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Ifetroban イフェトロバン
3-[2-({(1S,2R,3S)-3-[4-(Pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl}methyl)phenyl]propanoic acid
Ifetroban is a potent and selective thromboxane receptor antagonist.[1]
Ifetroban has been used in trials studying the treatment of Skin Diseases, Autoimmune Diseases, Pathologic Processes, Scleroderma, Limited, and Scleroderma, Diffuse, among others.
This compound belongs to the class of organic compounds known as phenylpropanoic acids. These are compounds with a structure containing a benzene ring conjugated to a propanoic acid.
SYN
BMS-180291 sodium salt was prepared from optically active 7-oxabicyclo[2.2.1]heptane lactol (I): The interphenylene side chain was introduced by deprotonation of (I) with ethylmagnesium bromide (0.95 eq.) followed by treatment with excess aryl Grignard (II) to afford crystalline diol (III). The extraneous benzylic hydroxyl group in (III) was removed by reduction with hydrogen in the presence of Pearlman’s catalyst to give alcohol (IV). Transformation of the alpha-side chain silyloxy carbinol of (IV) to a carboxymethyl ester was accomplished by initial protection of the omega-side chain alcohol as the acetate (Ac2O/py) followed by oxidation under Jones conditions and then exposure of the resulting crude acetate-acid to methanolic hydrogen chloride to afford crystalline alcohol-ester (V). Oxidation of (V) under Jones conditions furnished acid-ester (VI). The oxazole side chain was introduced into (VI) via serine-derived amino alcohol (VII). Standard coupling of acid (VI) with (VII) mediated by water-soluble carbodiimide (EDAC) gave amide (VIII). Acyclic side chain intermediate (VIII) was converted into oxazole (X) in three steps by mesylation followed by treatment with triethylamine to furnish cyclized oxazoline (IX). Dehydrogenation of (IX) employing a novel oxidative protocol (1) involving treatment with a mixture of copper (II) bromide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in chloroform/ethyl acetate solvent yielded oxazole (X). Saponification of (X) followed by acidification afforded (BMS-180291) as a white solid which could be purified by recrystallization from acetonitrile. The water-soluble sodium salt (XI) was available as a precipitate from BMS-18091 by treatment with sodium methoxide/methanol in acetone.
SYN
The interphenylene side chain was introduced by deprotonation of (I) with ethylmagnesium bromide (0.95 eq.) followed by treatment with excess aryl Grignard (II) to afford crystalline diol (III). The extraneous benzylic hydroxyl group in (III) was removed by reduction with hydrogen in the presence of Pearlman’s catalyst to give alcohol (IV). Transformation of the alpha-side chain silyloxy carbinol to a carboxy methyl ester was accomplished by initial protection of the omega-side chain alcohol as the acetate (Ac2O/pyr) followed by oxidation under Jones conditions and then exposure of the resulting crude acetate-acid to methanolic hydrogen chloride to afford crystalline alcohol-ester (V). Oxidation of (V) under Jones conditions furnished acid-ester (VI). The oxazole side chain was introduced into (VI) via serine-derived amino alcohol (VII). Standard coupling of acid (VI) with (VII) mediated by water-soluble carbodiimide (EDAC) gave amide (VIII). Acyclic side chain intermediate (VIII) was converted into oxazole (X) in three steps by mesylation followed by treatment with triethylamine to furnish cyclized oxazoline (IX). Dehydrogenation of (IX) employing a novel oxidative protocol involving treatment with a mixture of copper (II) bromide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in chloroform/ethyl acetate solvent yielded oxazole (X). Saponification of (X) followed by acidification afforded (XI) (BMS-180291) as a white solid which could be purified by recrystallization from acetonitrile. The water-soluble sodium salt was available as a precipitate from (XI) by treatment with sodium methoxide/methanol in acetone.
