Synthesis of multicyclic 2-pyridones from a formyl and...
Transcript of Synthesis of multicyclic 2-pyridones from a formyl and...
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Synthesis of multicyclic 2-pyridones from a formyl and
chlorometylene substituted precursor using a strategy of
directed diversity-oriented synthesis
Golla Krishna Prasad
Student Degree Thesis in Chemistry 45 ECTS Master’s Level Under Supervision of: Prof Fredrik Almqvist & Dr Magnus Sellstedt Examiner: Prof Mikael Elofsson Department of Chemistry Umeå University
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ABSTRACT
Multi ring-fused 2-pyridones have shown interesting activity in a variety of biological systems. It
would be of great interest to explore the biological application of even more multi heterocyclic
ring fused 2-pyridones. ‘Diversity oriented synthesis’ is an excellent concept emerged in recent
years to access compounds with structurally and stereochemically diverse skeletons. This
served as an efficient avenue for synthesizing various ring fused 2-pyridones using formyl,
chloromethylene substituted 2-pyridone (6) as a starting compound. By treating the starting
material (6) with various nucleopliles, different sized heterocyclic ring fused 2-pyridones has
been synthesized. Additionally, an improved methodology for the synthesis of naphthyridones
was presented.
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TABLE OF CONTENTS
1. INTRODUCTION........................................................................................................................1
2. RESULTS AND DISCUSSIONS................................................................................................3
2.1 Synthesizing multi hetero cyclic ring fused 2-pyridone compounds by using directed diversity
oriented synthesis………………………………………………………………………………………………………………….……….….3
2.2 Synthesis of chloromethylene substituted 2-pyridone………………………………………………………………….4
2.3 Synthesis of formyl and chloromethylene substituted 2-pyridone ……………………………….……………..4
2.4 Synthesis of 5-membered hetero cyclic ring fused 2-pyridones…………………………………………………….5
2.4.1 N-Substituted pyrroles fused to 2-pyridones at 6th and 7th positions………………………………………….5
2.4.2 Synthesis of thiophene and furan fused 2-pyridones at 6,7 positions……….……………….…………….…..5
2.4.3 Synthesis of γ-lactam fused 2-pyridone at 6th and 7th positions……………………………….…………………….6
2.5 Synthesis of six -membered heterocyclic ring-fused 2-pyridones…….……….…………….……………………7
2.5.1 Previous methodology to synthesize Napthyridones……………………………………………………………………7
2.5 .2 An improved methodology to synthesize Naphthyridones……………………………………………………………8
2.6 Synthesis of seven- membered heterocyclic ring-fused 2-pyridones .…………….…………..……………….10
2.7 Synthesis of eight- member heterocyclic fused 2-pyridones ………….…………………………..………….…..11
3. CONCLUSION……………….……………………………………………………………………………….……………………12
4. ACKNOWLEDGEMENT………………….………………………………………………………….………………….…13
5. EXPERIMENTS …….…………………………………………………………………….………………………………...14
5.1 General ………………………………………………………………………………………………………….………………………..14 5.2 Synthesis ……………………………………………………………………………………………………………………………………14
6. REFERENCES…………………………..........................................................................................23
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ABBREVIATIONS
AcOH acetic acid
calcd calculated
DMF N,N’-dimethylformamide
DMSO dimethylsulfoxide
DOS diversity oriented synthesis
EtOAc ethyl acetate
EtOH ethanol
eq. equivalents
HPLC high performance liquid chromatography
HRMS high resolution mass spectroscopy
IR infrared
LC-MS liquid chromatography mass spectrometry
MeCN acetonitrile
MeOH methanol
mol. molecular
MWI microwave irradiation
NMR nuclear magnetic resonance
Ac acetyl
ON overnight
Ph phenyl
RT room temperature
TEA triethylamine
TFA trifluoro aceticacid
UV ultraviolet
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1. INTRODUCTION
Heterocyclic compounds are widely present in biologically active, natural and synthetic
compounds. The majority of pharmaceutical products, pesticides, insecticides, cosmetics and
dyes e.t.c are heterocyclic compounds. In fact, in the Comprehensive Medicinal Chemistry
(CMC) data base, more than 67% of the compounds contain heterocyclic rings1. New strategies
to synthesize various heterocyclic compounds are significant for the lead identification and lead
optimization processes. In this context, it is certainly a more interesting and worthwhile
strategy to access skeletally different compounds rather than the single central fragment, for it
widens the scope to find lead compounds in the drug discovery process2.
2-pyridones are the significant core structures in synthetic as well as in natural products having
diverse medicinal properties like antifungal3, angiotensin converting enzyme inhibition4-6, Aβ
peptide aggregation7,8 , antibacterial9,10 and anticancer11,12 (Fig 1).
N
OH
COOHO
HOOC
N
O
MeO
ONHS
Et2N
1 2
A58365A, ACE Inhibitor (nM)5 RO 65 – 8835/001 Inhibitor of amyloid formation8
Figure 1. Example of biologically active molecules containing 2-pyridones.
The thiaozolo ring-fused 2-pyridones 3 and 4 possess various biological properties like
antibacterial13, inhibition of aggregation of an Alzheimer’s peptide into amyloids14 and
inhibition of curli protein aggregation15. By making new multiring fused systems based on 3 and
4 we envision it will result in substance classes with interesting activity in variety of biologiacal
systems. In order to prepare large number of mulitiring fused 2-pyridones that are diverse but
with maintained peptidomimetic backbone a directed diversity oriented synthesis has been
developed.
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N
S
O COOLi
N
S
CF3
O COOLi
3 4
Figure 2 Biologically active thiazolo ring-fused 2-pyridones with peptidomimetic backbones13,15.
The aim of this project was to prepare the formyl and chloromethylene substituted 2-pyridone
(6) from the compound chloromethylene substituted 2-pyridone (5). Using this as starting
compound, a small series of multi ring-fused 2-pyridones were to be synthesized.
