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The product is liberated by adding 30% NaOH to the aqueous layer (300 L), and re-extracted into
ethyl acetate (500 mL). Selective deprotection of the tert -butyl ester with concomitant
decarboxylation yields ethyl 2,4-dimethylpyrrole-3-carboxylate which can be formylated at the free
ring position by trimethyl orthoformate to yield the fully elaborated pyrrole aldehyde ( 41 ).
Mixtures of such solvents, in various proportions, are useful. Using the combined acidic extracts, the
pH is then adjusted to 14 by the addition of 4 N NaOH. The crude rizatriptan obtained after
extraction of the reaction mass into the organic layer is adsorbed on the silica gel. We deliver
compounds with high purity levels and a comprehensive Certificate of Analysis. The silica gel was
eluted with 8000 ml of isopropanol. Furthermore, this move towards novel heterocyclic structures
also allows for more flexible substitution patterns permitting extensive SAR studies through efficient
high throughput screenings commonly used today. Therefore, when the morpholine derived enamine
245 was used the desired 1,3,5-substituted pyrazole was formed with 100% regioselectivity (
Scheme 49 ). Google has not performed a legal analysis and makes no representation or warranty as
to the accuracy of the list.). Pouring the reaction mass into water below 25 0 C and maintaining for
about 2 to 3 hrs viii. It was also determined that more polar solvents such as acetonitrile and
nitromethane preferentially solvated the trans product and thereby allowed the isolation of the cis
compound by precipitation. Google has not performed a legal analysis and makes no representation
as to the accuracy of the status listed.). Catalytic hydrogenation of the nitro group of 2 yields aniline
3 in quantitative amounts. In addition, these reactions are usually accompanied by the release of heat
due to exothermic reaction profiles which might result in difficult to control and therefore undesired
chemical processes. Under basic conditions the chlorohydrin 438 can be converted to the
corresponding epoxide which can be ring opened by tert -butyl amine to furnish timolol ( Scheme 84
). The silica gel was eluted with 8000 ml of isopropanol. This might explain its general effectiveness,
but could also account for its potentially dangerous side effects. Hence, a sequence involving silyl
protection, chlorination and deprotection was established which gave the desired product in 90%
overall yield ( Scheme 33 ). The organic layer is separated, washed with water (100 ml) and brine
(100 ml) and dried (sodium sulfate). This synthesis of the benzimidazole precursor makes use of a
1,2,3-trisubstituted nitrophthalic acid 205, which had to be selectively monoesterified and subjected
to a Curtius rearrangement, which is cumbersome when the reaction is scaled up. In another
embodiment, the rizatriptan is rizatriptan benzoate. The autoclave is purged thrice with nitrogen and
then thrice with hydrogen. The concentration of the catalyst can be determined based on the type of
catalyst and the medium in which it is to be provided. Rizatriptan and the related derivatives are
known to be pharmaceutically useful, e.g. in the treatment of migraine. A lead compound ( 344, A-
80987) was also described by Abbott bearing pyridine rings on both ends of the peptidomimetic
structure, which resulted in good bioavailability as required for orally administered drugs, but this
compound had an insufficient plasma half-life. The substantially pure rizatriptan benzoate prepared
by the process of the invention is useful in the preparation of pharmaceutical compositions for the
treatment of the disease conditions mentioned above. Geer Find this author on Google Scholar Find
this author on PubMed Search for this author on this site Joan D. Coupling of the iodo-aniline
derivative of formula-V and the bis-silylated derivative of formula- VI in the presence of palladium
acetate gave the tryptopol derivative of formula- VII. This route has been used to prepare several
ondansetron analogues based on different amine components.