SYN
| Org Process Res Dev 1997,1(1),14 |
The synthesis of [1S-(1alpha,2alpha,3alpha,4alpha)]-2-[2-[2-(methoxycarbonyl)ethyl]benzyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylic acid (VI), a key intermediate in the synthesis of 203961 [see scheme 20396101a] has been presented: This compound has been obtained by two similar ways: 1) The condensation of L-valinol (XII) with anhydride (XXII) catalyzed by oxalic acid gives imide (XIII), which is treated with ethylmagnesium chloride, the Grignard reagent (XIV) and NaBH4 yielding intermediate (XV). This intermediate, without isolation, is treated with HCl in THF to afford the substituted benzaldehyde (XVI), which is condensed with trimethyl phosphonoacetate (XVII) and DBU in acetonitrile giving the propenoic ester (XVIII). Finally, this compound is submitted to a simultaneous reduction and hydrogenolysis with H2 over a Pearlman catalyst in methanol to provide the target of [1S-(1alpha,2alpha,3alpha,4alpha)]-2-[2-[2-(methoxycarbonyl)ethyl]benzyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylic acid (VI). 2) The preceding reaction sequence can also be performed using (S)-2-phenylglycinol (XIX) instead of the L-valinol (XII) yielding the previously reported benzaldehyde (XVI) through the imide (XX) and the nonisolated intermediate (XXI).
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| Identifiers | |
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| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C25H32N2O5 |
| Molar mass | 440.53 g/mol |
| 3D model (JSmol) | |
////////Ifetroban, BMS 18029, BMS 180291, BMS 180291A, BMS-180291-02, Boxaban, CPI 211, Hepatoren, Portaban, Vasculan, イフェトロバン
CCCCCNC(=O)C1=COC(=N1)C2C3CCC(C2CC4=CC=CC=C4CCC(=O)O)O3
Aceclofenac
アセクロフェナク
1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.896 (s, 2H, Aliphatic –CH2), 4.634 (s, 2H, Aliphatic –CH2), 6.279 (d J= 8.00HZ, 1H, Aromatic), 6.887 (t, J = 7.2 Hz, 1H), 6.936 (s, 1H, NH), 7.039(t, J = 7.6 Hz, 1H, Aromatic), 7.225 (t J= 8.00 HZ, 1H, Aromatic), 7.260 (d J= 8.00 HZ, 1H, Aromatic), 7.537 (d J= 8.4HZ, 2H, Aromatic), 13.076 (s, 1H, Carboxylic acid) …https://www.sciencedirect.com/science/article/pii/S2214180417301290
https://www.dea.gov/sites/default/files/pr/microgram-journals/2014/mj11-1_29-41.pdf
Aceclofenac is a nonsteroidal anti-inflammatory drug (NSAID) analog of diclofenac. It is used for the relief of pain and inflammation in rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.
Aceclofenac (C16H13Cl2NO4), chemically [(2-{2, 6-dichlorophenyl) amino} phenylacetooxyacetic acid], is a crystalline powder with a molecular weight of 354.19. It is practically insoluble in water with good permeability. It is metabolized in human hepatocytes and human microsomes to form [2-(2′,6′-dichloro-4′-hydroxy- phenylamino) phenyl] acetoxyacetic acid as the major metabolite, which is then further conjugated. According to the Biopharmaceutical Classification System (BCS) drug substances are classified to four classes upon their solubility and permeability. Aceclofenac falls under the BCS Class II, poorly soluble and highly permeable drug.[1]
Aceclofenac works by inhibiting the action of cyclooxygenase (COX) that is involved in the production of prostaglandins (PG) which is accountable for pain, swelling, inflammation and fever. The incidence of gastric ulcerogenicity of aceclofenac has been reported to be significantly lower than that of the other frequently prescribed NSAIDs, for instance, 2-folds lesser than naproxen, 4-folds lesser than diclofenac, and 7-folds lesser than indomethacin.
Aceclofenac should not be given to people with porphyria or breast-feeding mothers, and is not recommended for children. It should be avoided near term in a pregnant woman because of the risk of having a patent ductus arteriosus in the neonate.
SYN
Manufacturing Process for Aceclofenac
Stage-1
T Butanol and Chloro Acetyl Chloride react in presence of NN Dimethyl Aniline at low temperature. After reaction
organics mass wash with water and sodium bicarbonate solution to get stage-1
Stage-2
Stage-I react with Diclofenac Sodium in presence of TBAB in Toluene media, further react with formic acid and
reaction mass quenching in water and product is isolated by filtration. Finally Crude Aceclofenac purified in ethyl
acetate and charcoal. Pure product isolated by filtration.
SYN’EP 0119932; US 4548952
Alkylation of the sodium salt of diclofenac (I) with benzyl bromoacetate (II) in hot DMF yielded the (arylacetoxy)acetate (III). Subsequent hydrogenolysis of the benzyl ester of (III) in the presence of Pd/C gave the title carboxylic acid. Alternatively, the benzyl ester group of (III) was cleaved by means of the combination of chlorotrimethylsilane and sodium iodide. This method of selective ester hydrolysis with in situ generated iodotrimethylsilane was also applied to the corresponding methyl (IV) and tert-butyl (V) esters. In a related procedure, tert-butyl ester (V) was prepared by alkylation of diclofenac (VI) with tert-butyl bromoacetate (VII) in the presence of tertiary amines. Selective cleavage of the tert-butyl ester group of (V) was then performed by treatment with either trifluoroacetic or formic acid.
