Method of synthesis for camptotecin-bound compounds

FIELD: organic synthesis.

SUBSTANCE: invention relates to synthesis of camptotecin analogues from 2'-amino-5'-hydroxypropiophnone corresponding to AB ring portion of camptotecin structure and tricyclic ketone converted into CDE ring portion in camptotecin structure. Preparation of 2'-amino-5'-hydroxypropiophnone comprises following steps: (1) preparing compound (b) by mixing compound (a), benzylation agent, and a base followed by stirring mixture obtained in solvent on heating under reflux; (2) preparing compound (c) by dropwise adding Grignard reagent to compound (b) under an inert gas atmosphere; (3) preparing compound (d) by mixing compound (c) with an oxidant and stirring resulting mixture; and (4) preparing compound (e) via catalytic reduction of compound (d) (see scheme 1 below). Intermediate compounds (c') and (d') are described. Also described is a method for preparing tricyclic ketone to provide efficient complete synthesis of camptotecin serving as starting compound for irinotecan hydrochloride and a various types of camptotecin derivatives as well as for stable preparation of camptotecin and its derivatives. Scheme 1: .

EFFECT: expanded synthetic possibilities in camptotecin derivatives series.

5 cl, 17 tbl, 33 ex

 

The text descriptions are listed faxing

1. The method of obtaining 2'-amino-5'-hydroxypropiophenone for synthesis of analogues of camptothecin, in which connection (s):

get a connection (b):

of the compounds (b) receive the Ute connection (s):

from the compound (C) obtain the compound (d):

and from compound (d) receive connection (s):

this method contains the following steps:

(1) a step for obtaining compound (b) by mixing compound (a), benzylurea agent and the base and mixing the above-mentioned mixture in the solvent by heating under reflux;

(2) a step for obtaining compound (C) by adding dropwise the Grignard reagent to the compound (b) in an atmosphere of inert gas;

(3) a step for obtaining compound (d) by mixing compound (C) with an oxidizing agent and mixing the mixture;

(4) a step for obtaining compound (e) by catalytic reduction of compound (d);

where R is one of the protective groups benzylating type protective groups benzylmalonate type, which is removed by catalytic regeneration.

2. The method according to claim 1, wherein the protective group is removed by catalytic regeneration is a benzyl group.

3. The method according to claim 1, wherein in stage (1) the solvent is dimethylformamide.

4. The method according to claim 1, in which step (2) a Grignard reagent is vinylmania.

5. The method according to claim 1, in which step (3) ocil is the missing agent is a reagent Jones, manganese dioxide or TEMPO-sodium hypochlorite.

6. The compound represented by the formula (C'):

where Bn means benzyl group.

7. The compound represented by formula (d'):

where Bn means benzyl group.

8. The method of obtaining 2'-amino-5'-hydroxypropiophenone for synthesis of analogues of camptothecin, in which connection (s):

get connection ():

from the compound (C) obtain the compound (d"):

and from compound (d) receive connection (s):

this method contains the following steps:

(1) a step for obtaining compound (C) by adding dropwise the Grignard reagent to the compound (a) in an atmosphere of inert gas;

(2) a step for obtaining compound (d) by mixing the compound (s) and oxidizing agent and mixing the mixture; and

(3) a step for obtaining compound (e) by catalytic reduction of compound (d").

9. The method according to claim 8, in which in step (1) of the Grignard reagent is vinylmania.

10. The method of claim 8 where in step (2) oxidizing agent is a reagent Jones dioxide Marg the NCA or TAMRA-sodium hypochlorite.

11. The way to obtain the tricyclic ketone for synthesis of analogues of camptothecin in which of the compounds (k):

where TMS means trimethylsilyloxy, a Me - metal group, or the compound (v):

where TMS means trimethylsilyloxy, a Me - metal group have a connection (1):

where TMS means trimethylsilyloxy, a Me - metal group, of the compounds (1) receive connection (m):

where TMS means trimethylsilyloxy, a Me - metal group from the compound (m) receive connection (n):

where TMS means trimethylsilyloxy, Me is a metal, a Et is ethyl group, and compounds (n) get connection ():

where TMS means trimethylsilyloxy, Me is a metal, and Et is the ethyl group of the compounds (a) receive connection (R):

where TMS means trimethylsilyloxy, Me is a metal, and Et is the ethyl group of the compounds (p) receives the connection (q):

where Me denotes a metal, a Et is ethyl group from the compound (q) receive connection (r):

where Me denotes a metal, Et is ethyl, a Pr - through the group of compounds (g) receive connection (s):

where Et means ethyl, Pr - through group from compound (s) receive connection (t):

where Et means ethyl, a tBu - tertbutylphenol group, and compounds (t) to obtain the compound (h):

where Et means ethyl group,

moreover, this method contains the following steps:

