyl esters (797.4mg, 1.629mmol) MeOH (20mL) solution in, add 1NNaOH (6.5mL, 6.5mmol).Gained reaction mixture refluxed 15 minutes, vacuum concentration then.This resistates obtains the free acid of 0.62g and the mixture of sodium salt by chromatogram purification (10-30%MeOH in trichloromethane as eluent).This mixture of 0.5g is dissolved in the MeOH/ trichloromethane, mixes with 0.64mL 1N HCl then.This mixture vacuum concentration, this resistates then obtains the required product of 0.25g with recrystallizing methanol by chromatogram purification (10-30%MeOH in trichloromethane as eluent), is white solid: MS (APCI-): m/z474.1 (M-H).
Embodiment 101
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (6-carboxyl-2 pyridyl) methyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also
Figure A9981647502141
To pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (6-carboxyl 2-pyridyl) (167.5mg is in alcohol suspension 0.3522mmol) for methyl esters, the adding Choline Bicarbonate aqueous solution (5.66M, 0.056mL, 0.32mmol).The gained mixture refluxes up to obtaining clear solution.With this reaction mixture vacuum concentration, and this resistates is dissolved in the 2mL ethanol, then with the dilution of 70mL ether.In ice bath, after the cooling, filter and collect the required product that this precipitation obtains 0.15g (74%), be yellow solid: mp120-130 ℃; MS (APCI-): m/z474.1 (M-H).Analysis theories value C.H 28N 3O 51.0C 5H 14N 1O 10.2C 5H 15N 1O 21.8H 2O:C, 62.38; H, 7.71; N, 9.26.Measured value: C, 62.40; H, 7.58; N, 9.03.
Embodiment 102
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [5-(methoxycarbonyl)-3-pyridyl] methyl esters
Figure A9981647502142
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [5-(methoxycarbonyl)-3-pyridyl] methyl esters is synthetic by 5-hydroxymethyl-nicotinic acid methyl ester according to method Q.The EtOAc solution (40mL) of crude product mixes with 40mL 0.5N HCl solution in separating funnel and fully shakes, and then water is alkalized to pH=1 with the 2N sodium hydroxide solution, fully shakes.Be divided into two-layer then.After this method repeats twice, separate organic layer and use dried over mgso.Then obtain the required product of 0.4254g (25%) at the enterprising circumstances in which people get things ready for a trip of silicagel column spectrum purifying (EtOAc of 50-100% in hexane as eluent), be yellow solid: mp195-197 ℃ with the ether recrystallization; MS (APCI +): m/z490.1 (MH +).
Embodiment 103
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (5-carboxyl-3-pyridyl) methyl esters
Figure A9981647502151
To pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [5-(methoxycarbonyl)-3-pyridyl] methyl esters (391.6mg, 0.7999mmol) MeOH (30mL) solution in, add 1N NaOH (3.2mL, 3.2mmol).The gained reaction mixture stirred 60 minutes down at 50 ℃.After being cooled to room temperature, add 3.2mL 1N aqueous hydrochloric acid, then vacuum concentration.This resistates then grinds the required product that obtains 0.25g (67%) with ether by chromatogram purification (10-30%MeOH in trichloromethane as eluent), is white solid: mp224-227 ℃; MS (APCI-): m/z474.1 (M-H).
Embodiment 104
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (5-carboxyl 3-pyridyl) methyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also
Figure A9981647502161
To pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (170.3mg is in alcohol suspension 0.3580mmol) for (5-carboxyl-3-pyridyl) methyl esters, the adding Choline Bicarbonate aqueous solution (5.66M, 0.0569mL, 0.322mmol).The gained mixture refluxes up to obtaining clear solution.With this reaction mixture vacuum concentration, and this resistates is dissolved in 2mL ethanol, then with the dilution of 70mL ether.In ice bath, after the cooling, filter and collect the required product that this precipitation obtains 0.163g (79%), be beige solid: mp147-152 ℃; MS (APCI-): m/z474 (M-H).Analysis theories value C 27H 28N 3O 51.0C 5H 14N 1O 10.28C 4H 10O1.2Si 1O 21.4H 2O:C, 57.09; H, 6.89; N, 8.04.Measured value: C, 57.09; H, 6.70; N, 7.77.
Embodiment 105
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4 '-methyl [1,1 '-xenyl] 3-yl) ethyl ester
Figure A9981647502162
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4 '-methyl [1,1 '-xenyl]-3-yl) ethyl ester is synthetic by 1-(4 '-methyl-xenyl-3-yl)-ethanol according to method Q.Crude product obtains the required product of 0.67g (36%) at the enterprising circumstances in which people get things ready for a trip of silicagel column spectrum purifying (40% EtOAc in hexane as eluent), is white foam: mp105-115 ℃; MS (APCI +): m/z535 (MH +).
Embodiment 106
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2, the 6-3,5-dimethylphenyl) ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2, the 6-3,5-dimethylphenyl) ethyl ester is synthetic by 1-(2,6-dimethyl-phenyl)-ethanol according to method Q.Crude product obtains the required product of 1.02g at the enterprising circumstances in which people get things ready for a trip of silicagel column spectrum purifying (EtOAc of 30-50% in hexane as eluent), and it contains impurity, is yellow foam: mp100-105 ℃; MS (APCI +): m/z473.3 (MH +).
Method S: the method for arranging synthetic (array synthesis):
Mixed acid anhydride (1eq.) and corresponding alcohol (2-4eq.) are mixed in the VWR60826-202 pipe.This pipe is loosely covered and immerses in 120 ℃ of oil baths, up to obtaining clear solution (general 5-7 minute).After being cooled to room temperature, 6mL EtOAc and 5mL saturated aqueous sodium sulfate are joined in this pipe.And shake this mixture, and restir 1 minute, then, organic layer filters (being seated in the syringe filter) with the volumetric pipette sucking-off and by the sal epsom pad, then with 1mL EtOAc washing.This filtrate collection is dried up sample in 2-drachm (dram) bottle and with nitrogen gas stream.This resistates is carried out chromatogram purification with the ISCO system obtain required product on silicagel column.
Embodiment 107 to embodiment 142 prepares with parallel mode according to method S:
Embodiment 107
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S, 2R)-2-(dimethylamino)-1-phenyl propyl ester
MS(APCI +)：m/z502(MH +)。
Embodiment 108
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R, 2S)-2-(dimethylamino)-1-phenyl propyl ester
Figure A9981647502182
MS (APCI +): m/z502 (MH +).Embodiment 109 pyrrolo-es [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-naphthalene ester
Figure A9981647502191
MS(APCI +)：m/z?467(MH +)。
Embodiment 110
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenylbenzene methyl esters
Figure A9981647502192
MS(APCI +)：m/z507(MH +)。
Embodiment 111
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-2,3-dihydro-1H-indenes-1-base ester
MS(APCI +)：m/z457(MH +)。
Embodiment 112
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2-dihydro-1-acenaphthene ester
MS(APCI +)：m/z493(MH +)。
Embodiment 113
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, cyclohexyl (phenyl) methyl esters
MS(APCI +)：m/z513(MH +)。
Embodiment 114
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 9H-fluorenes-9-base ester
Figure A9981647502212
MS(APCI +)：m/z505(MH +)。
Embodiment 115
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2,3,4-tetrahydrochysene-1-naphthalene ester
Figure A9981647502213
MS(APCI +)：m/z471(MH +)。
Embodiment 116
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [(2R, 3R)-3-phenyl epoxy ethyl] methyl esters
Figure A9981647502221
MS(APCI +)：m/z473(MH +)。
Embodiment 117
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl, 2-oxo-1,2-phenylbenzene ethyl ester
Figure A9981647502222
MS(APCI +)：m/z535(MH +)。
Embodiment 118
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 10,11-dihydro-5H-dibenzo [a, d] suberene-5-base ester
Figure A9981647502231
MS(APCI +)：m/z533(MH +)。
Embodiment 119
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-aminomethyl phenyl) phenyl methyl esters
MS(APCI +)：m/z521(MH +)。
Embodiment 120
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, cyclopropyl (4-fluorophenyl) methyl esters
Figure A9981647502241
MS(APCI +)：m/z489(MH +)。
Embodiment 121
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3,4-dihydro-2H-benzo thiapyran-4-base ester
Figure A9981647502242
MS(APCI +)：m/z489(MH +)。
Embodiment 122
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(2-bromophenyl) ethyl ester
Figure A9981647502251
MS(APCI +)：m/z524(MH +)。
Embodiment 123
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2, the 2-trifluoro ethyl ester
Figure A9981647502252
MS(APCI +)：m/z423(MH +)。
Embodiment 124
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [(2S, 3S)-3-phenyl epoxy ethyl] methyl esters
Figure A9981647502253
MS (APCI +): m/z475 (MH +).
Embodiment 125
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three fluoro-1-methyl isophthalic acids-(trifluoromethyl) ethyl ester
Figure A9981647502261
MS(APCI +)：m/z505(MH +)。
Embodiment 126
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three fluoro-1-(4-fluorophenyl)-1-(trifluoromethyl) ethyl ester
Figure A9981647502262
MS (APCI +): m/z585 (MH +).Embodiment 127 pyrrolo-es [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-cyclopentyl-1-phenyl chlorocarbonate
MS(APCI +)：m/z513(MH +)。
Embodiment 128
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[1,1 '-xenyl]-4-base-1-methyl ethyl ester
Figure A9981647502272
MS(APCI +)：m/z535(MH +)。
Embodiment 129
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl isophthalic acid-phenyl-2-propynyl ester
MS(APCI +)：m/z469(MH +)。
Embodiment 130
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-phenylbenzene ethyl ester
Figure A9981647502282
MS(APCI +)：m/z521(MH +)。
Embodiment 131
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl isophthalic acid, 2-phenylbenzene ethyl ester
Figure A9981647502291
MS(APCI +)：m/z535(MH +)。
Embodiment 132
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) cyclohexyl
MS(APCI +)：m/z517(MH +)。
Embodiment 133
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2-phenylbenzene ethyl ester
Figure A9981647502301
MS(APCI +)：m/z521(MH +)。
Embodiment 134
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-phenyl-2-propynyl ester
Figure A9981647502302
MS(APCI +)：m/z455(MH +)。
Embodiment 135
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [1,1 ,-xenyl]-4-base methyl esters
MS(APCI +)：m/z507(MH +)。
Embodiment 136
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 4-pyridyl methyl ester
Figure A9981647502311
MS(APCI +)：m/z432(MH +)。
Embodiment 137
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2,3,4-tetrahydrochysene-7,8-dimethoxy-2-methyl-4-isoquinoline 99.9 ester
Figure A9981647502312
MS(APCI +)：m/z546(MH +)。
Embodiment 138
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[3-(dimethylamino) phenyl] and ethyl ester
Figure A9981647502321
MS(APCI +)：m/z488(MH +)。
Embodiment 139
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl-2-pyrazinyl ethyl ester
MS(APCI +)：m/z475(MH +)。
Embodiment 140
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-(dipropyl amino)-1,1-dimethyl-2-butyne ester
Figure A9981647502331
MS (APCI +): m/z520 (MH +).