SYN
| ES 2046141 |
Aceclofenac was prepared by selective hydrolysis of other labile ester precursors. Alkylation of diclofenac sodium (I) with tetrahydropyranyl chloroacetate (IX), prepared by protection of chloroacetic acid (VIII) with dihydropyran, furnished the tetrahydropyranyl ester of aceclofenac (X), which was then deprotected by treatment with HCl. Similarly, the preparation of aceclofenac was reported by acidic hydrolysis of the analogous tetrahydrofuranyl ester (XI).
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| Clinical data | |
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| Trade names | Hifenac, Cincofen, Zerodol, Nacsiv, Acenac, others |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration |
oral, topical |
| ATC code | |
| Legal status | |
| Legal status |
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| Identifiers | |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| ECHA InfoCard | 100.169.686  |
| Chemical and physical data | |
| Formula | C16H13Cl2NO4 |
| Molar mass | 353.02161 g/mol |
| 3D model (JSmol) | |
//////////Aceclofenac, ацеклофенак , أسيكلوفيناك , 醋氯芬酸 , アセクロフェナク
Diclofenac Sodium
15307-79-6; Sodium diclofenac; Diclofenac sodium salt; Voltaren; Solaraze
| Molecular Formula: | C14H10Cl2NNaO2 |
|---|---|
| Molecular Weight: | 318.129 g/mol |
Diclofenac, sold under the trade names Voltaren among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout.[3] It is taken by mouth or applied to the skin.[3] Improvements in pain typically occur within half an hour and last for as much as eight hours.[3] It is also available in combination with misoprostol in an effort to decrease stomach problems.[4]
Common side effects include abdominal pain, gastrointestinal bleeding, nausea, dizziness, headache, and swelling.[3] Serious side effects may include heart disease, stroke, kidney problems, and stomach ulceration.[4][3] Use is not recommended in the third trimester of pregnancy.[3] It is likely safe during breastfeeding.[4] It is believed to work by decreasing the production of prostaglandin.[5] It blocks both cycloxygenase-1 (COX-1) and cycloxygenase-2 (COX-2).[3]
Diclofenac was patented in 1965 by Ciba-Geigy and came into medical use in the United States in 1988.[3][6] It is available as a generic medication.[3] In the United States the wholesale cost per dose is less than US$0.15 as of 2018.[7] In 2016 it was the 78th most prescribed medication in the United States with more than 9 million prescriptions.[8] It is available as both a sodium and a potassium salt.[4]
Diclofenac is used to treat pain, inflammatory disorders, and dysmenorrhea.[9]
Inflammatory disorders may include musculoskeletal complaints, especially arthritis, rheumatoid arthritis, polymyositis, dermatomyositis, osteoarthritis, dental pain, temporomandibular joint (TMJ) pain, spondylarthritis, ankylosing spondylitis, gout attacks,[10] and pain management in cases of kidney stones and gallstones. An additional indication is the treatment of acute migraines.[11] Diclofenac is used commonly to treat mild to moderate postoperative or post-traumatic pain, in particular when inflammation is also present,[10] and is effective against menstrual pain and endometriosis.
Diclofenac is also available in topical forms and has been found to be useful for osteoarthritis but not other types of long-term musculoskeletal pain.[12]
It may also help with actinic keratosis, and acute pain caused by minor strains, sprains, and contusions (bruises).[13]
In many countries,[14] eye drops are sold to treat acute and chronic nonbacterial inflammation of the anterior part of the eyes (e.g., postoperative states). Diclofenac eye drops have also been used to manage pain for traumatic corneal abrasion.[15]
Diclofenac is often used to treat chronic pain associated with cancer, in particular if inflammation is also present (Step I of the World Health Organization (WHO) scheme for treatment of chronic pain).[16] Diclofenac can be combined with opioids if needed such as a fixed combination of diclofenac and codeine.