N
S
O COOMe
Cl
N
S
O COOMe
Cl
O
H
5 6
Figure 3. Structure of chloromethylene and formyl chloromethylene substituted 2-pyridone compounds.
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2. RESULTS AND DISCUSSIONS
2.1. Synthesizing multi heterocyclic ring fused 2-pyridone compounds by using a directed diversity
oriented synthesis
Inspired by the concepts of diversity oriented synthesis16 5 to 8 membered heterocyclic
ring fused 2-pyridones were synthesized using the formyl chloro substituted 2-pyridone (6) as
starting material. Compound 6 has two reactive electrophilic sites at left hand side, the
reactions were carried out in this side and gave compounds that have large change in one part
and no change in the other part (Fig 4).
Figure 4. Overview to access multi heterocyclic ring fused 2-pyridones using directed diversity
oriented synthesis strategy.
N
S
O COOMe
S
N
S
O COOMe
Cl
O
H
N
S
O COOMe
N
N
S
NH O
S
COOMeMeOOC
S
O COOMe
N
O
O
+N
S
O COOMe
HN
O
N
S
O COOMe
ON
S
O COOMe
N
N
S
O COOMe
N
N
S
O COOMe
N
S
O COOMe
N
O
O
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2.2. Synthesis of chloromethylene substituted 2-pyridone
The chloromethylene substituted 2-pyridone 5 was synthesized by using the chlorinated
Meldrum’s acid derivative (8) and ∆2thiazoline (7) according to the previously published
procedure17. One of these two 2-pyridone building blocks, the ∆2thiazoline (7) was synthesized
from nitriles according to the previously published procedure18. The chlorinated Meldrum’s acid
derivative (8) was synthesized from chloroacetic acid using a slight modification of previously
published precedures19.
S
COOMe
O O
O O
MWI 120oC
3 MIN
N
S
O COOMe
Cl+
TFADCE
yield 74%
ClHO
7 8 5
Scheme 1. Synthesis of chloromethylene substituted 2-pyridone (5).
2.3. Synthesis of formyl and chloromethylene substituted 2-pyridone
We made an attempt to introduce a formyl group at the sixth position in
compound 5 by following the previously published procedure20, in which the reaction was
carried out by using 4 eq of Arnold’s reagent and refulxing in acetonitrile. Unfortunately the
compound 6 was obtained in lower yield (22%). However, increasing the amount of Arnold’s
reagent to 10 eq gave the desired compound 6 in 53% yield (scheme 2).
N
S
O COOMe
Cl
N
Cl
N
S
O COOMe
Cl
O
H
yield 53%
+
MeCN,80oC
3.5 h
10 eq
5 6
Scheme 2. Synthesis of formyl chloromethylene substituted 2-pyridone.
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2.4. Synthesis of 5-membered heterocyclic ring-fused 2-pyridones
Several 5-membered heterocyclic fused 2-pyridones at 6th and 7th positions were
synthesized using different nuclophiles.
2.4.1. N-Substituted pyrroles fused to 2-pyridones at 6th and 7th positions
In order to synthesize N-substituted pyrrole fused 2-pyridones, the starting material 6 was
treated with amines in the presence of K2CO3 using acetonitrile as a solvent at room
temperature. However, when the aniline was used as reaction component the reaction mixture
was refluxed at 70oC overnight (Scheme 3).
N
S
O COOMe
Cl
O
H
RNH2K2CO3
MeCNN
S
O COOMe
NR
6 9
9a R = Me 85%
9b R = Ph 77%
Scheme 3. Synthesis of N- substituted pyrrole fused 2-pyridones.
2.4.2. Synthesis of thiophene and furan fused 2-pyridones at 6,7 positions.
The preparation of thiophene fused 2-pyridones at 6th and 7th positions is a three
step one pot reaction. The first step is the SN2 reaction. Subsequent hydrolysis of the thioester
and then addition of AcOH accelerated the dehydration reaction, which resulted in 10a. The
same procedure was followed for the preparation of furane fused 2-pyridone (10b). But in this
reaction the dehydration step was not accelerated by AcOH. The reason for low yield was its
low stability (Scheme 4).
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N
S
O COOMe
Cl
O
HN
S
O COOMe
X
X= O,S
2. CH3OH, RT
3. CH3COOH, RT
1.AcX-K
+, MeCN, RT
6 10
10a X = S 70%
10b X= O 23%
Scheme 4. Synthesis of thiophene and furan fused 2-pyridones
2.4.3. Synthesis of a γ-lactam fused 2-pyridone
When the starting material 6 was treated with sodium azide in MeCN under
microwave irradiation at 80oC to obtain the azide-substituted 2-pyridone compound 11
interestingly, a small amount of byproduct 12 was observed. As this product has two
peptidomimetic amide bonds, it enhanced our curiosity to increase the yield of 12. Fortunately,
using the same reaction conditions with an additional increase in temperature from 80oC to
100oC and reaction time from 10 to 30 min gave 62% yield of 12 (Scheme 5).
N
S
O COOMe
Cl
O
H
NaN3
MWI 80oC N
S
O COOMe
N3
O
H
MeCN, MeOH
30 min
6 11
N
S
O COOMe
Cl
O
H
MeCN, MeOH
MWI 100oC N
S
O COOMe
HN
O30 min
NaN3
6 12
Yield 62%
Scheme 5. Synthesis of γ-lactam fused 2-pyridones.
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Mechanism
Although the mechanism of the above reaction is not clear, a possible mechanism is a Schmidt type of
reaction.
N
S
O COOMe
Cl
O
H
NaN3, MeCN
MWI 100oC
N
S
O COOMeO
H
N
N
S
O COOMe
NN
+
N
N
S
O COOMe
NNN
H
..
.._
HO
+
O
.._
:
Figure 5: Outline of tentative mechanism.
