Tải bản đầy đủ - 0 (trang)
B. Compounds with Three Heteroatoms

B. Compounds with Three Heteroatoms

Tải bản đầy đủ - 0trang

192



BICYCLIC FUSED HETEROCYCLES



serious limitations. The benzodiazepines that came along in the 1960s were

better tolerated though these too had their drawbacks, such as drug hangover

and the propensity to induce dependence. These have now been largely

replaced by drugs, such as zolpidem. The structures of these drugs share the

purine 6–5 fused rings system found in purines; the placement of ring nitrogens atoms is usually quite different from that found in purines. The synthesis

of a recent example begins with the condensation of the substituted acetophenone (25) with DMF acetal. This reaction affords the chain-extended enamide

(26). The amide nitrogen is then alkylated (27). Reaction of this intermediate

with the aminopyrrazole (28) leads to formation of the fused pyrimidinopyrrazole (29). For bookkeeping purposes, the transform may be visualized to

involve addition–elimination of the enamide diethylamino group by the

amine on the pyrrazole. Imine formation between the carbonyl and pyrrazole

ring nitrogen then closes the fused ring. The product (29) is next acylated with

thiazole-carboxylic acid (30) in the presence of aluminum chloride (31). Thus,

indiplon (31) is obtained.5

H

N



CH3



H

N

O



(H3C)2N



N

O



OCH3



N



O



CH3I

NaH



O



H

N



H2N



O



O



N(CH3)2



N(CH3)2



28



25



26



27



CH3

N



CH3

O



N



ClOC



N



S



O



N



30

AlCl3



N



N



N



S

N



O

31



29



The enzyme, purine nucleoside phosphorylase (PNP), is directly

involved with blood levels of T-cells. Low levels of this enzyme will

inhibit T-cell proliferation. Drugs that inhibit the enzyme can also be

expected to act against proliferation of malignant T-cells. The PNP inhibitor forodesine (36) has shown early activity against T-cell malignancies.

Treatment of the deazapurine (32) with lithium leads to derivative 33



1. COMPOUNDS WITH FIVE-MEMBERED RINGS FUSED TO SIX-MEMBERED RINGS



193



lithiated on the pyrrole ring. Condensation of that species with the highly

protected aminosugar (34) results in addition of the anion to the imine

function on the sugar. Deprotection of that product (35) in several steps

then affords 36.6



OCH3



C6H5CH2OCH2



OCH3



C6H5CH2OCH2



TbdmsO



N



N



N



N



N



BuLi



Tbdms = t Bu(CH3)2Si–

N



N

O



Li

32



O



33

34

OH

H

N



HO



H

N



C6H5CH2OCH2



OCH3



N



N

TbdmsO



N



H

N



+ +



N

N



Bu4N F

H3O

HO



OH



H2



+



O



O



36

35



The pteridine, folic acid, comprises one of the essential factors required

for synthesis of DNA and by extension cell proliferation. As a result, folate

antagonists have been intensively investigated as potential antitumor

compounds. The pteridine-based antagonist methotrexate, which was developed many years ago, simply comprises folic acid in which the side-chain

amine is methylated and nitrogen replaces the oxygen atom at the 4 position. This drug is widely used as an antitumor compound. Methotraxate

in fact comprises the “M” in the acronym of the many multidrug cocktails

used by oncologists. Most of the more recent folate antagonist, as exemplified by palitrexate (202) and pelitrexol (213) described later in this chapter,

retain the two fused six-membered rings found in folic acid and replace the

side-chain amine group by a methylene group. Contraction of one of the

rings, is interestingly consistent with folate antagonism. The first few

steps in the construction of the nucleus of pemetrexed (46) follow a

well-precedented scheme. Reaction of the enolate from ethyl cyanoacetate

(37) with the methyl acetal from bromoacetaldehyde (38) leads to the alkylation product (39). Condensation of 39 with guanidine then forms the pyrimidine (40). The transient side-chain aldehyde from treatment of the

compounds with acid then forms an imine with the adjacent amino group,

thus closing the fused five-membered ring (41). The remaining primary



194



BICYCLIC FUSED HETEROCYCLES



amino group is then protected as its tert-butyl carbamate (42). Reaction of 42

with iodo sucinimide proceeds to form the 3-iodo derivative (43).

O



H2N

NaOC2H5



C2H5O2C



+



NC



Br



(H2CO)2HC



37



C2H5O2C

NC



38



NH



NH2



HN



CH(CH3O)2



H2N



CH(CH3O)2

NH2



N



39



40

HCl



O

HN

N

H



HN



HN



NIS

N



tBuCOHN



O



O



I



t BuCOCl

N

H



N



t BuCOHN



43



N

H



N



H2N



42



41



NIS = N -iodosuccinimide



The key step in this synthesis comprises grafting the benzenzamidoglutamate moiety found in folic acid onto the heterocycle. Thus, condensation of the iodo-substituted (43) with acetylide (44) catalyzed by

tetrakis-triphenylphosphine palladium affords the coupling product (45).