Embodiment 141
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-2,3-dihydro-1H-indenes-1-base ester
Figure A9981647502332
MS (APCI +): m/z457 (MH +).
Embodiment 142
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S, 2S)-2-(dimethylamino)-1-phenyl propyl ester
MS(APCI +)：m/z502(MH +)
Embodiment 143
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(trifluoromethyl) phenyl] methyl esters
Figure A9981647502342
Steps A: 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid-4-trifluoromethyl benzyl ester
To 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (4.5g, 23.54mmol) and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (3.58g, 23.54mmol) in the mixture in DMF (50mL), add 2 '-bromo-2,2,2-three fluoro-are right-and dimethylbenzene (6.2g, 25.89mmol).With stirring 2 days under this mixture room temperature, between ethyl acetate and water, distribute then.Organic phase water and salt water washing obtain resistates with dried over sodium sulfate and vacuum concentration, and it obtains the required product of 4.26g (52%) with re-crystallizing in ethyl acetate, is white solid: mp224-225 ℃; MS (APCI +): m/z350.1 (MH +); Theoretical value C 18H 14F 3N 1O 3: C, 61.89; H, 4.04; N, 4.01.Measured value: C, 61.87; H, 4.00; N, 3.98.
Step B:4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-three fluoro-methyl benzyl esters
Figure A9981647502351
With 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-trifluoromethyl benzyl ester (3.0g, 8.59mmol) and dimethylamine agueous solution (40%, 2.37mL 18.9mmol) mixes with 6.7mL ethanol.This mixture heats up to obtaining clear solution with heating gun.After being cooled to room temperature, and the adding HCHO aqueous solution (37%, 0.83g, 10.31mmol).The gained reaction mixture stirs down at 50 ℃ and spends the night.This reaction mixture is concentrated in vacuo to-halfbody is long-pending to obtain solid, and it is after filtration.This solid washs the pure title compound that also vacuum-drying obtains 1.8g (52%) with alcohol-water, is the canescence foam: MS (APCI +): m/z407.2 (MH +).
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(trifluoromethyl) phenyl] methyl esters
Figure A9981647502352
In the mixture of perchlorate (embodiment 3, step B for 1.37g, 5.75mmol) and 100mL ether, add 150mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layerly, water layer is with extracted with diethyl ether (2 * 50mL).The ether layer that merges is with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 25mL diox, and (1.8g, 4.42mmol), the gained reaction mixture refluxed 6 hours under nitrogen atmosphere to add indoles mannich alkali then.This reaction mixture is cooled to room temperature, and vacuum concentration obtains thickness oily matter.Crude product further obtains 1.21g (55%) title compound by chromatogram purification (the 10%-30% ethyl acetate is in hexane), is white foam: mp97-99 ℃; MS (APCI +): m/z499.2 (MH +);
C 28H 29F 3N 2O 3Theoretical value: C, 67.46; H, 5.86; N, 5.62; F, 11.43.Measured value: C, 67.13; H, 5.86; N, 5.45; F, 11.32.
Embodiment 144
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-chloro-phenyl-) methyl esters Steps A: 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-benzyl chloride ester
Figure A9981647502362
To 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (5.0g, 26.15mmol) and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (3.98g, 26.15mmol) in the mixture in DMF (50mL), add 4-chlorine bromotoluene (5.9g, 28.77mmol).With stirring 2 days under this mixture room temperature, between ethyl acetate and water, distribute then.The organic phase water and the salt water washing that merge obtain resistates with dried over sodium sulfate and vacuum concentration, and it obtains the required product of 5.0g (61%) with re-crystallizing in ethyl acetate, is pale solid: mp236-237 ℃; MS (APCI-): m/z314.1 (M-H).
Step B:4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-benzyl chloride ester
Figure A9981647502371
With 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-benzyl chloride ester (4.0g, 12.7mmol) and dimethylamine agueous solution (40%, 3.5mL 27.8mmol) mixes with 10.4mL ethanol.This mixture heats up to obtaining clear solution with heating gun.After being cooled to room temperature, and the adding HCHO aqueous solution (37%, 1.24g, 15.2mmol).The gained reaction mixture stirs down at 50 ℃ and spends the night.This reaction mixture vacuum concentration is obtained resistates, and it carries out the pure title compound that chromatogram purification obtains 2.3g (49%) with 100% ethyl acetate as eluent is the canescence foam: MS (APCI +): m/z373.2 (MH +).
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-chloro-phenyl-) methyl esters In the mixture of perchlorate (embodiment 3, step B for 1.9g, 8.02mmol) and 150mL ether, add 200mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layer, and with water layer with extracted with diethyl ether (2 * 100mL).The ether layer that merges is with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 30mL diox, and (2.3g, 6.17mmol), the gained reaction mixture refluxed 6 hours under nitrogen atmosphere to add indoles mannich alkali then.This reaction mixture is cooled to room temperature, and vacuum concentration obtains thickness oily matter.Crude product further obtains 1.7g (59%) title compound by chromatogram purification (the 20%-25% ethyl acetate is in hexane), is white solid: mp220-221 ℃; MS (APCI +): m/z465.3 (MH +).
Embodiment 145
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, the 15-decahydro-, the phenyl methyl esters
Figure A9981647502381
Steps A: 5-hydroxyl-1H-indole-3-carboxylic acid benzyl ester
To 5-hydroxyl-1H-indole-3-carboxylic acid (4.5g, 25.4mmol) and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (3.87g, 25.4mmol) in the mixture in DMF (50mL), add bromotoluene (4.78g, 27.94mmol).With stirring 2 days under this mixture room temperature, between ethyl acetate and water, distribute then.Dried over sodium sulfate is used in organic phase water and salt water washing, and vacuum concentration obtains resistates, and it obtains the required product of 2.4g (36%) with ethyl acetate-hexane recrystallization, is pale solid: mp184-186 ℃; MS (APCI-): m/z266.1 (M-H).
Step B:4-dimethylaminomethyl-5-hydroxyl-1H-indole-3-carboxylic acid benzyl ester
With 5-hydroxyl-1H-indole-3-carboxylic acid benzyl ester (2.3g, 8.6mmol) and dimethylamine agueous solution (40%, 2.37mL 18.9mmol) mixes with 6.67mL ethanol.This mixture heats up to obtaining clear solution with heating gun.After being cooled to room temperature, and the adding HCHO aqueous solution (37%, 0.84g, 10.32mmol).The gained reaction mixture stirs down at 50 ℃ and spends the night.This reaction mixture vacuum concentration is obtained resistates, and it carries out chromatogram purification is canescence foam as the pure title compound that eluent obtains 2.16g (77%) with the 50%-100% ethyl acetate in hexane: MS (APCI +): m/z325.3 (MH +).
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, the 15-decahydro-, the phenyl methyl esters
In the mixture of perchlorate (embodiment 3, step B for 1.91g, 8.02mmol) and 150mL ether, add 200mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layerly, and water layer is with extracted with diethyl ether (2 * 100mL).The ether layer that merges is with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 30mL diox, and (2.0g, 6.17mmol), the gained reaction mixture refluxed 6 hours under nitrogen atmosphere to add indoles mannich alkali then.This reaction mixture is cooled to room temperature, and vacuum concentration obtains thickness oily matter, it obtains 1.2g (47%) title compound with the acetonitrile recrystallization, is pale solid: mp255-257 ℃; MS (APCI +): m/z417.3 (MH +).
Embodiment 146
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, the 15-decahydro-, ethyl ester
Figure A9981647502401
Steps A: 5-hydroxyl-1H-indole-3-carboxylic acid ethyl ester
Figure A9981647502402
To 5-hydroxyl-1H-indole-3-carboxylic acid (4.5g, 25.4mmol) and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (3.87g, 25.4mmol) in the mixture in DMF (50mL), add iodic ether (4.36g, 27.94mmol).Spend the night stirring under this mixture room temperature, between ethyl acetate and water, distribute then.Organic phase water and salt water washing obtain resistates with dried over sodium sulfate and vacuum concentration, and it obtains the required product of 2.2g (42%) with ethyl acetate-hexane recrystallization, is the light brown solid: MS (APCI +): m/z206.2 (MH +).
Step B:4-dimethylaminomethyl-5-hydroxyl-1H-indole-3-carboxylic acid ethyl ester
Figure A9981647502411
With 5-hydroxyl-1H-indole-3-carboxylic acid ethyl ester (2.1g, 10.23mmol) and dimethylamine agueous solution (40%, 2.83mL 22.51mmol) mixes with 7.7mL ethanol.This mixture heats up to obtaining clear solution with heating gun.After being cooled to room temperature, and the adding HCHO aqueous solution (37%, 0.99g, 12.28mmol).The gained reaction mixture stirs down at 50 ℃ and spends the night.This reaction mixture vacuum concentration is obtained resistates, and it carries out chromatogram purification is jelly as the pure title compound that eluent obtains 2.1g (78%) with the 50%-100% ethyl acetate in hexane: MS (APCI +) :) m/z263.1 (MH +).