Voltaren (diclofenac) 50 mg enteric coatedtablets
Arthrotec (diclofenac and misoprostol) 50 mg tablets
Sintofarm (diclofenac) for suppositoryadministration
Diclofenac consumption has been associated with significantly increased vascular and coronary risk in a study including coxib, diclofenac, ibuprofen and naproxen.[18] Upper gastrointestinal complications were also reported.[18] Major adverse cardiovascular events (MACE) were increased by about a third by diclofenac, chiefly due to an increase in major coronary events.[18] Compared with placebo, of 1000 patients allocated to diclofenac for a year, three more had major vascular events, one of which was fatal.[18] Vascular death was increased significantly by diclofenac.[18]
In 2013, a study found major vascular events were increased by about a third by diclofenac, chiefly due to an increase in major coronary events.[18] Compared with placebo, of 1000 people allocated to diclofenac for a year, three more had major vascular events, one of which was fatal.[18] Vascular death was increased by diclofenac (1·65).[18]
Following the identification of increased risks of heart attacks with the selective COX-2 inhibitor rofecoxib in 2004, attention has focused on all the other members of the NSAIDs group, including diclofenac. Research results are mixed, with a meta-analysis of papers and reports up to April 2006 suggesting a relative increased rate of heart disease of 1.63 compared to nonusers.[19] Professor Peter Weissberg, Medical Director of the British Heart Foundation said, “However, the increased risk is small, and many patients with chronic debilitating pain may well feel that this small risk is worth taking to relieve their symptoms”. Only aspirin was found not to increase the risk of heart disease; however, this is known to have a higher rate of gastric ulceration than diclofenac. In Britain the Medicines and Healthcare Products Regulatory Agency (MHRA) said in June 2013 that the drug should not be used by people with serious underlying heart conditions—people who had suffered heart failure, heart disease or a stroke were advised to stop using it completely.[20] As of January 15, 2015 the MHRA announced that diclofenac will be reclassified as a prescription-only medicine (POM) due to the risk of cardiovascular adverse events.[21]
A subsequent large study of 74,838 Danish users of NSAIDs or coxibs found no additional cardiovascular risk from diclofenac use.[22] A very large study of 1,028,437 Danish users of various NSAIDs or coxibs found the “Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death (odds ratio, 1.91; 95% confidence interval, 1.62 to 2.42; and odds ratio, 1.66; 95% confidence interval, 1.06 to 2.59, respectively), with a dose-dependent increase in risk.”[23]
Diclofenac is similar in COX-2 selectivity to celecoxib.[24]
The primary mechanism responsible for its anti-inflammatory, antipyretic, and analgesic action is thought to be inhibition of prostaglandin synthesis by inhibition of the transiently expressed prostaglandin-endoperoxide synthase-2 (PGES-2) also known as cycloxygenase-2 (COX-2). It also appears to exhibit bacteriostatic activity by inhibiting bacterial DNA synthesis.[29]
Inhibition of prostaglandin synthesis occurs systemically resulting in undesirable symptoms such as irritation of the gastric epithelium.[citation needed] This is the main side effect of diclofenac. Diclofenac inhibits COX-2 with 20 times greater potency than the constitutively expressed isoenzyme COX-1[30] and has, therefore, a somewhat lower incidence of gastrointestinal complaints than noted with aspirin which inhibits COX-1 to a greater extent.
The action of one single dose is much longer (6 to 8 hr) than the very short 1.2–2 hr half-life of the drug would indicate. This could be partly because it persists for over 11 hours in synovial fluids.[31]
Diclofenac may also be a unique member of the NSAIDs. Some evidence indicates it inhibits the lipoxygenase pathways, thus reducing formation of the leukotrienes(also pro-inflammatory autacoids). It also may inhibit phospholipase A2 as part of its mechanism of action. These additional actions may explain its high potency – it is the most potent NSAID on a broad basis.[32]
Marked differences exist among NSAIDs in their selective inhibition of the two subtypes of cyclooxygenase, COX-1 and COX-2. Much pharmaceutical drug design has attempted to focus on selective COX-2 inhibition as a way to minimize the gastrointestinal side effects of NSAIDs such as aspirin. In practice, use of some COX-2 inhibitors with their adverse effects has led to massive numbers of patient family lawsuits alleging wrongful death by heart attack, yet other significantly COX-selective NSAIDs, such as diclofenac, have been well tolerated by most of the population.\
Besides the COX-inhibition, a number of other molecular targets of diclofenac possibly contributing to its pain-relieving actions have recently been identified. These include:
Use of diclofenac for animals is controversial due to toxicity when eaten by scavenging birds that eat dead animals; the drug has been banned for veterinary use in many countries.