The process utilizes apparatus commonly available in the laboratory, and involves easy adsorption
and elution operations without the need for any additional pre-purification. The Fischer indole
reaction provides a primary alcohol which is TMS-protected and condensed with methyl 3-
oxopentanoate under Lewis acid conditions. The former is represented by three drugs targeting
hypertension losartan ( 157, Cozaar), olmesartan ( 158, Benicar), eprosartan ( 159, Eprozar) as well
as nausea (ondansetron ( 119, Zofran)) ( Figure 5 ). Only the pharmaceutically acceptable salts or the
free compounds (optionally. Dissolving crude Rizatriptan benzoate in ethanol at 78 - 8O 0 C vi.
Mechanistic studies showed that the related imidoyl compounds do not themselves undergo ring
closure to form imidazoles and it was therefore proposed that the reaction between carbon
tetrachloride and triphenylphosphine to generate dichlorotriphenylphosphorane and
(dichloromethylene)triphenylphosphorane was pivotal. As shown previously, such benzimidazoles
can be formed through the condensation reaction of a 1,2-diaminobenzene and a suitable
functionalised carbonyl compound. In addition, these reactions are usually accompanied by the
release of heat due to exothermic reaction profiles which might result in difficult to control and
therefore undesired chemical processes. In addition, the use of precursor 82, already possesing the
desired dimethylamino group, simplifies the reaction sequence and tunes the reactivity of the amine
preventing it from participating in many side reactions. The desired 2,4,5-trisubstituted imidazole
core 178 is formed in high yield in the presence of carbon tetrachloride and triphenylphosphine (
Scheme 35 ). After about 45 minutes, the product starts to precipitate from the reaction mixture. The
most straightforward route was from thiophene-2-carbaldehyde ( 425 ) which was subjected to a
Henry reaction with nitromethane. This species is then employed in a nucleophilic aromatic
substitution with 2-fluoronitrobenzene ( 406 ) to give the coupled product 407. Where elevated
pressures are applied, the reaction, where required, takes place in a pressure vessel. Unlike NSAIDs,
which only deal with symptoms of rheumatoid arthritis, DMARDs target the cause of it. In order to
perform the acylation of the indole ring on larger scale, ethylmagnesium bromide and the
corresponding acid chloride 89 are added concurrently from two different sides of the reactor to stop
these reagents reacting with each other. Suitable acid addition salts include salts of protic acids such
as hydrochlorides or hydrobromides. Purity of pure rizatriptan base obtained in step (xii) is more than
99%. DMARDs are not necessarily structurally or mechanistically related. This method of adding the
reagents circumvents the necessity to isolate the magnesium salt of the indole and increases the yield
from 50 to 82%. To this, BF 3 -etherate is added dropwise during 30 minutes (157.6 g, 1.11 mol).
Initially there is a strong exothermic reaction (requires slow addition of BF3-etherate) and evolution
of a gas. Acid-mediated nitrile hydrolysis followed by esterification results in the corresponding
diester unit 182. The toluene is extracted for three times with 4 N HCl (300 mL, 2?150 mL).
Amongst the drugs containing a thiophene ring are raloxifene ( 392, Evista) and olanzapine ( 399
Zyprexa). After disposal of the inorganic the combined toluene layers are extracted for three times
with water (300mL, 2 x 150 mL), and the aqueous layer is again discarded. It therefore seems
feasible that certain common bioavailable cations might be involved in the absorption and activation
of this thiazole containing compound. The quantity of silica gel used can range from about 4 to 10
times, or about 4 to 6 times, with respect to the weight of the starting material having Formula III.
Formation of the impurity of formula-X is below 3% and its removal became easy. This result was
supported by X-ray crystallographic evidence, where celecoxib was shown to bind to one subunit of
the COX-1-dimer, implying that drugs like aspirin then bind to the other monomer of the same
enzyme consequently slowing down the irreversible acetylation of a serine residue by aspirin itself.
After about 45 minutes, the product starts to precipitate from the reaction mixture.
Urinary excretion of triazolomethyl-indole-3-acetic acid after i.v. and oral administrations of
rizatriptan accounted for 35 and 51% of the dose, respectively, whereas the corresponding values for
rizatriptan- N 10 -oxide were 4 and 2% of the dose. Indeed, the latter protocol has been further
expanded to make use of additional formamide surrogates such as a formamidinium salt 273 or
Gold’s reagent ( 274 ) ( Scheme 54 ). Mixtures of such solvents, in various proportions, are useful.