2.5. Synthesis of six-membered heterocyclic ring fused 2-pyridones
In order to synthesize six-membered heterocyclic rings fused to 2-pyridones we
focused on a previously published three component reaction21, which access naphthyridones.
The central fragment of these compounds shows a structural similarity to the natural product
lophocladine A, which has δ-opiod receptor antagonist activity22. Here, we present an improved
methodology to synthesize naphthyridones by changing the starting compound.
2.5.1. Previous methodology to synthesize naphthyridones
The three component reaction described before, used compound 13 as the starting
material21. Compound 13 was stirred with various aldehydes and amines at which resulted in
dihydro naphthyridones. In this method oxidation was nessesary and this was done by using
chloronil or oxygen (Fig 6).
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N
S
O COOMe
, R2CHO1.R
1NH2
AcOH,
N
S
O COOMe
NR
1
R2
+
MeOH, MeCN
O
H2.Oxidation
13 14
Figure 6. Previous method to synthesize naphthyridones21.
2.5.2. An improved methodology to synthesize naphthyridones
Here, to synthesize naphthyridones compound 6 was used as starting material instead
of compound 13 (Scheme6). The naphthyridones were isolated in high yields in low reaction
times and as there is a methylene chloride at seventh position, the intermediate
dihydronaphthridone spontaneously becomes aromatic as it eleminates the chloride and this is
confirmed by mechanism. Hence, there is no need to use any oxidizing agent in this method as
it was in the previous procedure21 (Scheme 6).
N
S
O COOMe
Cl PhCHO,
MeNH2, AcOH
MWI 80oC,10 min
N
S
O COOMe
N
Ph
+MeOH, MeCN
O
H
Cl-
6 15
Yield 74%
Scheme 6. Overview of naphthyridone synthesis from compound 6.
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The below mechanism supports the spontaneous aromatization of dihydronaphthyridones.
Mechanism
N
S
O COOMe
Cl
O
H
N
S
O COOMe
N
R2
R1
R1NH2
-HCl
N
S
O COOMeNR
1
Cl
N
S
O COOMe
N
R2
Cl
R1
R2CHO
N
S
O COOMe
Cl
HNR
1
N
S
O COOMe
Cl
NR
1
R2
+
+
+
Figure 7. Outline of tentative mechanism.
Besides the synthesis of charged naphthyridonium salts, the uncharged napthyridone
16 was also prepared. As with the previous method21, it was found that excess of ammonium
acetate (4 eq) was necessary to produce uncharged naphthyridones (Scheme 7).
N
S
O COOMe
Cl PhCHO
MeCOO-NH4
+
, AcOH
MWI 80oC,10 min
N
S
O COOMe
N
Ph
MeOH, MeCN
yield 62%
O
H
6 16
Scheme 7. Synthesis of uncharged naphthyridones.
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2.6. Synthesis of seven-membered heterocyclic ring-fused 2-pyridones
For the synthesis of seven-membered heterocyclic fused 2-pyridones, first the starting
material 6 was reduced to alcohol compound 17. Next, the alcohol compound 17 was treated
with different amines to give amino alcohols. Finally, the amino alcohols were reacted with
triphosgene to give 7-membered carbamate compounds (Scheme 8). It was possible to purify
the resulting compounds in each step for most amines but with aniline it was difficult to purify
the resulted carbamate and this compound was excluded.
N
S
O COOMe
Cl
O
H
NaBH4
N
S
O COOMe
Cl
MeOH,MeCN
yield 80%
OH
6 17
N
S
O COOMe
Cl
OH
N
S
O COOMe
NH
RNH2,K2CO3
MeCN, rt
R
OH
17 18
18a R=Me 58%
18b R=Bn 63%
N
S
O COOMe
HN
OH
N
S
O COOMe
triphosgene
DCM, rt
N
O
O
RR
18 19
18a 19a R=Me 63%
18b 19b R=Bn 61%
Scheme 8. Overview of carbamate synthesis.
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2.7. Synthesis of an eight-membered heterocyclic ring-fused 2-pyridones
In order to make an 8-membered heterocyclic ring fused 2-pyridone, compound 6
was first treated with BOC protected cysteine which resulted in a thio ether compound. Next,
the BOC deprotection was carried out by adding TFA in CH2Cl2 (1:1), which also promoted the
formation of the imine. If basic work-up was performed, thiophene fused 2-pyridone (10a)
was observed. In order to avoid unwanted thiophene fused 2-pyridone formation, the TFA was
removed by evoporation without proceeding with any basic work-up. The triacetoxy
borohydride was unable to reduce the imine. Sodium borohydride was used as an alternative
for the reductive amination (Scheme 9).
N
S
O
Cl
COOMeO
H N
S
O COOMe
S
NH
MeOOC
yield 22%
1. BOC cysteinemethylester
K2CO3, MeOH, MeCN
2.TFA, DCM
3.NaBH4, MeOH
6 20
Scheme 9. Synthesis of 8-membered heterocyclic fused 2-pyridone.
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3. CONCLUSION
Suitable reaction conditions to synthesize the starting compound, a formyl and chloro-
methylene substituted 2-pyridone were developed. Directed diversity-oriented synthesis was
used as a platform to synthesize multi heterocyclic ring-fused 2-pyridones in which one part of
the compounds was constant but with large change in the other part. In order to obtain
different heterocycles and rings, various nucleophiles were used. It was also shown that it is
possible to make new seven and eight-membered ring-fused 2-pyridones with this strategy.
Additionally, an improved methodology to synthesize charged and uncharged naphthyridones
has been developed.
These compounds will be hydrolyzed and screened on various biological systems and will
hopefully show significant biological activity on a particular biochemical process or processes.