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, the 15-decahydro-, ethyl ester
In the mixture of perchlorate (embodiment 3, step B for 2.36g, 9.9mmol) and 150mL ether, add 250mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layerly, water layer is with extracted with diethyl ether (2 * 100mL).The ether layer that merges is with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 30mL diox, and (2.0g, 7.6mmol), the gained reaction mixture refluxed 6 hours under nitrogen atmosphere to add indoles mannich alkali then.This reaction mixture is cooled to room temperature, and vacuum concentration obtains thickness oily matter, it obtains 1.7g (63%) title compound with the acetonitrile recrystallization, is pale solid: mp242-244 ℃;
MS(APCI +)：m/z355.3(MH +)。
Embodiment 147
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 2-hydroxy methacrylate
Figure A9981647502421
Steps A: 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid hydroxy methacrylate
To 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (5.0g, 26.15mmol) and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (3.91g, 26.15mmol) in the mixture in DMF (100mL), add ethylene bromohyrin (3.6g, 28.77mmol).With stirring 7 days under this mixture room temperature, between ethyl acetate and water, distribute then.Dried over sodium sulfate is used in the organic phase water and the salt water washing that merge, and vacuum concentration obtains resistates, and it carries out chromatographic grade 30%-100% ethyl acetate obtains 2.4g (39%) as eluent in hexane required product, is jelly: MS (APCI +): m/z236.1 (MH +).
Step B:4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid hydroxy methacrylate
Figure A9981647502431
With 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid hydroxy methacrylate (2.3g, 9.8mmol) and dimethylamine agueous solution (40%, 2.7mL 21.5mmol) mixes with 7.4mL ethanol.This mixture heats up to obtaining clear solution with heating gun.After being cooled to room temperature, and the adding HCHO aqueous solution (37%, 0.95g, 11.7mmol).The gained reaction mixture stirs down at 50 ℃ and spends the night.This reaction mixture vacuum concentration is obtained resistates, and it carries out chromatogram purification 100% ethyl acetate, and then 20% methyl alcohol is jelly as the pure title compound that eluent obtains 2.0g (70%) in methylene dichloride: MS (APCI +): m/z293.2 (MH +).
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 2-hydroxy methacrylate
Figure A9981647502432
In the mixture of perchlorate (embodiment 3, step B for 2.1g, 8.9mmol) and 150mL ether, add 250mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layerly, water layer is with extracted with diethyl ether (2 * 100mL).The ether layer that merges is with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 25mL diox, and (2.0g, 6.84mmol), the gained reaction mixture refluxed 6 hours under nitrogen atmosphere to add indoles mannich alkali then.This reaction mixture is cooled to room temperature, and vacuum concentration obtains resistates, be thickness oily matter, it obtains 1.6g (61%) title compound with the acetonitrile recrystallization, is light brown solid: mp221-223 ℃; MS (APCI +): m/z385.2 (MH +).
Embodiment 148
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-aminomethyl phenyl) methyl esters Steps A: 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methyl benzyl ester
Figure A9981647502442
To 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (4.0g, 20.92mmol) and 1, (3.18g is 20.92mmol) in the mixture in DMF (100mL) for 8-diazabicylo [5.4.0] 11 carbon-7-alkene, between adding α-bromo--and dimethylbenzene (4.28g, 23.1mmol).With stirring 7 days under this mixture room temperature, between ethyl acetate and water, distribute then.Organic phase water and salt water washing, use dried over sodium sulfate, and vacuum concentration obtains resistates, it carries out chromatogram purification, in hexane, obtain the required product of 3.0g (48%) with the 20%-50% ethyl acetate, be tawny solid: mp165-167 ℃ as eluent; MS (APCI +): m/z296.2 (MH +).
Step B:4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methyl benzyl ester
Figure A9981647502451
With 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methyl benzyl ester (2.7g, 9.14mmol) and dimethylamine agueous solution (40%, 2.52mL 20.1mmol) mixes with 7.4mL ethanol.This mixture heats up to obtaining clear solution with heating gun.After being cooled to room temperature, and the adding HCHO aqueous solution (37%, 0.89g, 10.97mmol).The gained reaction mixture stirs down at 50 ℃ and spends the night.This reaction mixture vacuum concentration is obtained resistates, and it carries out chromatogram purification, is jelly as the pure title compound that eluent obtains 2.0g (62%) with the 50%-100% ethyl acetate in hexane: MS (APCI +): m/z353.3 (MH +).
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-aminomethyl phenyl) methyl esters
Figure A9981647502452
In the mixture of perchlorate (embodiment 3, step B for 1.75g, 7.38mmol) and 100mL ether, add 150mL aqueous sodium hydroxide solution (2N).The gained mixture shakes in separating funnel up to all solids and dissolves.Be divided into two-layerly, water layer is with extracted with diethyl ether (2 * 50mL).The ether layer that merges is with dried over sodium sulfate and vacuum concentration.Remaining oily matter is dissolved in the 25mL diox, and (2.0g, 5.67mmol), the gained reaction mixture refluxed 6 hours under nitrogen atmosphere to add indoles mannich alkali then.This reaction mixture is cooled to room temperature, and vacuum concentration obtains thickness oily matter.Crude product further obtains 1.8g (55%) title compound by chromatogram purification (the 10%-25% ethyl acetate is in hexane), is white solid: mp80-82 ℃; MS (APCI +): m/z445.4 (MH +).
Embodiment 149
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-the 1-phenyl chlorocarbonate
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-the 1-phenyl chlorocarbonate is synthetic by (S)-(-)-1-phenylethyl alcohol according to method Q.Crude product carries out chromatogram purification and obtains 75mg required product as eluent with 30% ethyl acetate in hexane, is white solid: mp98-100 ℃; MS (APCI +): m/z445.2 (MH +).
Embodiment 150
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-phenyl chlorocarbonate
Figure A9981647502462
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-phenyl chlorocarbonate is synthetic by the 1-phenylethyl alcohol according to method Q.Crude product carries out chromatogram purification, connects in hexane with 40% ether and is using 50% ethyl acetate to obtain the required product of 480mg as eluent in hexane, is white solid: mp89-90 ℃; MS (APCI +): m/z445.2 (MH +).
Embodiment 151
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carbothioic acid carbothiolic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, S-(phenyl methyl) ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carbothioic acid carbothiolic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, S-(phenyl methyl) ester is synthetic by benzyl mercaptan according to method Q.Crude product carries out chromatogram purification, obtains 150mg required product as eluent with 50% ether in hexane, is white solid: MS (APCI +): m/z447.1 (MH +).
Embodiment 152
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridyl methyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridyl methyl ester is synthetic by 3-pyridyl methyl alcohol according to method Q.Crude product carries out chromatogram purification, then obtains 400mg required product as eluent with 10% methyl alcohol in ethyl acetate with 50% ethyl acetate in hexane, is white solid: MS (APCI-): m/z430.1 (M-H).
Embodiment 153
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[4-(trifluoromethyl) phenyl] and ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[4-(trifluoromethyl) phenyl]-ethyl ester is synthetic by 4-three fluoro-methylbenzyl alcohols according to method Q.Crude product carries out chromatogram purification, obtains 180mg required product as eluent with the 40%-50% ether in hexane, is white solid: mp104-106 ℃; MS (APCI-): m/z511.1 (M-H).
Embodiment 154
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(pentafluorophenyl group) ethyl ester
Figure A9981647502482
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(pentafluorophenyl group) ethyl ester is synthetic by five fluoro-methylbenzyl alcohols according to method Q.Crude product carries out chromatogram purification and obtains 160mg required product as eluent with 40% ether in hexane, is white solid: mp93-95 ℃; MS (APCI +): m/z535.1 (MH +).
Embodiment 155
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2, the 6-difluorophenyl) ethyl ester
Figure A9981647502491
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, by 2,6-two fluoro-methylbenzyl alcohols are synthetic according to method Q for 1-(2, the 6-difluorophenyl) ethyl ester.Crude product carries out chromatogram purification, obtains 180mg required product as eluent with 40% ether in hexane, is white solid: mp85-87 ℃; MS (APCI +): m/z481.1 (MH +).
Embodiment 156
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(2-furyl) ethyl ester
Figure A9981647502501
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(2-furyl) ethyl ester is synthetic by S (-)-1-(2-furyl) ethanol according to method Q.Crude product carries out chromatogram purification and obtains 300mg required product as eluent with the 40%-60% ether in hexane, is white solid: mp84-86 ℃; MS (APCI +): m/z435.1 (MH +).
Embodiment 157
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(4-morpholinyl)-1-phenyl chlorocarbonate
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(4-morpholinyl)-1-phenyl chlorocarbonate is synthetic by α-phenyl-4-morpholine ethanol according to method Q.Crude product carries out chromatogram purification, obtains 130mg required product as eluent with the 40%-60% ether in hexane, is white solid: mp251-252 ℃; MS (APCI-): m/z528.2 (M-H).
Embodiment 158
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-1-(2-furyl) ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-1-(2-furyl) ethyl ester is synthetic by R (+)-1-(2-furyl) ethanol according to method Q.Crude product carries out chromatogram purification, obtains 300 mgs required product as eluent with the 40%-60% ether in hexane, is white solid: mp79-81 ℃; MS (APCI +): m/z435.1 (MH +).
Embodiment 159
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methoxyl group-2-oxo-1-phenyl chlorocarbonate
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methoxyl group-2-oxo-1-phenyl chlorocarbonate is synthetic by (S)-(+)-methyl-mandelic acid ester according to method Q.Crude product carries out chromatogram purification, obtains 309mg required product as eluent with the 40%-60% ether in hexane, is white solid: mp103-105 ℃; MS (APCI +): m/z489.2 (MH +).
Embodiment 160
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(3-pyridyl) ethyl ester
Figure A9981647502521
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(3-pyridyl) ethyl ester is synthetic by 1-(3-pyridyl) ethanol according to method Q.Crude product carries out chromatogram purification, in hexane, then obtains 300mg required product as eluent with 10% methyl alcohol in methylene dichloride with 50% ether, is white solid: mp78-80 ℃; MS (APCI +): m/z446.2 (MH +).
Embodiment 161
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (S)-carboxyl (phenyl) methyl esters
To pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methoxyl group-2-oxo-1-phenyl chlorocarbonate (650mg, 1.33mmol) methyl alcohol (60mL) solution in, add 1N NaOH solution (5.32mL, 5.32mmol).The gained reaction mixture stirred 1 hour down at 50 ℃, then vacuum concentration.This resistates obtains the mixture of 0.58g free acid and sodium salt by chromatogram purification (10-30% methyl alcohol in chloroform as eluent).All this mixtures (0.58g) are dissolved in methyl alcohol-chloroform, mix with 0.53mL 1N HCl then.With this mixture vacuum concentration, this resistates then obtains the required product of 0.35g with recrystallizing methanol by chromatogram purification (10-30% methyl alcohol in chloroform as eluent), is white solid: mp250-251 ℃; MS (APCI-): m/z473.1 (M-H), C 28H 30N 2O 50.36H 2O theoretical value: C, 69.91; H, 6.44; N, 5.82.Measured value: C, 69.96; H, 6.33; N, 5.59.