After stirring for 48h, the vessel is allowed to cool down and is vented. The indole ring and its
substitution at the 3-position are identical to that of sumatriptan, however, the sulfonamide side
chain has been replaced by an oxazolinone ring. Combined organic layer was washed with 1OL of
water. Solvent was evaporated from the eluate to yield 108 g of the desired purified rizatriptan base
having a dimer impurity content of 0.095 area-% as measured by HPLC. Then water (250 mL) is
added, and the DME is removed on the rotavapor. After completion of reaction, cooled the mass to
3O 0 C, adjusted the pH to 6.0-6.5 and extracted with methylene chloride (2 x 35 It.). Aq.layer is
separated and adjusted the pH to 10-11 and extracted with ethyl acetate (3 x 55 It.). Ethyl acetate is
removed under vacuum and the residue is chromatographed on silica gel (55 kg.) and eluted with
ethyl acetate (25 It.) followed by methanol (30 It.) to give Rizatriptan as residue. Early antagonists
of the angiotensin II receptor were of a peptidic nature, suffered from poor bioavailability and also
showed some agonistic activities. The organic layer is washed with brine (2 x 250 mL), and after
removal of the solvent, 28.5 g of a brown oil is obtained. Although famotidine is orally administered,
its solubility and hence bioavailability under acidic conditions, as found in the stomach, is relatively
low. The end product nevertheless continues to require a column purification step, using a relatively
large quantity of solid support and a complex elution using an eluent that is a 30:8:1 mixture of
dichloromethane:ethanol:ammonia, and hence the process is not cost effective for operation on an
industrial scale. Structurally, it consists of a chlorinated dexamethasone core which is esterified with
2-furoic acid at the 17-position ( 373, Figure 12 ). It has also been demonstrated that the reduction of
the initially formed diazonium salt can be accomplished by using sodium metabisulfite (Na 2 S 2 O 5
) rather than using the more toxic stannous chloride or the less water soluble and more expensive
sodium sulfite. Upon hydrolysis and O -alkylation the desired 4-isobutoxy-1,3-dicyanobenzene (
363 ) is obtained in good overall yield. Hence, in this case the triazine can be considered as a
formamide donor. Deprotection and decarboxylation of the remaining tert -butyl ester produces the
desired pyrrole intermediate, which upon treatment with Vilsmeier reagent undergoes a formal
acylation. Xue Chemistry Organic letters 2023 A general and highly efficient photochemical C-N
coupling reaction of challenging (hetero)aryl chlorides with hydrazides is reported. This is dissolved
in ethyl acetate (500 mL) and the product is extracted with 4 N Hcl (550 mL). Certain modifications
and equivalents will be apparent to those skilled in the art and are intended to be included with in the
scope of the present invention in any way. In the prior art, Formula II is first converted to
corresponding diazonium salt which on further reduction with sodium sulfite yielded the
benzyltriazolehydrazine (compound 5) and this hydrazine product is isolated as dihydrochloride salt
in poor yield. Tryptopol derivative of formula- VIII was converted to. Subsequent treatment of the
substituted intermediate with trifluoroacetic anhydride furnished the corresponding bis-hydrazide
278 which underwent cyclisation at elevated temperatures in the presence of polyphosphoric acid.
Expand 18 Save Advanced Nitroso Aldol Reaction: Metal-Free Cross-Coupling of Anilines with
Silyl Enol Ethers en Route to ?-Amino Ketones. Although it is considered a class III antiarrhytmic
with its mode of action being principally the blocking of potassium channels, it is anticipated that it
is also capable of targeting additional sodium and calcium channels. An imidazole ring is also a
component of the biogenic amine histamine. Two specific drugs containing this structure are
leflunomide ( 446, Arava) and sulfamethoxazole ( 447, Bactrim). The solution is slowly cooled to
room temperature and allowed it to crystallize and finally cooled to 5-8 0 C and stirred for lhr.