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4. ACKNOWLEDGEMENT
I would like to thank my supervisor, Fredrik Almqvist for allowing and encouraging me to do
this project. I am profoundly grateful to Magnus Sellstedt who helped me immensely for what I
have learned from him is invaluable. I would also like to thank other members of the group;
Christoffer Bengtsson, Syam Krishnnan, Munawar Hussain, The Hung Dang, Karl Gustafson and
wu lian pao for their encouragement and assistance. Lastly, I also wish to thank all the members
involved in general club meeting for I have attained valuable information from their work and
article discussions.
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5. EXPERIMENT
5.1 General
All reactions were carried out under nitrogen atmosphere, unless otherwise stated. CH2Cl2 and DMF were passed through a column of Al2O3 and MeCN was distilled from CaH2. These were stored over 3 Å molecular sieves. The amberlite® IR-120(plus) ion exchange resin was washed with methanol prior to use. Optical rotations were mesured on a perkin Elmer polarimeter at 20oC and 589 nm. TLC was performed om silica gel 60 F254 (Merck) with detection by UV light. Flash coloumn chromatography was performed on silica gel (Merk, 60 AO, 40.63 µm). 1H NMR and 13C NMR spectra were recorded on a Bruker DRX-400 spectrometer. NMR experiments were conducted at 298K and spectra were calibrated against solvent residue to 7.26 (1H) 77.0 (13C) for CDCl3, 3.30 (
1H) 49.0 (13C) for MeOD d4. IR spectra were recorded on ATI Mattson Infinity Series FTIRTM. HRMS was conducted using a BrukermicrOTOF II mass spectrometer with electrospray ionization. LC-MS was conducted on a Micromass ZQ mass spectrometer. One of the NMR spectras is quite complex (compound 20) due to diastereomeric mixture.
Fractional proton integrals indicate presence of isomers. (maj) indicate peak from major isomer
and (min) indficate peak from minor isomer in both 1H and 13C spectra.
5.2 Synthesis
5-Chloromethyl-2,2-dimethyl-[1,3]dioxane-4,6-dione (8)
Chloroacetic acid 4725 mg (50.00 mmol), Meldrum’s acid 7209 mg (50.02 mmol), and 4-
dimethylaminopyridine, 7326 mg (59.97 mmol) were dissolved in 250 ml CH2Cl2 and cooled at -
10oC. Dicyclohexylcarbodimide, 1350 mg (55.01 mmol) in 50 ml CH2Cl2 was added slowly over
one hour and the resulting mixture was stirred overnight at room temperature. The reaction
mixture was filtered off and dichloromethane phase was washed three times with 2% aqueous
KHSO4 solution and then brine. The organic phase was concentrated under reduced pressure
gave 8, 5787 mg (53%) as solid.
IR λ 3012, 1732, 1667, 1538, 1380, 1264, 1380, 1264, 1199, 1155, 906; 1H NMR (400 MHz,
CDCl3) 15.54 (m, 1H), 4.88 (s, 2H), 1.76 (s, 6H); 13C NMR (400 Mz,CDCl3) 188.5, 170.4 (broad), 159.6
(broad), 106.0, 91.7, 41.8, 27.1 (2C)
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5-Cyclopropylmethyl-2,3-dihydro-thiophene-3-carboxylic acid methyl ester (7)
Thiazoline 7 was prepared according to published procedure18.
The data is in agreement with published data18.
7-Chloromethyl-8-cyclopropyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid meth
yl ester (5)
Thiazoline 7 (1990 mg, 10 mmol) and Meldrum’s acid (10) (5500mg, 25 mmol), were dissolved in 15 ml 1,2 dichloroethane. Trifluoroacetic acid (1.54 ml, 20 mmol) was added. The solution was heated with microwave irradiation for 3 min then quenched by addition of saturated NaHCO3 and then extracted with CH2Cl2. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure and resulting residue was purified with silica gel chromatography using heptane ; ethyl acetate 1:2 as elutent to give 2236 mg (74%) of compound 5. [α]D -255 (c 1.0, CHCl3); IR λ 2952, 1747, 1648, 1578, 1484, 1430, 1202, 1170, 842, 734;
1H NMR (400 MHz, CDCl3) 6.40 (s, 1H), 5.58 (dd, J = 8.6, 2.4 Hz, 1H), 4.62 (d, J = 12.5 Hz, 1H), 4.50 (d, J = 12.5 Hz, 1H), 3.79 (s, 3H), 3.66 (dd, J = 11.7, 8.6 Hz, 1H), 3.50 (dd, J = 11.7, 2.4 Hz, 1H), 1.72-1.63 (m, 1H), 1.00-0.87 (m, 2H), 0.69-0.60 (m, 2H); 13C NMR (400 Mz,CDCl3) 168.5, 161.1, 152.1, 148.4, 115.6, 112.3, 62.9, 53.3, 42.7, 31.8, 10.5, 7.4, 7.2
7-Chloromethyl-8-cyclopropyl-6-formyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic
acid methyl ester (6)
5319 mg (53 mmol) DMF in 30 ml MeCN, was cooled at 0oC. Oxalyl chloride, 6.06 ml (53
m mol), was slowly added and the resulting slurry was then stirred at room temperature for 10
minutes. Compound 5, 1600 mg (5.3 mmol) in 20 ml MeCN was added and the mixture was
heated at 75oC in oil bath for 4 hours. The mixture was quenched with saturated aqueous
NaHCO3 and extracted with CH2Cl2. The organic extract was dried over anhydrous Na2SO4 ,
filtered and concentrated under reduced pressure. The residue was purified by
chromatography on silica gel using heptane : ethyl acetate 1:1 as eluent to give 925 mg (53%) of
compound 6 as yellow foam.