(1) a step for obtaining compound (1) by mixing the compounds (k), n-utility, formuliruiutsia agent and jodorowski agent, where the reaction temperature is constant and is in the range from -30 to -40°C;

(2) a step for obtaining compound (t) by mixing the compound (1), catelouge alcohol, triethylsilane and acid and carrying out the reaction without using a solvent;

(3) a step for obtaining compound (1) by mixing the compound (v), a by-product of stage (2)with an oxidizing agent and a base;

(4) a step for obtaining compound (n) by mixing the compounds (m), palladium catalyst, a base and a catalyst phase transfer and heat this mixture in a solvent under reflux;

(5) a step for obtaining compound (o) PU is eaten mixing compound (n), osmanaga catalyst soogilauaga agent, a base and an asymmetric reagent;

(6) a step for obtaining compound (b) by mixing compound (a), the base and iodine and heating this mixture under reflux in a liquid mixture of alcohol and water;

(7) a step for obtaining compound (q) by mixing compound (p) and desilicious-jodorowski reagent;

(8) a step for obtaining compound (r) by mixing compound (q), palladium catalyst and a base and the reaction in 1-propanol in the gaseous atmosphere of carbon monoxide;

(9) a step for obtaining compound (s) by mixing compound (r) and demetrious reagent and the reaction at room temperature;

(10) a step for obtaining Compound (t) by introducing into the reaction of the Compound (s) in the presence of t-butyl acrylate and grounds.

12. The method according to claim 11, in which step (3) oxidizing agent is TEMRO-sodium hypochlorite.

13. The method according to claim 11, in which step (4) the base is potassium carbonate or diisopropylethylamine.

14. The method according to claim 11 or 13, in which step (4) the solvent is tetrahydrofuran or a liquid mixture of diisopropyl ether - acetonitrile - water.

15. The method according to claim 11, in which step (5) osmium catalyst is potassium osmate (VI).

16. The method according to claim 11, in which step (6)amount of iodine in relation to the compound (o) is 4 equivalent.

17. The method according to claim 11, in which step (7) desilicious-Jodorowsky reagent is iodine-triptorelin silver or N-chlorosuccinimide-sodium iodide.

18. The method according to claim 11 or 17, in which the compound (q) chemically cleaned by means of cleaning steps including the step of adding the product of the reaction of obtaining compound (q) from compound (p) to aqueous alkali solution and mixing; the step of adding an organic solvent and mixing with the subsequent removal of the organic layer; a step of acidification of the aqueous layer and extraction with an organic solvent.

19. The method according to p, in which the aqueous alkali solution is an aqueous solution of sodium hydroxide.

20. The method according to p, in which the organic solvent is chloroform.

21. The method according to claim 11 or 17, in which the compound (q) optically clear through treatment stages, including the stage of dissolution of the reaction product to obtain a compound (q) from compound (p) in a highly polar solvent, followed by layering nizkoposhibnogo solvent and the step of filtering off the precipitate with subsequent concentration of the filtrate to dryness under reduced pressure.

22. The method according to item 21, in which the highly polar solvent is chloroform.

23. The method according to item 21, in which iskopaemym solvent is n-hexane.

24. The method according to claim 11, where step (10) cos the cation is potassium carbonate.

Priority items:

05.10.2001 - claims 1 to 4, 6 and 7

21.02.2001 - pp.5, 8-24



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry of heterocyclic compounds, biology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of the general formula (1): or (2): or their pharmaceutically acceptable salts, N-oxides or hydrate possessing physiologically active properties, in particular, eliciting ability to induce apoptosis in tumor cells causing their death. In the general formula (1) or (2) X represents sulfur or oxygen atom; Y represents sulfur atom, group -SO, group -SO2, group -NH or group -NR6; R1 represents aryl, substituted aryl, heteroaryl; R2 and R5 represent hydrogen atom, alkyl, allyl, substituted benzyl, group -CH2-C(O)R3, group -CH2-C(O)NR3R4 wherein R3, R4 and R6 represent inert substitute. Also, invention relates to new combinatory libraries for search compound-leaders and candidates for medicinal compounds preparing by screening the combinatory libraries.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