Removal of the solvent from the filtrate gives a brown oil, which is dissolved in toluene.
To optimize the formation of rizatriptan and to reduce the formation of impurity of formula-X,
reaction was conducted at different temperatures. The hydrogen is then released, and the catalyst is
removed via filtration through a millipore syringe filter. The obtained orange slurry is then extracted
with TBME (1000 mL, 2x 600 mL), and the combined organic layers are washed with water (800
mL) and brine (700 mL), and concentrated on the rotavapor to about 600 mL. HIV uses a member
of the G-protein coupled receptor family called CCR-5 as an anchor to attach itself to white blood
cells such as T-cells and macrophages followed by viral fusion and entry into white blood cells.
Functionalisation of the resulting 2-amino group on the thiazole ring using benzoyl isothiocyanate
generates the guanidine precursor 357. Google has not performed a legal analysis and makes no
representation or warranty as to the accuracy of the list.). The product was extracted with ethyl
acetate and the solvent was removed by distillation under reduced pressure to obtain the Rizatriptan
base as an oily mass. Owing to the vast number of potential structures, we have concentrated only on
those drugs containing five-membered heterocycles and focused principally on the assembly of the
heterocyclic core. In addition, these reactions are usually accompanied by the release of heat due to
exothermic reaction profiles which might result in difficult to control and therefore undesired
chemical processes. The reaction mass was maintained at this temperature for 4-5hr. However, like
many antipsychotic drugs its main therapeutic activity is probably due to its antagonistic action on
dopamine receptors. All of these drugs aptly highlight a different synthetic approach to the imidazole
core. In order to target the most representative chemical entities the examples discussed have been
selected from the top 200 best selling drugs of recent years. Early antagonists of the angiotensin II
receptor were of a peptidic nature, suffered from poor bioavailability and also showed some
agonistic activities. Then triethyl amine (49.2g, 0.486 mol) is added, and the pyridinium salt dissolves
to give a deep brown solution. Concentrated hydrochloric acid (4L) was added to the reaction mass
at 25-30 0 C. The final synthesis and its dipole precursor are represented in Scheme 49. Reference
Example 3: Preparation of 3-(2-dimethylamino- ethyl)-1 H-indole-5-carbonitrile. The end product
nevertheless continues to have the disadvantages on quality of product even a column purification
step is involved, so that it is not cost-effective to carry out the process in industrial scale. Subsequent
alkylation under Williamson conditions provides the final compound 325 in good yield ( Scheme 64
). Quality of final pharma grade rizatriptan benzoate obtained according to this process is more than
99.7% and impurity of formula -X is less than 0.1%. The basic substance can be in the form of a
solution in a suitable solvent such as, for example: alcohols such as methanol, ethanol, and propanol;
ketones such as acetone and tertiary-butyl ketone; hydrocarbons such as C. The alkali metal sulfite
employed suitably is selected from sodium sulfite or potassium sulfite more preferably sodium
sulfite. This result was supported by X-ray crystallographic evidence, where celecoxib was shown to
bind to one subunit of the COX-1-dimer, implying that drugs like aspirin then bind to the other
monomer of the same enzyme consequently slowing down the irreversible acetylation of a serine
residue by aspirin itself. This is suspended in ammonia (100 ml 25% solution in water), and the
mixture is stirred over night. The product is liberated by adding 30% NaOH to the aqueous layer
(300 mL), and re-extracted into ethyl acetate (500 mL). The reaction mass was filtered and the cake
washed with 2OL of methanol. Preferred as base NB are N,N-dicyclohexyl-N-lower alkylamines,
such as dicyclohexyl-ethylamine, or especially tri-lower alkylamines, such as triethylamine. Still it
would be desirable to avoid the formation of the undesired 4-alkylation product, which is one of the
problems to be solved by the present invention.