Embodiment 162
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (S) carboxyl (phenyl) methyl, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also
Figure A9981647502531
To pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (S)-(181mg is in ethanol 0.38mmol) (5mL) suspension for carboxyl (phenyl) methyl esters, the adding Choline Bicarbonate aqueous solution (5.66M, 0.06mL, 0.34mmol).The gained mixture refluxes up to obtaining clear solution.With this reaction mixture vacuum concentration, and this resistates is dissolved in 2mL ethanol and again with the dilution of 70mL ether.In ice bath, after the cooling, filter and collect the required product that this precipitation obtains 0.17g (77%), be pale solid: mp223-225 ℃; MS (APCI+): m/z475.2 (MH +).C 28H 29N 2O 5C 5H 14NO1.2H 2O analysis theories value: C, 66.13; H, 7.64; N, 7.01.Measured value: C, 65.96; H, 7.56; N, 6.78.
Embodiment 163
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-2-methoxyl group-2-oxo-1-phenyl chlorocarbonate
Figure A9981647502541
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-2-methoxyl group-2-oxo-1-phenyl chlorocarbonate is synthetic by (R)-(-)-methyl-mandelic acid ester according to method Q.Crude product carries out chromatogram purification and obtains 750mg required product as eluent with the 40%-60% ether in hexane, is white solid: mp106-108 ℃; MS (APCI +): m/z489.2 (MH +).
Embodiment 164
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (R)-carboxyl (phenyl) methyl esters
To pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-2-methoxyl group-2-oxo-1-phenyl chlorocarbonate (670mg, 1.37mmol) methyl alcohol (60mL) solution in, add 1N NaOH (5.5mL, 5.5mmol).The gained reaction mixture stirred 1 hour under 50 ℃ and adds 1N HCl (5.5mL).This mixture vacuum concentration obtains resistates, and it then obtains the required product of 0.35g with recrystallizing methanol by chromatogram purification (10-30% methyl alcohol in chloroform as eluent), is white solid: mp248-250 ℃; MS (APCI-): m/z473.1 (M-H).
Embodiment 165
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (R)-carboxyl (phenyl) methyl, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also
To pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (R)-(210mg is in ethanol 0.44mmo1) (5mL) suspension for carboxyl (phenyl) methyl esters, the adding Choline Bicarbonate aqueous solution (5.66M, 0.07mL, 0.40mmol).The gained mixture refluxes up to obtaining clear solution.With this reaction mixture vacuum concentration, and this resistates is dissolved in 2mL ethanol and again with the dilution of 70mL ether.In ice bath, after the cooling, filter and collect the required product that this precipitation obtains 0.2g (78%), be pale solid: mp215-217 ℃; MS (APCI +): m/z475.2 (MH +).C 28H 29N 2O 5C 5H 14NO1.8H 2O analysis theories value: C, 64.96; H, 7.7.70; N, 6.89.Measured value: C, 65.04; H, 7.59; N, 6.55.
Embodiment 166
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 4-pyridyl methyl ester
Figure A9981647502561
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 4-pyridyl methyl ester is synthetic by 4-pyridyl methyl alcohol according to method Q.Crude product carries out chromatogram purification, in hexane, then obtains the required product of 260mg with 100% ethyl acetate as eluent with 50% ethyl acetate, is white solid: mp199-201 ℃; MS (APCI +): m/z432.5 (MH +).
Embodiment 167
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-pyridyl) ethyl ester
Figure A9981647502562
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-pyridyl) ethyl ester is synthetic by 1-(4-pyridyl) ethanol according to method Q.Crude product carries out chromatogram purification, in hexane, then obtains the required product of 210mg with 100% ethyl acetate as eluent with 50% ethyl acetate, is white solid: mp219-221 ℃; MS (APCI +): m/z446.2 (MH +).
Embodiment 168
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-pyridyl) ethyl ester
Figure A9981647502571
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-pyridyl) ethyl ester is synthetic by 1-(2-pyridyl) ethanol according to method Q.Crude product carries out chromatogram purification, obtains 200mg required product as eluent with the 50%-75% ethyl acetate in hexane, is white solid: mp87-89 ℃; MS (APCI +): m/z446.2 (MH +).
Embodiment 169
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-thienyl methyl esters
Figure A9981647502572
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-thienyl methyl esters is synthetic by the 3-thiophen(e)alcohol according to method Q.Crude product carries out chromatogram purification, obtains 330mg required product as eluent with 50% ether in hexane, is white solid: mp115-116 ℃; MS (APCI +): m/z437.5 (MH +).
Embodiment 170
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,11,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(4-fluorophenyl) ethyl ester
Figure A9981647502581
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(4-fluorophenyl) ethyl ester is synthetic by S (-)-1-(4-fluorophenyl) ethanol according to method Q.Crude product carries out chromatogram purification, obtains 300mg required product as eluent with the 30%-50% ether in hexane, is white solid: mp108-110 ℃; MS (APCI +): m/z463.3 (MH +).
Embodiment 171
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-1-(4-fluorophenyl) ethyl ester
Figure A9981647502582
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-1-(4-fluorophenyl) ethyl ester is synthetic by R (+)-1-(4-fluorophenyl) ethanol according to method Q.Crude product carries out chromatogram purification, obtains 300mg required product as eluent with the 30%-50% ether in hexane, is white solid: MS (APCI +): m/z463.3 (MH +).
Embodiment 172
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridyl methyl ester
Figure A9981647502591
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridyl methyl ester is synthetic by 3-pyridyl methyl alcohol according to method Q.Crude product carries out chromatogram, and (purifying of 1: 1 hexane/EtOAc) obtains the required product of 1.43g (49.4%), is solid: mp73-80 ℃; MS (APCI +): m/z432.6 (MH +).
Embodiment 173
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-oxyethyl group-2-oxo-ethyl ester
Figure A9981647502592
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-oxyethyl group-2-oxo-ethyl ester is synthetic by the glycolic acid ethyl ester according to method Q.Crude product carries out chromatogram, and (purifying of 1: 1 hexane/EtOAc) obtains the required product of 0.5287g (36.8%), is solid: mp60-70 ℃; MS (APCI +): m/z427.2 (MH +).
Embodiment 174
Pyridine, 3-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-yl also) carbonyl] the oxygen base] methyl]-the 1-methyl-, mesylate
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-pyridyl methyl ester (1eq) and methyl mesylate (4eq) and 1,2-ethylene dichloride are mixed together and refluxed 30 minutes down at 88 ℃.After being cooled to room temperature, separating this precipitation and obtain the pure required product of 86mg (41.2%), be crystallization: mp228-232 ℃ with the ether washing by suction filtration; MS (APCI +): m/z446.2 (M +).
Some compounds of closed loop I can further form N-oxide compound and N-alkyl quaternary ammonium salts on the theheterocyclic nitrogen atom of N-11 position.In addition, some compounds of closed loop I are also at R 10In form N-oxide compound and N-alkyl quaternary ammonium salts on the nitrogen-atoms that arbitrarily selectivity exists.These structure formations within the scope of the invention.
Embodiment 175
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the carbonyl of 11-dimethyl-1-[(S)-(1-phenyl ethoxy)]-, mesylate
Figure A9981647502611
With pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-phenyl chlorocarbonate (0.6g, 1.349mmol) and methyl mesylate (1.089g 10.7964mmol) 1, is mixed together in the 2-ethylene dichloride (8ml) and refluxed 18 hours down at 88 ℃.With this reaction mixture vacuum concentration.Crude product carries out chromatogram purification (2: 10 MeOH/CH 2Cl 2), obtain the required product of 0.41g (61.5%), be solid: mp160-170 ℃; MS (APCI +): m/z459.3 (M +).
Some compounds of closed loop I can further form N-oxide compound and N-alkyl quaternary ammonium salts on the theheterocyclic nitrogen atom of N-11 position.In addition, some compounds of closed loop I are also at R 10In form N-oxide compound and N-alkyl quaternary ammonium salts on the nitrogen-atoms that arbitrarily selectivity exists.These structure formations within the scope of the invention.
Embodiment 176
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-furyl methyl esters
Figure A9981647502612
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-furyl methyl esters is synthetic by furans-3-base-methyl alcohol according to method Q.Crude product carries out chromatogram purification, and (1: 1 hexane/EtOAc), obtain the required product of 0.40g (42.4%) is solid: mp174-177 ℃; MS (APCI +): m/z421.4 (MH +).
Embodiment 177
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-nitrophenyl) methyl esters
Figure A9981647502621
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-nitrophenyl) methyl esters is synthetic by 2-nitrobenzyl alcohol according to method Q.Crude product carries out chromatogram purification (1: 1 hexane/EtOAc), obtain required product: mp200-203 ℃ of 0.39g (35.9%); MS (APCI +): m/z476.5 (MH +).
Embodiment 178
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-furyl methyl esters
Figure A9981647502622
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-furyl methyl esters is synthetic by furans-2-base-methyl alcohol according to method Q.Crude product carries out chromatogram purification, and (1: 1 hexane/EtOAc), obtain the required product of 0.24g (24.8%) is solid: mp65-77 ℃; MS (APCI+): m/z421.4 (MH +).
Embodiment 179
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-chloro-phenyl-) ethyl ester
Figure A9981647502631
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-chloro-phenyl-) ethyl ester is synthetic by 1-(2-chloro-phenyl-) ethanol according to method Q.Crude product carries out chromatogram purification (1: 1 hexane/ether), obtains the required product of 80mg (5.0%), is solid: mp95-105 ℃; MS (APCI +): m/z479.2 (MH +).
Embodiment 180
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, carboxyl ester
Figure A9981647502632
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-oxyethyl group-2-oxo-ethyl ester (0.47g, 0.96mmol) (5.73mmol 5.73mL) mixes and remained in 50 ℃ of oil baths heating 3 hours with being present in 1N NaOH in the methyl alcohol.Then this reaction mixture is cooled to room temperature, then adds 1N HCl neutralization.With this reaction mixture vacuum concentration, crude product carries out chromatogram purification (begin 1: 1 hexane/ether, 10%MeOH is in chloroform then), obtains 0.374g crude product solid.This crude product solid is dissolved in the chloroform again and filters and obtains the required product of 78mg (20.6%), is solid: MS (APCI +): mp260 ℃; M/z399.1 (MH +).