Use of diclofenac in animals has been reported to have led to a sharp decline in the vulture population in the Indian subcontinent – a 95% decline by 2003[34] and a 99.9% decline by 2008. The mechanism is presumed to be renal failure;[35] however, toxicity may be due to direct inhibition of uric acid secretion in vultures.[36] Vultures eat the carcasses of livestockthat have been administered veterinary diclofenac, and are poisoned by the accumulated chemical,[37] as vultures do not have a particular enzyme to break down diclofenac. At a meeting of the National Wildlife Board in March 2005, the Government of India announced it intended to phase out the veterinary use of diclofenac.[38] Meloxicam is a safer alternative to replace use of diclofenac.[39] It is more expensive than diclofenac, but the price is coming down as more pharmaceutical companies begin to manufacture it.
Steppe eagles have the same vulnerability to diclofenac as vultures and may also fall victim to it.[40] Diclofenac has been shown also to harm freshwater fish species such as rainbow trout.[41][42][43][44] In contrast, New World vultures, such as the turkey vulture, can tolerate at least 100 times the level of diclofenac that is lethal to Gyps species.[45]
“The loss of tens of millions of vultures over the last decade has had major ecological consequences across the Indian Subcontinent that pose a potential threat to human health. In many places, populations of feral dogs (Canis familiaris) have increased sharply from the disappearance of Gyps vultures as the main scavenger of wild and domestic ungulatecarcasses. Associated with the rise in dog numbers is an increased risk of rabies“[39] and casualties of almost 50,000 people.[46] The Government of India cites this as one of the major consequences of a vulture species extinction.[38] A major shift in the transfer of corpse pathogens from vultures to feral dogs and rats could lead to a disease pandemic, causing millions of deaths in a crowded country like India, whereas vultures’ digestive systems safely destroy many species of such pathogens. Vultures are long-lived and slow to breed. They start breeding only at the age of six and only 50% of young survive. Even if the government ban is fully implemented, it will take several years to revive the vulture population.[47]
The loss of vultures has had a social impact on the Indian Zoroastrian Parsi community, who traditionally use vultures to dispose of human corpses in Towers of Silence, but are now compelled to seek alternative methods of disposal.[39]
Despite the vulture crisis, diclofenac remains available in other countries including many in Europe.[48] It was controversially approved for veterinary use in Spain in 2013 and continues to be available, despite Spain being home to around 90% of the European vulture population and an independent simulation showing that the drug could reduce the population of vultures by 1-8% annually. Spain’s medicine agency presented simulations suggesting that the number of deaths would be quite small.[49][50]
The name “diclofenac” derives from its chemical name: 2-(2,6-dichloranilino) phenylacetic acid. Diclofenac was first synthesized by Alfred Sallmann and Rudolf Pfister and introduced as Voltaren by Ciba-Geigy (now Novartis) in 1973, now by Glaxo SmithKline.[51]
In the United Kingdom, United States, India, and Brazil diclofenac may be supplied as either the sodium or potassium salt; in China, it is most often supplied as the sodium salt, while in some other countries it is only available as the potassium salt.
Pennsaid is a minimally systemic prescription topical lotion formulation of 1.5% w/w diclofenac sodium, which is approved in the US, Canada and other countries for osteoarthritis of the knee.
Flector Patch, a minimally systemic topical patch formulation of diclofenac, is indicated for acute pain due to minor sprains, strains, and contusions. The patch has been approved in many other countries outside the US under different brand names.
Voltaren and Voltarol contain the sodium salt of diclofenac. In the United Kingdom, Voltarol can be supplied with either the sodium salt or the potassium salt, while Cataflam, sold in some other countries, is the potassium salt only. However, Voltarol Emulgel contains diclofenac diethylammonium, in which a 1.16% concentration is equivalent to a 1% concentration of the sodium salt. In 2016 Voltarol was one of the biggest selling branded over-the-counter medications sold in Great Britain, with sales of £39.3 million.[52]
Diclofenac is available in stomach acid-resistant formulations (25 and 50 mg), fast-disintegrating oral formulations (25 and 50 mg), powder for oral solution (50 mg), slow- and controlled-release forms (75, 100 or 150 mg), suppositories (50 and 100 mg), and injectable forms (50 and 75 mg).