These amounts can be expressed, respectively, as less than about 0.15 area-%, less than about 0.1
area-%, and less than about 0.05 area-% in an analysis by HPLC. Other well represented
transformations include reductions, amide and ester formations, rearrangements and saponifications,
which can be performed in an atom-economic manner based on numerous well established protocols.
The undesired 4-alkylation product can be removed (see Tetrahedron Lett. 1994, 35, 6981 ) or its
formation can be avoided by alkylation of 4-amino-1,2,4-triazol and the subsequent removal of the
4-amino group by diazotation (see EP 0 573 221 ). To the black suspension, which has formed, THF
(100 mL) is added, and this is extracted with 1 N NaOH (100 mL). Therefore, only column
chromatography technique is useful in separating this impurity from rizatriptan. c. Cooling the mass
to -1O 0 C to 2O 0 C 5 preferably -5 to 15 0 C, v. Deprotection and decarboxylation of the
remaining tert -butyl ester produces the desired pyrrole intermediate, which upon treatment with
Vilsmeier reagent undergoes a formal acylation. Interestingly, ritonavir itself is a result of further
improvements on earlier candidates for the treatment of AIDS. To this solution is added a solution of
HCI (11g of 32% aqueous HCI in 100 ml of ethanol). The reaction mixture is then filtered over a
pad of Hyflo, and the solvent removed from the filtrate on the rotavapor to give the product (2.6g,
86%) as a pale yellow residue. For example, the substituted aryl hydrazine 237 can be reacted with
trifluoromethyl butynone in a one pot reaction. A significant body of the literature representing the
synthesis of these drugs date back many years to origins in the late seventies and early eighties. To
this mixture, then 4N NaOH (555 mL) is added and the mixture is heated under reflux for 50
minutes. The toluene is extracted for three times with 4 N HCI (300 mL, 2 x 150 mL). The process
utilizes apparatus commonly available in the laboratory, and involves easy adsorption and elution
operations without the need for any additional pre-purification. The reaction mixture is hated to 70-
75 0 C and maintained for 60 min. This route has been used to prepare several ondansetron
analogues based on different amine components. The amidonitrile substrate 173 can then react with
both species to form seven-membered cyclic intermediate 175 which collapses to form the imidazole
compound. After about 45 minutes, the product starts to precipitate from the reaction mixture.
Where both acidic and basic groups are present, also internal salts may be formed. The reaction
mixture is then filtered over a pad of Hyflo, and the solvent removed from the filtrate on the
rotavapor to give the product (2.6g, 86%) as a pale yellow residue. The mixture is cooled with an ice
bath and quenched by the addition of 4N NaOH (200 mL). This procedure can also be employed to
prepare the related series of imidazobenzodiazepines if TosMIC ( 303 ) or the aminopropanol 304
are used as nucleophiles ( Scheme 59 ). The benzimidazole ring is then assembled by treating this
diamine with tetraethyl orthocarbonate under Lewis acid conditions. As this activity is not shared
with all COX-2 inhibitors, it is believed that the structural features such as the polar sulfonamide
group, the lipophilic tolyl moiety and the trifluoromethylated pyrazole core with its negative
electrostatic potential play a key role in apoptosis induction. The resultant (5-
((dimethylamino)methyl)furan-2-yl)methanol ( 378 ) is then treated with cysteamine hydrochloride (
380 ) which leads to replacement of the hydroxyl functionality. Where both acidic and basic groups
are present, also internal salts may be formed. For example, a process involving acetaldehyde,
glyoxal and ammonium carbonate furnishes the desired compound in an excellent 95% yield (
Scheme 37 ). The obtained orange slurry is then extracted with TBME (1000 mL, 2?600 mL), and
the combined organic layers are washed with water (800 mL) and brine (700 mL), and concentrated
on the rotavapor to about 600 mL. In order to target the most representative chemical entities the
examples discussed have been selected from the top 200 best selling drugs of recent years.