[α]D -417 (c 0.5,CHCl3); IR λ 1747, 1671, 1635, 1473, 1214, 1147, 737; 1H NMR (400 MHz, CDCl3)
10.35 (s, 1H), 5.67 (dd, J=9.20,2.35 Hz, 1H), 5.34 (d, J=9.68Hz, 1H), 5.09 (d, J=9.68 Hz, 1H), 3.82
(s,3H), 3.74 (dd, J=9.2, 11.87 Hz,1H), 3.56 (dd, J=11.74, 2.35 Hz, 1H), 1.82-1.68 (m, 1H), 1.12-
0.92 (m, 2H), 0.81-0.7 (m,2H); 13C NMR (400 Mz,CDCl3) 190.1, 167.8, 162.1, 158.2, 155.5, 116.9,
114.3, 63.4, 53.6, 36.9, 31.5, 10.5, 8.0, 7.3
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8-Cyclopropyl-6-methyl-4-oxo-2,3,4,6-tetrahydro-1-thia-3a,6-diaza-s-indacene-3-carboxylic acid
methyl ester (9a) Compound 6 (50 mg, 0.15 mmol) and K2CO3 (32 mg, 0.22 mmol) were taken up in 2ml
acetonitrile. 0.14 ml (0.22 mmol) methylamine (1.6M in MeOH) was added and the reaction
mixture was stirred at room temperature over night. Saturated aqueous NaHCO3 was added
and the mixture was extracted with CH2Cl2. The organic extract was dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel using heptane : ethyl acetate 1:3 as eluent to give 40 mg (85%) of
compound 9a as yellow foam.
[α]D -206 (c 0.5,CHCl3); IR λ 1739, 1649, 1587, 1317, 1175, 1206, 762; 1H NMR (400 MHz,
CDCl3); 7.35 (d, J=1.99 Hz, 1H), 6.74 (d, J=2.0 Hz, 1H), 5.55 (dd, J=7.7, 1.20 Hz, 1H), 3.81 (s,3H),
3.75(s,3H), 3.59 (dd, J=11.4, 7.6 Hz,1H), 3.46 (dd, J=11.4, 2.0 Hz, 1H), 1.72-1.64 (m, 1H), 0.87-
0.79 (m,2H), 0.71-0.64 (m, 2H); 13C NMR (400 Mz,CDCl3) 167.7, 158.9, 133.4, 127.5, 121.1,
114.3, 112.4, 106.9, 61.2,52.8, 37.4, 32.1, 10.8, 5.8, 5.5
8-Cyclopropyl-4-oxo-6-phenyl-2,3,4,6-tetrahydro-1-thia-3a,6-diaza-s-indacene-3-carboxylic acid
methyl ester (9b)
Compound 6 (110 mg, 0.33 mmol) and K2CO3 (67.4 mg, 0.48 mmol) were taken up in 2ml
acetonitrile. Aniline (77.6 mg, 0.84 mmol) was added and the reaction mixture was refluxed at
70oC overnight. Cooled the reaction mixture at room temperature and saturated aqueous
NaHCO3 was added and the mixture was extracted with DCM. The organic extract was dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel using heptane: ethyl acetate 1:2→1:3 as eluent
to give 95 mg (77%) of compound 9b as yellow foam.
[α]D -86 (c 0.5,CHCl3); IR λ 1742, 1651, 1597, 1496, 1243, 1208, 754, 691; 1H NMR (400 MHz,
CDCl3) 7.80 (d, J=2.2 Hz,1H), 7.51-7.45 (m, 4H), 7.39-7.33 (m, 1H), 7.18 (d, J=2.2 Hz, 1H), 5.59
(dd, J=7.7, 1.8 Hz, 1H), 3.78 (s, 3H), 3.63 (dd, J=7.7, 11.5 Hz, 1H), 3.49 (dd, J=11.5, 1.9 Hz), 1.79-
1.70 (m,1H), 0.90-0.84 (m,2H), 0.78-0.69 (m, 2H); 13C NMR (400 Mz,CDCl3) 169.7, 159.1, 140.1,
134.4, 129.2 (2C), 128.2, 127.3, 121.7 (2C), 118.9, 115.8, 110.2, 106.7, 61.3, 53.0, 32.1, 10.9,
6.0, 5.6.
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8-Cyclopropyl-4-oxo-2,3-dihydro-4H-1,6-dithia-3a-aza-s-indacene-3-carboxylic acid
methyl ester (10a)
Compound 6 (50 mg, 0.15 mmol) and potassium thio acetate (17 mg, 0.15 mmol) were
taken up in 2ml acetonitrile and stirred at room temperature for 2 hours. 2 ml MeOH was
added to the above reaction mixture and stirred at room temperature for 2 hours. 180 mg (3
mmol) AcOH was added and stirred at room temperature for 1 hour. The saturated aqueous
NaHCO3 was added to the reaction mixture and extracted with CH2Cl2 three times. The organic
extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
The residue was purified by coloumn chromatography on silica gel using heptane: ethylacetate
1:1 as eluent to give 31 mg (70%) of compound 10a as yellow foam.
[α]D -95 (c 0.5, CHCl3); IR λ 1739, 1643, 1586, 1197, 1153, 854, 762; 1H NMR (400 MHz, CDCl3)
8.29 (d, J=3.2 Hz,1H), 7.37 (d, J=3.2 Hz,1H), 5.55 (dd, J=7.8, 2.0 Hz, 1H), 3.78 (s, 3H), 3.63 (dd,
J=11.7, 7.9 Hz,1H), 3.39 (dd, J=11.7, 2.0 Hz,1H), 1.80-1.72 (m, 1H), 0.98-0.88 (m, 2H), 0.75-0.65
(m,2H); 13C NMR (400 Mz,CDCl3) 169.2, 157.4, 140.9, 137.2, 130.1, 129.2, 114.4, 107.6, 61.1,
53.1, 32.0, 10.9, 6.5, 6.2
8-Cyclopropyl-4-oxo-2,3-dihydro-4H-6-oxa-1-thia-3a-aza-s-indacene-3-carboxylic acid
methyl ester (10b)
Compound 6 (100 mg, 0.3 mmol) and 29.4 mg (0.3 mmol) potassium acetate were taken up in
2ml DMF and stirred at room temperature for 2 hours. 2ml MeOH was added to the above
mixture and stirred at room temperature for 2 hours. 360 mg (6 mmol) AcOH was added and
stirred at room temperature for 1 hour. The saturated aqueous NaHCO3 was added and
extracted with ethyl acetate three times. The organic extract was dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The residue was purified by coloumn
chromatography on silica gel using heptane: ethylacetate 1:1 as eluent to give 17 mg (22%) of
compound 10b as yellow foam.