Embodiment 181
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2, the 6-dichlorophenyl) ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2, the 6-dichlorophenyl) ethyl ester is synthetic by 1-(2, the 2-dichlorophenyl) ethanol according to method Q.Crude product carries out chromatogram purification (1: 1 hexane/ether), obtains the required product of 93mg (5.30%), is solid: mp130-135 ℃; MS (APCI +): m/z513.1 (M +).
Embodiment 182
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-p-methoxy-phenyl) ethyl ester
Figure A9981647502651
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-p-methoxy-phenyl) ethyl ester is synthetic by 1-(2-p-methoxy-phenyl) ethanol according to method Q.Crude product carries out chromatogram purification (1: 1 hexane/ether), obtains the required product of 0.90g (42%), is solid; Mp115-125 ℃; MS (APCI +): m/z475.2 (MH +).
Embodiment 183
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-and the 1-phenyl chlorocarbonate, the 11-oxide compound
Figure A9981647502652
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-phenyl chlorocarbonate (0.3g) and the 50%H that is present in the methyl alcohol 2O 2Mixing also will be stirred 3 hours under this mixture room temperature.Then, with excessive H 2O 2Destroy with Pd/C.With this reaction soln after filtration and vacuum concentration.Crude product carries out chromatogram purification (10%MeOH is in methylene dichloride), obtains the pure required product of 52mg (48.2%), is solid: mp180-190 ℃; MS (APCI +): m/z461.2 (MH +).
Some compounds of closed loop I can further form N-oxide compound and N-alkyl quaternary ammonium salts on the theheterocyclic nitrogen atom of N-11 position.In addition, some compounds of closed loop I are also at R 10In form N-oxide compound and N-alkyl quaternary ammonium salts on the nitrogen-atoms that arbitrarily selectivity exists.These structure formations within the scope of the invention.
Embodiment 184
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(5-carboxyl-3-pyridyl) ethyl ester
Steps A: 1-(5-bromo-pyridin-3-yl)-ethyl ketone
3-(5-bromo-pyridin-3-yl)-3-oxo-methyl propionate (8.75g, 30mmol) and 2NH 2SO 4Mix and this mixture was refluxed 24 hours.Again with this reaction soln with solid sodium bicarbonate neutralization and use extracted with diethyl ether.Organic phase is dry and the ether evaporation obtained the pure required product of 6.06g (89.5%), is crystallization: MS (APCI +): m/z201 (MH +).
Step B:1-(5-bromo-pyridin-3-yl)-ethanol
(5.85g 29.2mmol) is dissolved among the MeOH (100mL) and the slow NaBH of adding with compound 1-(5-bromo-pyridin-3-yl)-ethyl ketone 4(1.104g, 29.19mmol).This reaction is monitored by TLC.When initiator thoroughly reacts, with neutralize this mixture and obtain the crude product product of sodium hydrogen carbonate solution with extracted with diethyl ether.The crude product product is mixed with 1: 1 hexane/ethyl acetate and filter.This filtrate concentrating obtains pure required product.MS(APCI +)：m/z203(MH +)。
Step C:5-(1-hydroxyl-ethyl)-nicotinic acid methyl ester
With 1-(5-bromo-pyridin-3-yl)-ethanol (6.0g), palladium (0.14g), DPPP (0.28g), triethylamine (6mL), DMSO (60mL) and MeOH (60mL) is mixed together and with this reaction mixture 100-110 ℃ of stirring heating 18 hours.When reaction finishes, mixture is removed by filter this solid, and with this filtrate vacuum concentration.This resistates grinds and filters with ethyl acetate, collects this filtrate and this solid.This solid is dissolved in sodium bicarbonate and uses ethyl acetate extraction.Extract and this filtrate combine and use dried over sodium sulfate.Vacuum concentration obtains crude product, and it carries out chromatogram purification, obtains the pure required product of 3.32g (61.8%) with 1: 1 hexane/EtOAc wash-out: MS (APCI +): m/z182 (MH +).
Step D: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[5-(methoxycarbonyl)-3-pyridyl] and ethyl ester
Figure A9981647502671
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[5-(methoxycarbonyl)-3-pyridyl] and ethyl ester is synthetic by 5-(1-hydroxyl-ethyl)-nicotinic acid methyl ester according to method Q.Crude product carries out chromatogram purification, and (1: 1 hexane/EtOAc), obtain the required product of 0.81g (37%) is solid: MS (APCI +): m/z504.3 (MH +).
Step e: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(5-carboxyl-3-pyridyl) ethyl ester
Embodiment 184, step D, pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[5-(methoxycarbonyl)-3-pyridyl] (0.2202g, 0.4378mmol) (1.75mmol 1.75mL) mixes in MeOH (10mL) ethyl ester with 1NNaOH.This reaction flask is remained in 50 ℃ of oil baths heating 1 hour.Then, this reaction mixture is cooled to room temperature, then adds 1N HCl (2mL) this reaction mixture that neutralizes.The mixture vacuum concentration is obtained crude product, and it carries out chromatogram purification (20: 10, the MeOH/ methylene dichloride), obtains the required product of 0.2665g (100%), is solid: MS (APCI +): m/z490.2 (MH +).
Embodiment 185
1, the 3-phthalic acid, 5-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-yl also) carbonyl] the oxygen base] methyl]-, diethyl ester
Figure A9981647502681
With benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, acid anhydrides (embodiment 86) (0.502g, 1.13mmol) (0.859g 3.40mmol) mixes and places 150 ℃ of oil baths 6 minutes with diethyl-5-(hydroxymethyl) isophthalic acid ester.Reaction is cooled to room temperature, dilutes and stir with ethyl acetate and saturated sodium bicarbonate and dissolve up to all resistatess.Layering and with organic layer water and salt water washing, dry (MgSO 4) and evaporation.This product is by the column chromatography purifying, with ether/hexane gradient elution (30% yield).
1H NMR (CDCl3,300MHz): δ 8.64 (s, 1H), 8.31 (s, 2H), 8.11 (s, 1H), 7.03 (d, and 1H) 6.76 (d, 1H), 5.40 (d, 2H), 4.44 (q, 4H), 3.38-3.44 (dd, 1H), 3.04 (m, 1H), 2.76-2.82 (m, 2H), 2.61 (s, 3H), 2.44-2.56 (m, 2H), 1.40 (t, 6H), 1.23-1.78 (m, 11H) .MS (APCI, m/z, M+1): 575.2C 33H 38N 2O 70.67H 2O. calculated value: C, 67.50; H, 6.70; N, 4.77. measured value: C, 67.19; H6.54; N, 4.37.
Embodiment 186
1, the 3-phthalic acid, 5-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-yl also) carbonyl] the oxygen base] methyl]-
To be present in 1 among the 10mL THF, 3-phthalic acid, 5-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-yl also) carbonyl] the oxygen base] methyl]-, diethyl ester (0.4787g, 0.83mmol), the 2MNaOH of 2mL MeOH and 0.83mL (1.66mmol) mixes and be heated to 50-60 ℃.The 2M NaOH that adds two 0.83mL batch is up to determining to react completely by MS.This reaction is cooled to room temperature and washs with ether.With this water layer neutralization and concentrated.This resistates is dissolved in hot MeOH and filters to remove sodium-chlor.This filtrate concentrates and at room temperature is dissolved in MeOH, and filters once more.This filtrate is used dried over mgso, filter and concentrate.This product freeze-drying obtains 362.2mg (83%).LCMS：88.17％
Embodiment 187
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl) methyl esters
Steps A: 2-chloro-5-nitrobenzyl alcohol
3 neck flasks of oven dried are equipped with 2 intervals and reflux exchanger, wherein add 2-chloro-5-nitrobenzoic acid (5.53g, 27.43mmo1), 14mL THF and drip BF 3-OEt 2(3.5mL, 27.62mmol).With this vlil 2 hours, in 30 minutes, drip this moment borine methyl sulfide mixture (2M/THF, 18mL, 36mmol).Continue again to reflux 2 hours up to determining to react completely by TLC.This reaction is cooled to room temperature and slowly adds 1: 1 THF/H of 4mL 2O then adds 20.5mL 5M NaOH.This reaction reflux 16 hours is also passed through thick sintered glass funnel heat filtering, and this solid washs with THF (2x).With this filtrate drying (MgSO 4), filter, concentrate and, use the ethyl acetate/hexane gradient elution by the column chromatography purifying.This product is obtained product, yield 79% with hexane grinding and filtration. 1HNMR(CDCl 3，300MHz)：δ8.45(d，1H)，8.11(dd，1H)，7.52(d，1H)，8.86(d，2H)，2.18(t，1H)。MS(APCI，AP -)??186.9
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl) methyl esters
With 2-chloro-5-nitrobenzyl alcohol (1.0879g, 5.80mmol) and with benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (0.512g 1.15mmol) mixes and places 150 ℃ of oil baths 6 minutes acid anhydrides (embodiment 86).This reaction is cooled to room temperature and dilutes with ethyl acetate.With mixture saturated sodium bicarbonate, water and salt water washing, dry (MgSO 4), filter, concentrate and, obtain this product with the ethyl acetate/hexane gradient elution, yield 57% by the column chromatography purifying.