Diclofenac is also available over-the-counter in some countries: 12.5 mg diclofenac as potassium salt in Switzerland (Voltaren dolo), the Netherlands (Voltaren K), and preparations containing 25 mg diclofenac as the potassium salt in Germany (various trade names), New Zealand, Australia, Japan, (Voltaren Rapid), and Sweden (Voltaren T and Diclofenac T). Diclofenac as potassium salt can be found throughout the Middle East in 25 mg and 50 mg doses (Cataflam).
Solaraze (3% diclofenac sodium gel) is topically applied, twice a day for three months, to manage the skin condition known as actinic or solar keratosis. Parazone-DP is a combination of diclofenac potassium and paracetamol, manufactured and supplied by Ozone Pharmaceuticals and Chemicals, Gujarat, India. It is sold in Uruguay alone or, in combination with orphenadrine to treat muscle spasms/pain due to injuries (Dicloflex Ion).
On 14 January 2015, diclofenac oral preparations were reclassified as prescription-only medicines in the UK. The topical preparations are still available without prescription.[53]
Diclofenac formulations are available worldwide under many different trade names.[1]
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Title: Diclofenac
CAS Registry Number: 15307-86-5
CAS Name: 2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid
Additional Names: [o-(2,6-dichloroanilino)phenyl]acetic acid
Trademarks: Motifene (Sankyo)
Molecular Formula: C14H11Cl2NO2
Molecular Weight: 296.15
Percent Composition: C 56.78%, H 3.74%, Cl 23.94%, N 4.73%, O 10.80%
Literature References: Prepn: NL 6604752; A. Sallmann, R. Pfister, US 3558690 (1966, 1971 both to Geigy). Pharmacology: Renaud, Lecompte, Thromb. Diath. Haemorrh. 24, 577 (1970), C.A. 74, 86215m (1971); Krupp et al., Experientia 29, 450 (1973). HPLC determn in plasma and urine: J. Godbillon et al., J. Chromatogr. 338, 151 (1985). Symposium on pharmacology and clinical experience: Semin. Arthritis Rheum. 15, Suppl. 1, 57-110 (1985); on pharmacology, efficacy and safety: Am. J. Med. 80, Suppl. 4B, 1-87 (1986). Comprehensive description: C. M. Adeyeye, P-K. Li, Anal. Profiles Drug Subs. 19, 123-144 (1990). Review of clinical trials in actinic keratosis: D. C. Peters, R. H. Foster, Drugs Aging 14, 313-319 (1999).
Properties: Crystals from ether-petr ether, mp 156-158°.
Melting point: mp 156-158°
Derivative Type: Diethylammonium salt
CAS Registry Number: 78213-16-8
Trademarks: Voltarol (Novartis)
Molecular Formula: C14H11Cl2NO2.C4H11N
Molecular Weight: 369.29
Percent Composition: C 58.54%, H 6.00%, Cl 19.20%, N 7.59%, O 8.66%
Derivative Type: Sodium salt
CAS Registry Number: 15307-79-6
Manufacturers’ Codes: GP-45840
Trademarks: Allvoran (TAD); Benfofen (Sanofi-Synthelabo); Dealgic (Pharmacia); Deflamat (Sankyo); Delphinac (Riemser); Dicloflex (Dexcel); Diclomax (Provalis); Diclophlogont (Azupharma); Dicloreum (Alfa); Duravolten (Dura); Ecofenac (Ecosol); Effekton (Teofarma); Lexobene (Merckle); Neriodin (Nagase); Novapirina (Novartis); Primofenac (Streuli); Prophenatin (Nipro); Rewodina (AWD); Rhumalgan (Sandoz); Voldal (Novartis); Voltaren (Novartis); Xenid (RPG)
Molecular Formula: C14H10Cl2NNaO2
Molecular Weight: 318.13
Percent Composition: C 52.86%, H 3.17%, Cl 22.29%, N 4.40%, Na 7.23%, O 10.06%
Properties: Crystals from water, mp 283-285°. uv max (methanol) 283 nm (e 1.05 ´ 105); (phosphate buffer, pH 7.2) 276 nm (e1.01 ´ 105). Soly at 25°C (mg/ml): deionized water (pH 5.2) >9; methanol >24; acetone 6; acetonitrile <1; cyclohexane <1; HCl (pH 1.1) <1; phosphate buffer (pH 7.2) 6. pKa 4. Partition coefficient (N-octanol/aq. buffer): 13.4. LD50 in mice, rats (mg/kg): ~390, 150 orally (Krupp).