1H NMR (400 MHz, CDCl3) 8.20 (d, J=1.3, 1H), 7.66 (d, J=1.3), 5.51 (dd, J=7.5, 1.5 Hz,1H), 3.78
(s,3H), 3.6 (dd, J=7.5, 11.5, 1H), 3.48 (dd, J=11.5, 1.5 Hz, 1H), 1.78-1.60 (m, 1H), 0.91-0.79 (m,
2H), 0.76-0.62 (m, 2H); 13C NMR (400 Mz,CDCl3) 169.3, 157.8, 143.9, 136.3, 134.0, 125.4, 117.5,
104.4, 60.9, 53.1, 31.9, 10.7, 5.98, 5.6
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18
8-Cyclopropyl-4,5-dioxo-2,3,4,5,6,7-hexahydro-1-thia-3a,6-diaza-s-indacene-3-carboxylic acid
methylester (12)
Compound 6 (32.7 mg, 0.1 mmol) of, and NaN3 (7.1 mg, 0.11 mmol) were dissolved in 1 ml 1:1
mixture of MeOH and MeCN. The reaction mixture was heated with microwave irradiation at
100oC for 30 min and then concentrated under reduced pressure. The residue was absorbed
onto silica and purified with silica gel chromatography using CH2Cl2 : MeOH 95:5 as eluent to
give 19 mg (62%)of compound 12 as yellow color solid.
[α]D -120 (c 0.5,CHCl3+CH3OH); IR λ 1694, 1664, 1594, 1504, 1265, 1168, 771, 695; 1H NMR (400
MHz, CDCl3+MeOD-d4) 5.37 (d, J=8.8,1H), 4.14-3.99 (m, 2H), 3.58-3.49 (m, 1H), 3.47 (s, 3H), 3.36
(d, 11.5 Hz, 1H), 1.37-1.27 (m,1H), 0.65-0.51 (m,2H), 0.39-0.22 (m, 2H); 13C NMR (400 MHz,
CDCl3+MeOD-d4) 174.5, 172.3, 167.4,160.9, 159.2, 118.4, 114.2, 66.7, 57.0, 48.5, 35.9, 13.0, 9.6,
9.4
9-Cyclopropyl-6-methyl-4-oxo-7-phenyl-2,3-dihydro-4H-1-thia-3a,6-diaza-cyclopenta[b]naphthalene-
3-carboxylic acid methyl ester (15)
Compound 6 (30 mg, 0.092 mmol) and) benzaldeyhde (15 mg, 0.14 mmol) were dissloved in a
1:1 mixture of 1.5 ml acetonitrile and methanol. Then methanolic methylamine (1.6 M) (0.14
ml, 0.22 mmol) was added followed by acetic acid (15 eq) and the solution was heated with
microwave irradiation at 80oC for 10 minutes and then concentrated under reduced pressure.
The residue was absorbed onto silica and purified with silicagel chromatography using CH2Cl2:
MeOH 95:5 as eluent to give 29 mg (74%) of compound 15 as yellow foam.
[α]D -481 (c 0.5,CHCl3); IR λ 1739, 1649, 1586, 1354, 1319, 854, 761; 1H NMR (400 MHz,
CDCl3+MeOD) 9.15 (s, 1H), 7.74 (s,1H), 7.41-7.32 (m, 3H), 7.30-7.24 (m, 2H), 5.53 (dd, J=8.7, 1.6
Hz,1H), 3.08 (s, 3H), 3.66 (dd, J=8.6, 12.0 Hz, 1H), 3.44 (dd, J=1.6, 12.0 Hz,1H), 1.52-1.44 (m,1H),
0.89-0.75 (m, 2H), 0.47-0.35 (m,2H); 13C NMR (400 MHz, CDCl3+MeOD-d4) 169.2, 162.0, 159.1,
155.9, 149.6, 149.3, 133.0, 132.9, 130.9 (2C), 130.2 (2C), 122.8, 120.4, 110.0, 64.6, 54.8, 47.6,
33.2, 10.5, 8.8, 8.7
9-Cyclopropyl-4-oxo-7-phenyl-2,3-dihydro-4H-1-thia-3a,6-diaza-cyclopenta[b]naphthalene-
3-carboxylic acid methyl ester (16)
Compound 6 (50 mg, 0.15 mmol), benzaldehyde 40 mg (0.38 mmol), and ammonium acetate 47
mg (0.61 mmol) were dissloved in a 1.1 ml acetonitrile and 1.1 ml methanol. Acetic acid 0.13
ml (2.3 mmol) was added and the reaction mixture was heated with microwave irradiation at
100oC for 20 minutes. The mixture was diluted with dichloromethane and washed with
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19
saturated aqueous NaHCO3. The aqueous phase was extracted with CH2Cl2 and the organic
extract was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue
was purified coloumn chromatography on silica gel using heptane : ethyl acetate 2:1 as eluent
to give 35 mg (61%) of compound 16.