1H NMR (DMSO, 300MHz): δ 11.65 (s, 1H), 8.39 (s, 1H), 8.24 (dd, 1H), 7.85 (d, 1H), 7.07 (d, 1H), 6.63 (d, 1H), 5.42 (d, 2H), 3.23 (m, 1H), 2.8-3.0 (m, 1H), 2.60-2.70 (m, 2H), 2.30-2.60 (m, 3H), 2.37 (s, 3H), 1.82-1.87 (m, 1H), 1.0-1.75 (m, 11H) MS (APCI, Ap +): 510.1 LCMS:98.23% retention time: 7.627 minutes
Embodiment 188
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (5-amino-2-chloro-phenyl-) methyl esters
Steps A: 5-amino-2-chloro-benzoic acid
Raney Ni (Raney-Nickel) (3gm) is joined 5-nitro-2-chloro-benzoic acid, and (10gm in methanol solution 150mL), is connected this mixture then with sources of hydrogen, after 4 hours, monitor (the 30%MeOH/CH that reacts completely by TLC 2Cl 2).Remove by filter catalyzer and this filtrate is evaporated to dried, collect the product of 8g and its not purified the next step that is used for.MS(APCI，AP +)：172.0
Step B:5-amino-2-chlorine benzyl alcohol
Two neck flasks of oven dried are equipped with dividing plate and condenser, and (2.611g is 15.22mmol) with 7.5mL THF wherein to charge into 5-amino-2-chloro-benzoic acid.Drip BF 3OEt 2And will react reflux 2 hours.Dropping borine methyl sulfide mixture (2M/THF, 10mL, 20mmol).This reaction was refluxed 3 hours, and add 3.8mL borine methyl sulfide mixture (7.2mmol) again.Reflux and continued 1 hour, be cooled to room temperature, and slowly add 1: 1 THF/H of 3mL 2O then adds 11.2mL 5M NaOH.Filter with this reaction reflux 16 hours and by thick sintered glass funnel, clean this solid with THF (2x).This filtrate concentrated and with this resistates at methylene dichloride/H 2Distribute between the O.With dichloromethane extraction three times of this product.Filter the tawny solid in the collected organic layer and obtain the product of 0.6374g in dried overnight in 40 ℃ of vacuum ovens.With this organic filtrate drying (MgSO 4), filter, concentrate and, obtain the 0.56g product with MeOH/ dichloromethane gradient wash-out by the column chromatography purifying. 1HNMR(DMSO，300MHz)：δ6.93(d，1H)，6.75(d，1H)，6.39(dd，1H)，5.16(s，2H)，4.38(d，2H)。MS(APCI，AP +)：158.0
Step C: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (5-amino-2-chloro-phenyl-) methyl esters
With 5-amino-2-chlorobenzyl alcohol (1.055g, 6.70mmol) and with benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (0.7023g 1.58mmol) mixes and places 150 ℃ of oil baths 6 minutes acid anhydrides (embodiment 86).With this reaction cooling, use dilution of ethyl acetate and saturated sodium bicarbonate and stirring up to all resistates dissolvings.Organic layer water and salt water washing, dry (MgSO 4), filter and concentrate.This product is by the column chromatography purifying, with 5%MeOH/ methylene dichloride wash-out.With this product is to place high vacuum following two days, obtains the rose pink solid of 0.260g (34%).
1HNMR (DMSO, 300MHz): δ 11.16 (s, 1H), 10.13 (s, 1H), 8.02 (d, 1H), 7.60 (dd, 1H), 7.29 (d, 1H), 7.05 (d, 1H), 6.60 (d, 1H), 5.37 (t, 1H), 4.51 (d, 2H), 3.14-3.18 (m, 1H), 2.90-3.00 (m, 1H), and 2.65-2.72 (m, 1H), 2.30-3.20 (m, 3H), 2.39 (s, 3H), 1.10-1.75 (m, 11H) .MS (APCI, Ap +): 480.1 LCMS:91.44% retention time: 4.623 minutes
Embodiment 189
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-acetate also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-alpha-oxo--, ethyl ester
With 2-methyl-pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine (0.296gm, 1mm) and ethyl oxalate (0.123mL 1.1mm) mixes in 20mL THF and will stir 48 hours under this mixture room temperature.Evaporate THF and resistates is dissolved in EtOAc again,, and be evaporated to dried organic layer supercarbonate, salt water washing.Separate by column chromatography, with hexane/EtOAc=1: 1 wash-out is isolated pure product (50mg, 12.4%).MS (APCI, Ap +): 397.1. 1H NMR (CDCl 3, 300MHz): δ 8.3 (s, NH), 7.05 (d, 1H), 6.8 (d, 1H), 4.4 (q, 2H), 2.4-3.6 (m, 6H), 2.75 (s, 3H), 1.22-2.15 (m, 11H), 1.4 (t, 3H), C 23H 28N 2O 41/3H 2O. calculated value: C, 68.69; H, 7.19; N, 6.96. measured value: C, 68.85; H6.98; N, 6.51.MP:200 ℃
Embodiment 190
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,4, the 5-trimethylammonium-, the phenyl methyl esters
Figure A9981647502732
Steps A: 2, the 3-xyloquinone
To NaOAc (16.4gm in 200mL aqueous solution 60mm), adds 2,3-dimethyl-4-hydroxyl phenol (5.526gm, 20mm) and the solution of tribromide benzyltrimethylammon.um (17.6gm, 22mm).This mixture is stirred up to this solution decolourization (3 hours).Separate organic layer and use the salt water washing, dry and evaporation, heavy altogether 5gm, the not purified the next step that is used for of this material.
Step B:5-hydroxyl-2,6,7-trimethylammonium-1H-indole-3-carboxylic acid ethyl ester
To 2, and the 3-xyloquinone (3.5gm, in 60mL EtOH solution 25.7mm), adding 3-amino-but-2-ene acid benzyl ester solution under nitrogen atmosphere (5.41gm, 28.3mm).White solid after filtration, and this filtrate concentrates, with this product by the column chromatography purifying and with hexane/EtOAc=1: 1 wash-out (0.5gm, 6.3%).MS(APCI，AP +)：367.1.
Step C:4-dimethylaminomethyl-5-hydroxyl-2,6,7-trimethylammonium-1H-indole-3-carboxylic acid ethyl ester
(0.157mL 1.94mm) joins 5-hydroxyl-2,6 with 40% dimethylamine solution, in the 11mL EtOH solution of 7-trimethylammonium-1H-indole-3-carboxylic acid ethyl ester to 37.5% formaldehyde solution.This reaction mixture was stirred 48 hours down at 55 ℃.Remove and desolvate, pure product separate by column chromatography, use MeOH/EtOAc=1: 4 wash-outs (0.22gm, 37.3%).MS(APCI，AP +)：367.1.
Step D: pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,4, the 5-trimethylammonium-, the phenyl methyl esters
With 1,2,3,4,6,7,8, (0.204gm 0.855mm) is dissolved in 10mL 1N NaOH also with 3 * 35mL extracted with diethyl ether to 9-octahydro-quinolizine perchlorate.Ether is concentrated and this resistates is dissolved in the 4mL diox again.This imide liquor is joined the 4-dimethylaminomethyl-5-hydroxyl-2,6 that is present in the 8mL diox, in 7-trimethylammonium-1H-indole-3-carboxylic acid ethyl ester.This is reflected at 110 ℃ of reflux 18 hours.Evaporating solvent and pure product separate by column chromatography, use MeOH/EtOAc=1: 4 wash-outs (0.117gm, 44.5%).MS(APCI，AP +)：459.2.MP：75-80℃C 23H 28N 2O 4·2/3H 2O。Theoretical value: C, 74.11; H, 7.52; N, 5.966.96.Measured value: C, 74.12; H 7.37; N, 5.77.
Embodiment 191
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl-2-propynyl ester
Figure A9981647502751
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl-2-propynyl ester is synthetic by 2-methyl-Ding-3-alkynes-2-alcohol according to method Q.MS：m/z407.52(MH +)。
Embodiment 192
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three chloro-1,1-dimethyl ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2, by 1,1,1-three chloro-2-methyl-propan-2-ols are synthetic according to method Q for 2-three chloro-1,1-dimethyl ethyl ester.MS：m/z500.86(MH +)。
Embodiment 193
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, three ring [3.3.1.1 3,7] last of the ten Heavenly stems-1-base ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, three ring [3.3.1.1 3,7] last of the ten Heavenly stems-1-base ester is synthetic by diamantane-1-alcohol according to method Q.MS：m/z474.63(MH +)。
Embodiment 194
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl isophthalic acid-phenyl chlorocarbonate
Figure A9981647502762
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl isophthalic acid-phenyl chlorocarbonate is synthetic by 2-phenyl-propan-2-ol according to method Q.MS：m/z459.59(MH +)。
Embodiment 195
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl cyclohexane ester
Figure A9981647502771
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl cyclohexane ester is synthetic according to method Q.MS：m/z437.59(MH +)。
Embodiment 196
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1,2-trimethylammonium propyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1,2-trimethylammonium propyl ester is synthetic according to method Q.MS：m/z425.58(MH +)。
Embodiment 197
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl ring pentyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl ring pentyl ester is synthetic according to method Q.MS：m/z423.56(MH +)。
Embodiment 198
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-cyclohexyl-1-methyl ethyl ester
Figure A9981647502782
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-cyclohexyl-1-methyl ethyl ester is synthetic according to method Q.MS：m/z465.64(MH +)。
Embodiment 199
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,4-dimethyl-4-piperidine ester
Figure A9981647502791
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,4-dimethyl-4-piperidine ester is synthetic according to method Q.MS：m/z452.60(MH +)。
Embodiment 200
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-fluorobenzene ester
Figure A9981647502792
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-fluorobenzene ester is synthetic according to method Q.MS：m/z435.50(MH +)。
Embodiment 201
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-methyl phenyl ester
Figure A9981647502801
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-methyl phenyl ester is synthetic according to method Q.MS：m/z431.54(MH +)。
Embodiment 202
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenyl ester is synthetic according to method Q.MS：m/z417.51(MH +)。
Embodiment 203
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(methoxycarbonyl) phenyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(methoxycarbonyl) phenyl ester is synthetic according to method Q.MS：m/z475.55(MH +)。
Embodiment 204
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridine ester
Figure A9981647502812
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridine ester is synthetic according to method Q.MS：m/z417.50(MH +)。
Embodiment 205
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(trifluoromethyl)-, ethyl ester
Figure A9981647502821
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(trifluoromethyl)-, ethyl ester is synthetic according to method Q.MS：m/z423.44(MH +)。
Embodiment 206
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [the 5-[(dimethylamino) methyl]-the 2-furyl] methyl esters
Figure A9981647502822
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [5-[(dimethylamino) methyl]-2-furyl] and methyl esters is synthetic according to method Q.MS：m/z478.60(MH +)。
Embodiment 207
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-carboxyl-2-methyl propyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-carboxyl-2-methyl propyl ester is synthetic according to method Q.MS：m/z441.53(MH +)。
Embodiment 208
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(dimethylamino)-2,2-dimethyl propyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(dimethylamino)-2,2-dimethyl propyl ester is synthetic according to method Q.MS：m/z454.62(MH +)。
Embodiment 209
With 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene propanedioic acid monoester anhydride of [3,2-i] quinolizine-1-formic acid also, 1,1-dimethyl ethyl ester
With 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene propanedioic acid monoester anhydride of [3,2-i] quinolizine-1-formic acid also, 1,1-dimethyl ethyl ester is synthetic according to method Q.MS：m/z483.57(MH +)。
Embodiment 210
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino)-2-methyl propyl ester
Figure A9981647502842
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino)-2-methyl propyl ester is synthetic according to method Q.MS：m/z440.59(MH +)。
Embodiment 211
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(1H-imidazoles-1-yl) ethyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(1H-imidazoles-1-yl) ethyl ester is synthetic according to method Q.MS：m/z435.53(MH +)。
Embodiment 212
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-benzofuryl methyl esters
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-benzofuryl methyl esters is synthetic by cumarone-2-base-methyl alcohol according to method Q.MS(APCI +)：m/z471.2(MH +)。
Embodiment 213
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R, 2S)-2-(dimethylamino)-1-phenyl propyl ester
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R, 2S)-2-(dimethylamino)-1-phenyl propyl ester according to method Q by (1R, 2S) dimethylamino-phenyl-third-1-alcohol is synthetic.MS(APCI +)：m/z502.1(MH +)。
Embodiment 214
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S, 2R)-2-(dimethylamino)-1-phenyl propyl ester
Figure A9981647502861
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S, 2R)-2-(dimethylamino)-1-phenyl propyl ester according to method Q by (1S, 2R)-(dimethylamino-phenyl-third-1-alcohol is synthetic for 2-.MS(APCI +)：m/z502.1(MH +)。
Embodiment 215
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) encircles propyl ester
Figure A9981647502862
Steps A: 1-(4-fluorophenyl) encircles propyl alcohol
According to Kulinkovich, O.G.; Sviridov, S.V.; Vasilevskii, D.A.; Savchenko, A.I.; And Pritytskaya, T.S. is at J.Org.Chem.USSR (English) 1991; The method for preparing 1-benzyl ring propyl alcohol of 27 (2): 250 reports, (65.72mmol 11.05g) changes 1-(4-fluorophenyl) ring propyl alcohol (5.34g, 53%) into, is yellow liquid with the 4-ethyl fluoro benzoate; 1H NMR (400MHz, CDCl 3) δ 0.99-1.02 (m, 2H, cyclopropyl CH 2), 1.23-1.26 (m, 2H, cyclopropyl CH 2), 2.22 (bs, 1H, OH), 6.98-7.05 (m, 2H, ArH), 7.26-7.32 (m, 2H, ArH) 19F NMR (CDCl 3) δ-117.09 (d, J=15.43Hz); MS (APCI +) m/z152.9 (MH +).