The invention relates to a method for producing a condensed polycyclic alkaloids of General formula I, including new, including phase cyclization of azometynoylid General formula II, where a is optionally substituted aryl, Z is oxygen, n = 1, Y is optionally substituted aryl, W and X together with the nitrogen atoms and the carbon to which they are attached, form a saturated or unsaturated nitrogen-containing heterocyclic group, possibly substituted and possibly condensed with aryl, carbocyclic or heterocyclic group

The invention relates to novel condensed pyrrolo (2,3-C)carbazole-6-Onam represented by the General formulas (I) and (II)

The invention relates to new derivatives of 5H-pyrano[2,3-d:6,5-d']dipyrimidine General formula I possess anti-microbial, antiviral and immunomodulatory effects

The invention relates to a new process for the preparation of 9-amino-20/S/-camptothecin formula /I/

< / BR>
which is a well-known anti-cancer agent: Wani, etc

The invention relates to the field of macrolides

FIELD: organic chemistry, medicine.

SUBSTANCE: invention proposes new compounds of the general formula (I):

wherein R1 means one or more similar or different substitutes taken among the group consisting of hydroxy-group, halogen atom including F, Cl, Br and J, (C1-C5)-alkyl, (C1-C5)-alkoxy-group under condition that when R1 means one substitute then it is in ortho-position and when R1 means above one substitute then at least one substitute at R1 is in ortho-position; R2 means halogen atom including F, Cl, Br and J, (C1-C5)-alkyl, (C1-C5)-alkoxy-group; R3 means halogen atom including F, Cl, Br and J; R6 means hydrogen atom or methyl; and its salts with pharmaceutically acceptable acids, hydrates or solvates. Compounds elicit activity against acne and acne-related diseases.

EFFECT: valuable medicinal properties of compounds.

7 cl, 4 tbl, 43 ex

The invention relates to a method for producing 2-aminobenzophenones, which are intermediate compounds in obtaining reducing cholesterol agents, which are agents for the treatment of mental disorders, and anti-inflammatory agents

The invention relates to new nitromethylene formula (I)

< / BR>
in which A represents C6-C10aryl, thienyl, benzothiazyl; X denotes halogen, cyano, C1-C7alkyl, trifluoromethyl, C2-C7alkoxy, or cryptometer; p is chosen from 0, 1, 2, 3, 4, or 5; Z represents a bond, -CO-NH-, SO2-NH-, a sulfur atom, sulfinyl group or a C2-C7alkenylamine radical; R1, R2, R3and E indicated in paragraph 1

The invention relates to 1-phenylalanine - new ligands of 5-HT4receptors of formula I, where R1- halogen; R2- H, C1-C4alkoxy; R3- C1-C4alkoxy, phenyl C1-C4alkoxy, where phenyl optionally substituted by 1-3 substituents, independently selected from C1-C4of alkyl, C1-C4alkyloxy, 3,4-methylendioxy; R2and R3together represent methylenedioxy, Ethylenedioxy; R4denotes a group of formula (a) or (b), where n = 3, 4, 5; p = 0; q = 1 or 2; R5and R6each C1-C4alkyl or together are - (CH2)4- , - (CH2)6-, - (CH2)2O(CH2)2-,

-CHR8CH2CR9R10CHR11CH2- where R8and R11each H or together are - (CH2)t- where t =1; R9- H, HE, C1-C8alkyl, C1-C4alkyloxy; R10- H, C1-C8alkyl, phenyl, - (CH2)xR12where x = 0, 1, 2, 3; R12HE, C1-C4alkyloxy, - C(O)NR13R14, - NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15, -NR13C(O)NR14R15; R13, R14, R15- independently - H, C1-C4e is phenyl optionally substituted C1-C4alkyloxy, methylendioxy, Ethylenedioxy; or R7- (CH2)z- R12where z = 2, 3

The invention relates to a method for producing 2-aminobenzophenones, which are intermediate compounds in obtaining reducing cholesterol agents, which are agents for the treatment of mental disorders, and anti-inflammatory agents
Up!