Melting point: mp 283-285°
pKa: pKa 4
Log P: Partition coefficient (N-octanol/aq. buffer): 13.4
Absorption maximum: uv max (methanol) 283 nm (e 1.05 ´ 105); (phosphate buffer, pH 7.2) 276 nm (e 1.01 ´ 105)
Toxicity data: LD50 in mice, rats (mg/kg): ~390, 150 orally (Krupp)
Derivative Type: Potassium salt
CAS Registry Number: 15307-81-0
Manufacturers’ Codes: CGP-45840B
Trademarks: Cataflam (Novartis)
Molecular Formula: C14H10Cl2KNO2
Molecular Weight: 334.24
Percent Composition: C 50.31%, H 3.02%, Cl 21.21%, K 11.70%, N 4.19%, O 9.57%
Therap-Cat: Anti-inflammatory.
Keywords: Anti-inflammatory (Nonsteroidal); Arylacetic Acid Derivatives.
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The mechanism begins with the condensation of hydrazine onto a ketone (details not shown) to give a hydrazone. Under basic conditions, this hydrazone is deprotonated at nitrogen to give an anionic intermediate. In this case, the negative charge can be delocalized onto oxygen, resulting in an enolate structure. Typically, the negative charge is only shared between a nitrogen and carbon, so this substrate gives a particularly stable intermediate. Protonation of the enolate at carbon gives the first C-H bond necessary to form the product. A second deprotonation at nitrogen gives a similar flow of electrons to form another enolate structure, this time with cleavage of the C-N bond and release of nitrogen gas. Another C-protonation gives the lactam precursor to diclofenac. Cleavage of the amide with hydroxide (details not shown) gives the target.
Manufacturing Process
2, 6-Dichlorophenol is reacted with MMCA, Aniline and Chloro Acetyl Chloride and AlCl3 to yield (2, 6 –
Dichlorophenol) Indolinone is hydrolyzed using isopropyl alcohol and sodium hydroxide to give crude Diclofenac
Sodium. This on purification using deminerlised water and isopropyl alcohol gives the pure Diclofenac Sodium
 |
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 |
|
| Clinical data | |
|---|---|
| Trade names | Cataflam, Voltaren, others[1] |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a689002 |
| Pregnancy category |
|
| Routes of administration |
By mouth, rectal, intramuscular, intravenous(renal- and gallstones), topical |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Protein binding | More than 99% |
| Metabolism | Liver, oxidative, primarily by CYP2C9, also by CYP2C8, CYP3A4, as well as conjugative by glucuronidation (UGT2B7) and sulfation;[2] no active metabolites exist |
| Elimination half-life | 1.2–2 hr (35% of the drug enters enterohepatic recirculation) |
| Excretion | 40% biliary 60% urine |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| PDB ligand | |
| ECHA InfoCard | 100.035.755 |
| Chemical and physical data | |
| Formula | C14H11Cl2NO2 |
| Molar mass | 296.148 g/mol |
| 3D model (JSmol) | |
//////////////Diclofenac Sodium
C1=CC=C(C(=C1)CC(=O)[O-])NC2=C(C=CC=C2Cl)Cl.[Na+]
| FDA Orange Book Patents: 1 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 9339551 |
| Expiration | Oct 17, 2027 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 2 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 9339552 |
| Expiration | Oct 17, 2027 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 3 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 9415029 |
| Expiration | Jul 10, 2029 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 4 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 9370501 |
| Expiration | Jul 10, 2029 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 5 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 9375412 |
| Expiration | Jul 10, 2029 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 6 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 8946292 |
| Expiration | Mar 22, 2027 |
| Applicant | JAVELIN PHARMS INC |
| Drug Application | N022396 (Prescription Drug: DYLOJECT. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 7 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 9168305 |
| Expiration | Oct 17, 2027 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 8 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 9168304 |
| Expiration | Oct 17, 2027 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 9 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 9220784 |
| Expiration | Oct 17, 2027 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 10 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 6407079 |
| Expiration | Jun 18, 2019 |
| Applicant | JAVELIN PHARMS INC |
| Drug Application | N022396 (Prescription Drug: DYLOJECT. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 11 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 8252838 |
| Expiration | Apr 21, 2028 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 12 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 8618164 |