Step B: pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) encircles propyl ester
According to embodiment 47, the method for step B, 1-(4-fluorophenyl)-ring propyl alcohol (35.1mmol, 5.34g) and with benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, acid anhydrides (embodiment 86), (8.77mmol 3.90g) changes pyrrolo-[3 ' into, 2: 5,6] [1] chromene also [3,2-i] quinolizine-1-formic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) encircles propyl ester.This product is by silica gel flash column chromatography purifying (25-50% ethyl acetate/hexane, 30-50% ether/hexane then) and obtain faint yellow solid (0.364g, 9%) with the pure isooctane recrystallization: mp130-135 ℃;
IR (KBr) 3302,29.31,2857,1689,1515,1429,1221,1194,1147,1068cm -1 1HNMR (400MHz, DMSO-d 6) δ 1.13-1.60 (m, 13H, fatty CH), 1.71-1.74 (m, 1H, fatty CH), 1.88 (d, J=13.18Hz, 1H, fatty CH), 2.36 (d, J=10.74Hz, 1H, fatty CH), 2.43-2.49 (m, 1H, fatty CH), 2.53 (s, 3H, ArCH 3), 2.66-2.71 (m, 2H, fatty CH), 2.87-2.90 (m, 1H, fatty CH), 3.22 (dd, J=18.31,6.84Hz, 1H, fatty CH), 6.61 (d, J=8.79Hz, 1H, ArH), 7.04 (d, J=8.55Hz, 1H, ArH), 7.11-7.15 (m, 2H, ArH), 7.28-7.32 (m, 2H, ArH), 11.57 (s, 1H, NH); 19F NMR (DMSO-d 6) δ-117.03; MS (APCI +) m/z475.2 (MH +) .C 29H 31F 1N 2O 3Computational analysis value: C, 73.40; H, 6.58; F, 4.00; N, 5.90. measured value: C, 73.58; H, 6.79; F, 3.93; N, 5.52.

Claims (17)

1. the compound or pharmaceutically acceptable salt thereof of formula I,
Figure A9981647500021
Wherein:
A is O, S, and when X be C-R 9The time, A can also be NR 1
When A is NR 1The time, X is N, perhaps
X is C-R 9, R wherein 9Be halogen, hydrogen atom, alkyl ,-CF 3, CH 2F, CHF 2,-(CH 2) m-OR 1, aryl, aralkyl ,-(CH 2) m-NR 7R 8Or
Figure A9981647500022
Wherein m is 0 to 2 integer, and when occurring, m is 0 to 2 integer independently at every turn, and q is 0 to 1 integer, and r is 0 to 3 integer;
Y is hydrogen atom, alkyl, aralkyl, aryl, (CH 2) m-NR 7R 8,-N (R 1)-(CH 2) v-C (R 7R 8)-aryl or OR 10, R wherein 10Be hydrogen atom, alkyl, cycloalkyl, with aromatic ring condensed cycloalkyl, aryl, (CH 2) sAryl ,-CH 2CF 3, (CH 2) tC (R 7R 8)-(CH 2) uAryl,
Figure A9981647500031
Wherein s is 1 to 3 integer, and t is 0 to 3 integer, and u is 0 to 3 integer, and v is 1 to 3 integer, and w is 0 to 2 integer;
Z is CR or N;
R 1Be hydrogen atom or alkyl, and when occurring, R. at every turn 1Be hydrogen atom or alkyl independently;
R and R 2Be independently from each other:
Hydrogen atom,
Alkyl,
Halogen,
-CN，
-NO 2，
-(CH 2) m-NR 7R 8，
-(CH 2) m-COOR 7，
-(CH 2) m-CONR 7R 8，
-(CH 2) m-OR 7，
-(CH 2) m-SO 2NR 7R 8, and
-(CH 2) m-S (O) pR 7, when wherein occurring at every turn, R 7And R 8Be independently of one another hydrogen atom, alkyl, aryl, aralkyl ,-CF 3, or R 7And R 8Can form the ring of 3 to 7 atoms together, in this ring O, S or NR can be arranged 1, and p is 0 to 2 integer;
R 3Be hydrogen atom or alkyl;
R 4Be hydrogen atom, alkyl, aryl or aralkyl;
R 5Be alkyl, aryl, aralkyl, acyl group; Or
R 4And R 5Form the ring of 5 to 7 atoms with the atom that connects with them;
R 6Be hydrogen atom or alkyl;
When not with R 4One time-out, R 5Can with R 6Form the ring of 5 to 7 atoms with the atom that connects with them;
N-R 5It also is corresponding N-oxide compound;
R 11Be hydrogen atom or alkyl;
N is 1 to 3 integer; J is 1 to 2 integer, and when Y was hydrogen atom, alkyl, aralkyl or aryl, j was an integer 0;
Condition be do not comprise pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester.
2. the compound of claim 1, wherein R 1It is hydrogen atom.
3. the compound of claim 1, wherein R 1Be hydrogen atom, and X is C-R 9
4. the compound of claim 1, wherein R 1Be hydrogen atom, and X is C-R 9, R wherein 9It is alkyl.
5. the compound of claim 1, wherein R 1Be hydrogen atom, X is C-R 9, R wherein 9It is alkyl; R 4And R 5Form the ring of 5-7 atom with the atom that connects with them; And Y is OR 10
6. the compound of claim 1, wherein R 1Be hydrogen atom, X is C-R 9, R wherein 9It is alkyl; R 4And R 5Form 6 yuan of rings together; And Y is OR 10, R wherein 10Be alkyl, aryl or-(CH 2) sAryl ,-(CH 2) t-C (R 7R 8)-(CH 2) u-aryl.
7. the compound of claim 1, wherein R 1Be hydrogen atom, X is C-R 9, R wherein 9Be Me; R 4And R 5Form 6 yuan of rings together; R 6It is hydrogen atom; N is 2; And Y is OR 10, R wherein 10Be alkyl, aryl or R 10Be-(CH 2) t-C (R 7R 8)-(CH 2) u-aryl, wherein t is O, R 7And R 8Can be independently of one another H, alkyl ,-(CH 2) vOH or (CH 2) uCOOR 7And-(CH 2) vNR 1R 2, wherein u and v definition as above.