[α]D -220 (c 0.5,CHCl3); IR λ 1755, 1655, 1591, 1262, 1171, 769, 695. 1H NMR (400 MHz, CDCl3)
9.52 (s, 1H), 8.15-8.12 (m, 1H), 8.11-8.05 (m, 2H), 7.54-7.43 (m, 3H), 5.96 (dd, J=2.0, 11.6 Hz,
1H), 3.8 (s, 3H), 3.71 (dd, J=11.6, 8.4 Hz, 1H), 3.55 (dd, J=2.08, 11.63), 1.80-1.70 (m, 1H), 1.17-
1.04 (m,2H), 0.78-0.68 (m,2H); 13C NMR (400 Mz,CDCl3) 168.6, 160.5, 159.2, 151.4, 146.5, 144.9,
139.1, 129.6, 128.8 (2C), 127.5 (2C), 117.4, 112.5, 109.0, 62.3, 53.5, 31.6, 9.6, 7.3 (2C)
7-Chloromethyl-8-cyclopropyl-6-hydroxymethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-
3-carboxylic acid methyl ester (17)
Compound 6, 98 mg (0.3 mmol) was dissolved in 4ml, 1:1 acetonitrile and methanol. Sodiumborohydride, 13 mg (0.35 mmol) was added and the mixture was stirred at room temperature for 15 minutes and then quenched by addition of 1 M aqueous hydrochloric acid. the mixture was extracted with CH2Cl2 and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using heptane : ethyl acetate 1:2→1:4 as eluent to give 78 mg (80%) of compound 17. [α]D -244 (c 0.5,CHCl3); IR λ 3418, 1744, 1625, 1569, 1477, 1226, 1147, 742, 602;
1H NMR (400 MHz, CDCl3) 5.57 (dd, J = 8.7, 2.2 Hz, 1H), 4.80-4.69 (m, 2H), 4.70-4.59 (m, 2H), 3.78 (s, 3H), 3.73-3.65 (m, 1H), 3.65 (dd, J = 11.8, 8.7 Hz, 1H), 3.48 (dd, J = 11.8, 2.2 Hz, 1H), 1.75-1.64 (m, 1H), 1.03-0.88 (m, 2H), 0.77-0.67 (m, 2H); 13C-NMR (400MHz,CDCl3) 168.3, 161.7, 148.6, 147.5, 125.8, 113.3, 63.3, 57.8, 53.4, 38.3, 31.6, 11.1, 7.6, 7.2
General procedure for SN2 reaction between 17 and primary amines
Compound 17 (1.0 eq) and K2CO3 (1.5 eq) was taken up in acetonitrile (30ml/ mmol of 17). The
amino compound (3.0 eq) was added and the reaction was stirred at room temperature over
night. Saturated aqueous NaHCO3 was added and the mixture was extracted with CH2Cl2. The
organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by coloumn chromatography on silica gel.
8-Cyclopropyl-6-hydroxymethyl-7-methylaminomethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3
-carboxylic acid methyl ester (18a)
Compound 17, 66 mg (0.20 mmol) was converted to 38 mg (59%) of compound 18a by
following the above general procedure, in this reaction methylamine was used as an amino
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20
reagent. To purify the compound 18a, CH2Cl2: MeOH 95: 5 was used as eluent in the
chromatography.
[α]D -310 (c 0.5,CHCl3); IR λ 3295, 1733, 1635, 1490, 1477, 1351, 1218, 792, 649; 1H NMR (400
MHz, CDCl3) 5.61 (dd, J=8.5,2.5 Hz,1H), 4.71 (d, J=12.2 Hz, 1H), 4.55 (d,J=12.2 Hz, 1H),4.02 (d,
J=11.5 Hz,1H), 3.79 (s,3H), 3.65 (dd, J=8.5,11.5 Hz,1H), 3.47 (dd, J=11.5, 2.5Hz,1H), 3,29 (bs,2H),
1.66 (m,1H), 0.95 (m,1H), 0.63(m,1H); 13C-NMR (400MHz, CDCl3) 169.1, 161.8, 152.5, 147.2,
126.6, 114.3, 63.9, 57.7, 53.9, 50.2, 36.8, 31.9, 12.1, 8.3, 7.9.
7-(Benzylamino-methyl)-8-cyclopropyl-6-hydroxymethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid methyl ester (18b)
Compound 17, 70 mg (0.21 mmol) was converted to 54 mg (63%) of compound 18b by
following the above general procedure, in this reaction benzyl amine was used as an amino
reagent. To purify the compound 18b, CH2Cl2: MeOH 95:5 was used as eluent in the
chromatography.
[α]D -193 (c 0.5,CHCl3); IR λ 3306,1745, 1627, 1497, 1452, 1207, 1173, 739, 697; 1H NMR (400
MHz, CDCl3) 7.39-7.32 (m, 4H), 7.31-7.26 (m,1H), 5.60 (dd, J=2.5, 8.6 Hz, 1H), 4.72 (d, J=12.4,
1H), 4.58 (d, J=12.4, 1H), 4.01 (d, J=11.5 Hz, 1H), 3.94-3.86 (m, 3H), 3.80 (s, 3H), 3.64 (dd,
J=11.6, 8.7 Hz, 1H), 3.47 (dd, J=11.6, 2.5 Hz, 1H), 1.61-1.53 (m, 1H), 0.84-0.76 (m, 2H), 0.62-0.52
(m, 2H); 13C-NMR (400MHz, CDCl3) 168.6, 161.2, 151.9, 146.7, 138.9, 128.6(2C), 128.4 (2C),
127.4, 127.0, 133.8, 63.4, 57.2, 54.3, 53.2, 46.9, 31.5, 11.5, 7.7, 7.3
General procedure for carbamate formation
The aminoalcohol (1.0 eq ) and triethylamine (6.0 eq) were dissolved in CH2Cl2 (50ml / mmol of
amino alcohol). Triphosgene (0.5) was added and the solution was stirred at room temperature
for one hour. Saturated aqueous NaHCO3 was added, the reaction mixture was extracted with
CH2Cl2. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified with silica gel chromatography.