The triple bond is then converted to the saturated bridge by catalytic

hydrogenation. Saponification then removes the protecting group and at

the same time hydrolyzes the esters on the glutamate fragment to afford 46.7

CO2CH3

O

N

H



CO2CH3

O



O

+

N

H



43



CO2CH3



Pd(Ph3P)4

HN

t BuCOHN



N

H



N



44



45



1. H2



CO2H



2. NaOH



O

O

NH2



N

H



CO2H



H2N



H

N



HN



N

N



N

N



N



CH3



H2N



N

46



Methotrexate



N

H



CO2H



O

CO2H



CO2CH3



195



1. COMPOUNDS WITH FIVE-MEMBERED RINGS FUSED TO SIX-MEMBERED RINGS



C. Compounds with Four Heteroatoms

The A1 adenosine receptors fulfill a largely inhibitory role. Research has

thus recently focused on agonist with structures based on adenosine

itself as agents that will overcome responses due to inappropriate excitation, such as tachycardia and some arrhythmias. Replacement of one of

the hydrogen atoms on the exocyclic amine in adenosine by a tetrahydrofuryl group provides an effective A1 adenosine agonist. Preparation of this

fragment as a single enantiomer starts with a modern version of the Curtius

reaction. Thus, reaction of tetrahydrofuroic acid (47) with triphenylphosphoryl azide leads to isocyanate (48). Treatment of this intermediate

with benzyl alcohol then affords the corresponding carbamate (49).

Catalytic hydrogenation removes the benzyloxy group leading to the free

primary amine 50. The product is then resolved by way of its camphorsulfonyl salt to afford 51. Reaction of this intermediate with desamino chloroadenosine (52) affords tecadenoson (53).8



Ph2PON3

O

47



CO2H



O



C6H5CH2OH

O



NCO



Resolve



H2

O



N

H



OCH2C6H5



48



NH2



O



51



Cl



NH



O



NH2



O



50



49



N



N



N



N



N



N



N



N

HO



HO



OH



HO

53



HO



OH

52



Another approach to preparing A1 adenosine receptors agonists involves

converting the hydroxymethyl group on the sugar moiety to an amide in

addition to adding a substituent to the amine of adenosine. The starting

material (56) is arguably obtainable by oxidation of inosine acetonide

(54), followed by acetylation of the hydrolysis product. Reaction of the

acid (55) with thionyl chloride followed by ethanol affords the corresponding ethyl ester (56). The ring oxygen on this intermediate is next replaced

by chlorine by means of phosphorus oxychloride to yield 57. Reaction of

57 with cyclopentylamine displaces the halogen to form the cyclopentylamino derivative (58). Treatment with triethylamine under somewhat more

strenuous conditions effects ester –amide interchange to form the

amide; the acetyl protecting groups are cleaved under those reaction



196



BICYCLIC FUSED HETEROCYCLES



conditions. Thus, the A1 adenosine receptors agonist selodenoson is

obtained (59).9

OH



OH



OH

N



N



N



N

1. SO2Cl



O



O



HO2C



HO



N



N



N



N



N



N



N



N



2. C2H5OH



O



C2H5OCO



O



C2H5OCO



OCOC2H5



OCOC2H5

56



55

54



POCl3



Cl



NH

NH



CH3CH2NH2

H

N



N



N

NH2



O



O



O



N



N



N



N



N



N



N



N



N



N



O



O



HO



OH

59



C2H5OCO



OCOC2H5



58



C2H5OCO



OCOC2H5



57



Yet another modification leading to an adenosine agonist involves conversion of one of the amino groups on the fused pyrimidine ring of adenosine to a pyrazole. The synthesis begins with the conversion of guanosine

to its 50 acetate by reaction with acetic anhydride. The hydroxyl at the

4 position is replaced by chlorine in the usual manner by treatment with

phosphorus oxychloride to afford 61. In a variation on the Sandmeyer reaction, this last intermediate is allowed to react with amyl nitrite in the presence of methylene iodide in an aprotic solvent. The low concentration of

nitrite ion from decomposition of its amyll ester serves to diazotize the

amine; the diazonium intermediate then captures iodine from the other

reagent to form the iodo derivative (62). Reaction of 62 with ammonia

interestingly proceeds selectively at the 4 position on the purine to

afford 63. Treatment of this product with hydrazine, presumably under

more strenuous conditions, displaces iodine to form 64. Condensation of

64 with carbethoxymalonaldehyde (65) then affords the pyrazole ring,



Tài liệu bạn tìm kiếm đã sẵn sàng tải về

B. Compounds with Three Heteroatoms

Tải bản đầy đủ ngay(0 tr)

×