8. the compound of claim 1 is characterized in that being selected from following compound:
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-bromo-3,7,8,9,10,12,13,14, and 14a, 15-decahydro-2-methyl-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2-dimethyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the cyclopropyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(piperidino) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(phenyl methyl)-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 2-ethyl-3,7,8,9,10,12,13,14, and 14a, the 15-decahydro-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 2-cyclopropyl-3,7,8,9,10,12,13,14, and 14a, the 15-decahydro-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-propyl group-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(2-methyl-propyl)-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl ethyl ester;
2,6a, 7-trimethylammonium-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diazacyclo penta [a] anthracene-1-ethyl formate;
7-ethyl-2,6a-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;
6a-ethyl-2,7-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;
6a, 7-diethyl-2-methyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;
7-benzyl-2,6a-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;
2,7-dimethyl-6a-phenyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-e] indoles-1-formic acid also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-, ethyl ester;
3H, 7H-pyrroles's piperazine be [1 ', 8 ': 5,6] pyrans [3,2-e] indoles-1-acetate also also, and 8,9,11,12,12a, 13-six hydrogen-2-methyl-, ethyl ester;
2-methyl-8,9,10,10a, 11,12,12a, 13-octahydro-3H, 6aH, 7H-6-oxa--3,6b-diaza-benzo [a] ring penta [h] anthracene-1-ethyl formate;
3H-pyrido [1 ", 2 ": 1 ' 2 '] azepines is [3 ' 2 ': 5,6] pyrans [3,2-e] indoles-1-acetate also also, 7,8,9,10,12,13,14,15,15a, 16-decahydro-2-methyl-, ethyl ester or
The 7H-azepines is [1 ", 2 ": 1 ' 2 '] pyrido [3 ' 2 ': 5,6] pyrans [3,2-e] indoles-1-acetate also also, and 3,8,9,10,11,13,14,15,15a, 16-decahydro-2-methyl-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-methane amide also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-N-(phenyl methyl)-;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-methane amide also, N-ethyl-8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formaldehyde also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-methane amide also, and 8,9,11,12,13,13a, 14,14a-octahydro-N, the 2-dimethyl-;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-, (4-fluorophenyl)-methyl esters;
Indazole is [4 ', 5 ': 5,6] pyrans [3,2-i] quinolizine-1-formic acid also also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,12, the 12-trimethylammonium-, the phenyl methyl esters,
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,10, the 10-trimethylammonium-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters;
The 12H-furo [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluoro-7,8,9,10,13,14,14a, 15-octahydro-2-methyl-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 4,5-two fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 4,5-two chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-4,5-dimethoxy-2-methyl-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 5-dimethyl-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 4-dimethyl-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 4-dimethyl-, 1-(4-fluorophenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[3-(methoxycarbonyl) phenyl] and ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(3-carboxyl phenyl) ethyl ester;
1-third ammonium, N, N, the N-trimethylammonium-, with 1-(3-carboxyl phenyl) ethyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-nitrophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(3-cyano-phenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-[3-[(dimethylamino) and carbonyl] phenyl] ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-[3-[(dimethylamino) and methyl]-phenyl] ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,1,13,14,14a, 15-decahydro-2-methyl-, the 2-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(methoxycarbonyl) phenyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2 ,-methyl-, (4-carboxyl phenyl) methyl esters;
1-[3-(4-carboxyl-benzyloxycarbonyl)-5-hydroxy-2-methyl-1H-indoles-4-ylmethyl]-1,2,3,4,6,7,8,9-octahydro-quinolizine; Muriate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(hydroxymethyl) phenyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-2-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-naphthyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(methoxycarbonyl) phenyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(hydroxymethyl) phenyl]-methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-carboxyl phenyl) methyl esters);
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (3-carboxyl phenyl) methyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1]-chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [the 3-[(dimethylamino) methyl] phenyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [the 3-[(dimethylamino) carbonyl]-phenyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [2-(4-morpholinyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[1,1 '-xenyl]-4-base ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2, the 6-difluorophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1-phenyl-2,2,2-trifluoro) ethyl ester:
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[3-(trifluoromethyl) phenyl]-ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(1-pyrrolidyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(1-naphthyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring butyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-pyrazinyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-quinolyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-pyrimidyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-chloro-3,7,8,9,10,12,13,14, and 14a, 15-decahydro-2-methyl-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl, 1-(4-fluorophenyl) ethyl ester;
Quinolizine, the 1-[[(4-fluorophenyl) methoxyl group] carbonyl]-5-hydroxy-2-methyl-1H-indoles-4-yl] methyl]-1,2,3,4,6,7,8, the 9-octahydro-, muriate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-1, the 2-dimethyl-, (4-fluorophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-phenyl propyl ester;
Quinolizine, 1,2,3,4,6,7,8,9-octahydro-1-[[5-hydroxy-2-methyl-3-[(phenyl methoxyl group) carbonyl]-1H-indoles-4-yl] methyl]-, muriate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-nitrophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-the 1-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three fluoro-1-phenyl-1-(trifluoromethyl) ethyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, two ring [2.2.1] heptane-2-base ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl)-1-methyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring pentyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-phenyl cyclohexyl;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(hydroxymethyl) phenyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(hydroxy phenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(4-pyridyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [6-(methoxycarbonyl)-2-pyridyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 2-pyridyl methyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (6-carboxyl-2-pyridyl) methyl esters;
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (6-carboxyl-2-pyridyl) methyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [5-(methoxycarbonyl)-3-pyridyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (5-carboxyl-3-pyridyl) methyl esters;
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (5-carboxyl-3-pyridyl) methyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4 '-methyl [1,1 '-xenyl]-3-yl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2, the 6-3,5-dimethylphenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S, 2R)-2-(dimethylamino)-1-phenyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R, 2S)-2-(dimethylamino)-1-phenyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-naphthalene ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenylbenzene methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-2,3-dihydro-1H-indenes-1-base ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2-dihydro-1-acenaphthene ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, cyclohexyl (phenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 9H-fluorenes-9-base ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2,3,4-tetrahydrochysene-1-naphthalene ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [(2R, 3R)-3-phenyl epoxy ethyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-oxo-1,2-phenylbenzene ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 10,11-dihydro-5H-dibenzo [a, d] suberene-5-base ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-aminomethyl phenyl) phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, cyclopropyl (4-fluorophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3,4-dihydro-2H-1-benzo thiapyran-4-base ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(2-bromophenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2, the 2-trifluoro ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [(2S, 3S)-3-phenyl epoxy ethyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three fluoro-1-methyl isophthalic acids-(trifluoromethyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three fluoro-1-(4-fluorophenyl)-1-(trifluoromethyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-cyclopentyl-1-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[1,1 '-xenyl]-4-base-1-methyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl isophthalic acid-phenyl-2-propynyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-phenylbenzene ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl isophthalic acid, 2-phenylbenzene ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) cyclohexyl;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2-phenylbenzene ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-phenyl-2-propynyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [1,1 '-xenyl]-4-base methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 4-pyridyl methyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2,3,4-tetrahydrochysene-7,8-dimethoxy-2-methyl-4-isoquinoline 99.9 ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[3-(dimethylamino) phenyl]-ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl-2-pyrazinyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-(dipropyl amino)-1,1-dimethyl-2-butyne ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-2,3-dihydro-1H-indenes-1-base ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S, 2S)-2-(dimethylamino)-1-phenyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(trifluoromethyl) phenyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-chloro-phenyl-) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, the 15-decahydro-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, the 15-decahydro-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 2-hydroxy methacrylate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-aminomethyl phenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-the 1-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carbothioic acid carbothiolic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, S-(phenyl methyl) ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridyl methyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[4-(trifluoromethyl) phenyl]-ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(pentafluorophenyl group) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2, the 6-difluorophenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(2-furyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(4-morpholinyl)-1-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-1-(2-furyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methoxyl group-2-oxo-1-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(3-pyridyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (S)-carboxyl (phenyl) methyl esters;
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (S)-carboxyl (phenyl) methyl, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-2-methoxyl group-2-oxo-1-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (R)-carboxyl (phenyl) methyl esters;
The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (R) carboxyl (phenyl) methyl, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 4-pyridyl methyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-pyridyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-pyridyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-thienyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(4-fluorophenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-1-(4-fluorophenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridyl methyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-oxyethyl group-2-oxo ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-furyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-nitrophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-furyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-chloro-phenyl-) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, carboxyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2, the 6-dichlorophenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-p-methoxy-phenyl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(5-carboxyl-3-pyridyl) ethyl ester;
1, the 3-phthalic acid, 5-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-yl also) carbonyl] the oxygen base] methyl]-, diethyl ester;
1, the 3-phthalic acid, 5-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-yl also) carbonyl] the oxygen base] methyl]-;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (5-amino-2-chloro-phenyl-) methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-acetate also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-. alpha-oxo--, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,4, the 5-trimethylammonium-, the phenyl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl-2-propynyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three chloro-1,1-dimethyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, three rings [3.3.1.13,7] last of the ten Heavenly stems-1-ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl isophthalic acid-phenyl chlorocarbonate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl cyclohexane ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1,2-trimethylammonium propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1) chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl ring pentyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-cyclohexyl-1-methyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,4-dimethyl-4-piperidine ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-fluorobenzene ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-methyl phenyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(methoxycarbonyl) phenyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridine ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(trifluoromethyl)-, ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [the 5-[(dimethylamino) methyl]-the 2-furyl] methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-carboxyl-2-methyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(dimethylamino)-2,2-dimethyl propyl ester;
With 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1]-chromene propanedioic acid of [3,2-i] quinolizine-1-formic acid also, an acid anhydrides, 1,1-dimethyl ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino)-2-methyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(1H-imidazoles-1-yl) ethyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-benzofuryl methyl esters;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R, 2S)-2-(dimethylamino)-1-phenyl propyl ester;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S, 2R)-2-(dimethylamino)-1-phenyl propyl ester; With
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) encircles propyl ester.
9. compound, its name be called pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine also, 3,7,8,9,10,12,13,14,14a, the 15-decahydro-, or pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-compound.
10. pharmaceutical composition, wherein contain with pharmaceutical excipient, the described compound of diluent or carrier blended claim 1 or pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester.
11. regulate the method for mammalian chemokines receptor active, comprising the described compound of the claim 1 of using significant quantity or pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester or its pharmaceutical salts.
12. regulate the method for Mammals CCR-5 chemokine receptor activity, comprising the described compound of the claim 1 of using significant quantity or pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester or its pharmaceutical salts.
13. prevention HIV infects, treatment HIV infects, postpones the method for AIDS outbreak or treatment AIDS, comprising the described compound of claim 1 of giving the administration treatment significant quantity that needs described treatment or pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester or its pharmaceutical salts.
14. the method for treatment inflammatory diseases, comprise to the described compound of claim 1 of the administration of the described treatment of needs treatment significant quantity or pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester or its pharmaceutical salts.
15. formula I compound and one or more are used to prevent and/or treat the cooperative programs of AIDS preparation.
16. compound, it is selected from as follows:
Pyridine, 3-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-yl also) carbonyl] the oxygen base] methyl]-the 1-methyl-, mesylate;
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the carbonyl of 11-dimethyl-1-[(S)-(1-phenyl ethoxy)]-, mesylate; And
Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-and the 1-phenyl chlorocarbonate, the 11-oxide compound.
17. compound, its name be called with benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, acid anhydrides.
CN99816475A 1999-01-13 1999-12-20 Functionalized heterocycles as chemokine receptor modulators Pending CN1344270A (en)

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