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21
10-Cyclopropyl-8-methyl-4,7-dioxo-2,3,5,7,8,9-hexahydro-4H-6-oxa-1-thia-3a,8-diaza-cyclohepta[f]
indene-3-carboxylic acid methyl ester (19a)
Amino alcohol 19a (49 mg, 0.15 mmol) was converted to 30 mg (57%) of compound 20a by
using the above general procedure. Inorder to purify the compound 19a Heptane: ethyl acetate
1:3 was used as eluent in the chromatography.
[α]D -255 (c 0.5,CHCl3); IR λ 1710, 1639, 1588, 1512, 1351, 1214, 1094, 746, 701; 1H NMR (400
MHz, CDCl3) 5.50 (dd, J=8.5, 2.3 Hz, 1H), 5.07-4.95 (m, 2H), 4.58-4.44 (m, 2H), 3.74 (s, 3H), 3.61
(dd, J=8.6, 11.5 Hz, 1H), 3.44 (dd, J=11.5, 2.4 Hz), 3.00 (s, 3H), 1.56-1.47 (m, 1H), 1.00-0.87 (m,
2H), 0.60-0.51 (m, 2H); 13C-NMR (400 MHz, CDCl3) 168.3, 159.1, 158.8, 147.3, 146.4, 120.7,
111.8, 66.5, 62.9, 53.3, 48.8, 38.0, 31.6,10.8, 8.1, 8.0
8-Benzyl-10-cyclopropyl-4,7-dioxo-2,3,5,7,8,9-hexahydro-4H-6-oxa-1-thia-3a,8-diaza-cyclohepta[f]
indene-3-carboxylic acid methyl ester (19b)
Amino alcohol 19b, 46 mg (0.11 mmol) was converted to 30 mg (61%) of compound 20b by
using the above general procedure. Inorder to purify the compound 19b CH2Cl2: MeOH 95 : 5
was used as eluent in the chromatography.
[α]D -196 (c 0.5,CHCl3); IR λ 1744, 1711, 1632, 1586, 1507, 1211, 743; 1H NMR (400 MHz, CDCl3)
7.37-7.22 (m, 5H), 5.58 (dd, J=8.5,2.4 Hz,1H), 5.25-5.12 (m, 2H), 4.72-4.43 (m, 4H), 3.83 (s, 3H), 3.66 (dd, J=11.7, 8.6 Hz, 1H), 3.50 (dd, J=2.4, 11.7 Hz, 1H), 1.13- 1.05 (m, 1H), 0.83-0.73 (m, 2H), 0.48-0.33 (m,2H); 13C-NMR (400 MHz, CDCl3) 168.3, 159.3, 158.9, 147.7, 146.2, 136.3, 126.7(2C), 128.2 (2C), 128.0, 120.5, 111.8, 66.7, 62.9, 53.5, 53.3, 45.8, 31.6, 10.4, 7.9, 7.6.
8-Cyclopropyl-2-oxo-6,11-dithia-3,14-diaza-tricyclo[7.6.0.03,7
]pentadeca-1(9),7-diene-4,
13-dicarboxylic acid dimethyl ester (20)
Compound 6 (65mg, 0.2 mmol) and K2CO3 (27 mg, 0.2 mmol) were taken up in 1:2 mixture of
1.8 ml methanol and acetonitrile. To this mixture N-boc protected cysteinmethyl ester (0.2
mmol) was added and stirred at room temperature for 2 hours. Then the reaction was washed
with NaHCO3 and extracted with CH2Cl2. The extract was dried over anhydrous Na2SO4, filtered
and concentrated under reduced pressure. The residue was dissolved in 1 ml CH2Cl2 and 1 ml of
trifluroaceticacid was added and stirred at room temperature for 10 min. the solvent was
removed under reduced pressure. The residue was dissolved in 2ml methanol and 110 mg (15
mmol) of sodium borohydride was added, stirred at room temperature over night. Diluted with
CH2Cl2 and washed with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic
phase was dried with anhydrous Na2SO4 the compound was purified by using reverse phase
HPLC (30%H20, 70%MeCN, 0.1%TFA, 25 min). The purified compound dissolved in 5 ml
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22
methanol and treated 1ml The amberlite® IR-120(plus) ion exchange resin for 5 min and filtered and evaporated the solvent under reduced pressure gave 18 mg (22%) of 2:1
diastereomeric mixture of compound 20.
[α]D -40 (c 0.5,CHCl3); IR λ 1733, 1629, 1576, 1576, 1501, 1206, 1173, 823, 739; 1H NMR (400
MHz, CDCl3) 5.62 (maj) &5.59 (min) (dd, j=8.6,2.5 Hz, 1H), 4.20-3.85 (m,4H), 3.80 (min) & 3.79
(maj) (s, 3H), 3.77-3.73 (m,1H), 3.71 (s,3H),3.68-3.60 (m, 1H),3.51-3.45 (m, 1H),3.09 (min) &
3.06 (maj) (dd, J=15.8, 2.2 Hz,1H), 2.87 (min) &2.79 (maj) (dd, J=15.8, 5.6 Hz, 1H),2.47
(s,1H),1.70-1.58 (m, 1H), 1.00-0.86 (m, 2H),0.85-0.76 (m, 1H), 0.71-0.62 (m,1H); 13C-NMR (400
MHz, CDCl3) 172.8, 168.7 (min), 168.6 (maj), 160.7, 150.9 (min), 149.9 (maj), 146.3 (min), 146.2
(maj), 123.3 (maj)122.6 (min),112.5, 63.9 (maj), 63.6 (min), 63.3 (min), 63.2 (maj), 53.3, 52.4,
42.4 (maj), 42.1 (min), 32.9 (min), 32.8 (maj), 31.5 (maj),31.4 (min), 28.9 (min), 28.6 (maj), 11.3,
7.9,7.8(min), 7.5 (maj)
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23
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