| Expiration | Jul 10, 2029 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 13 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 8546450 |
| Expiration | Aug 9, 2030 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 14 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 8217078 |
| Expiration | Jul 10, 2029 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 15 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 8563613 |
| Expiration | Oct 17, 2027 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 16 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 8871809 |
| Expiration | Oct 17, 2027 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 17 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 9066913 |
| Expiration | Oct 17, 2027 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 18 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 8741956 |
| Expiration | Jul 10, 2029 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 19 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 9101591 |
| Expiration | Oct 17, 2027 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 20 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 9132110 |
| Expiration | Oct 17, 2027 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
| FDA Orange Book Patents: 21 of 21 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 9539335 |
| Expiration | Oct 17, 2027 |
| Applicant | HZNP |
| Drug Application | N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM) |
 |
|
Title: Clotrimazole
CAS Registry Number: 23593-75-1
CAS Name: 1-[(2-Chlorophenyl)diphenylmethyl]-1H-imidazole
Additional Names: 1-(o-chloro-a,a-diphenylbenzyl)imidazole; 1-[a-(2-chlorophenyl)benzhydryl]imidazole; 1-[(o-chlorophenyl)diphenylmethyl]imidazole; diphenyl-(2-chlorophenyl)-1-imidazolylmethane; 1-(o-chlorotrityl)imidazole
Manufacturers’ Codes: FB-5097; Bay b 5097
Trademarks: Canesten (Bayer); Canifug (Wolff); Empecid (Bayer-Takeda); Gyne-Lotrimin (Schering-Plough); Lotrimin (Schering-Plough); Mono-Baycuten; Mycelex-G (Miles); Mycofug (Hermal); Mycosporin (Bayer); Pedisafe (Sagitta); Rimazole (Cheil Sugar); Tibatin (Dak); Trimysten
Molecular Formula: C22H17ClN2
Molecular Weight: 344.84
Percent Composition: C 76.63%, H 4.97%, Cl 10.28%, N 8.12%
Literature References: Prepn: K. H. Buechel et al., ZA 6805392; eidem, US 3705172 (1969, 1972 both to Bayer). Pharmacology: Plempel et al., Antimicrob. Agents Chemother. 1969, 271; eidem, Dtsch. Med. Wochenschr. 94, 1356 (1969). Clinical findings: Oberste-Lehn et al., ibid. 1365. Series of articles on prepn, toxicology, pharmacokinetics, clinical studies: Arzneim.-Forsch. 22,1260-1272, 1276-1299 (1972). Toxicity: D. Tettenborn, ibid. 1276. Comprehensive description: J. G. Hoogerheide, B. E. Wyka, Anal. Profiles Drug Subs. 11, 225-255 (1982).
Properties: Crystals, mp 147-149°. A weak base, slightly sol in water, benzene, toluene; sol in acetone, chloroform, ethyl acetate, DMF. Hydrolyzes rapidly upon heating in aq acids. LD50 in male mice, rats (mg/kg): 923, 708 orally (Tettenborn).
Melting point: mp 147-149°
Toxicity data: LD50 in male mice, rats (mg/kg): 923, 708 orally (Tettenborn)
Derivative Type: Hydrochloride
Molecular Formula: C22H17ClN2.HCl
Molecular Weight: 381.30
Percent Composition: C 69.30%, H 4.76%, Cl 18.60%, N 7.35%
Properties: mp 159°.
Melting point: mp 159°
Therap-Cat: Antifungal.
Therap-Cat-Vet: Antifungal.
Keywords: Antifungal (Synthetic); Imidazoles.
|
Clotrimazole, sold under the brand name Canesten among others, is an antifungal medication.[1] It is used to treat vaginal yeast infections, oral thrush, diaper rash, pityriasis versicolor, and types of ringworm including athlete’s foot and jock itch.[1] It can be taken by mouth or applied as a cream to the skin or in the vagina.[1]
Common side effects when taken by mouth include nausea and itchiness.[1] When applied to the skin common side effects include redness and burning.[1] In pregnancy, use on the skin or in the vagina is believed to be safe.[1] There is no evidence of harm when used by mouth during pregnancy but this has been less well studied.[1] When used by mouth, greater care should be taken in those with liver problems.[1] It is in the azole class of medications and works by disrupting the cell membrane.[1]
Clotrimazole was discovered in 1969.[2] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[3] It is available as a generic medication.[1] The wholesale cost in the developing world as of 2014 is 0.20–0.86 USD per 20 gram tube of cream.[4] In the United States a course of treatment typically costs less than 25 USD.[5]
It is commonly available without a prescription in various dosage forms, such as a cream, vaginal tablet, or as a prescription troche or throat lozenge (prescription only). Topically, clotrimazole is used for vulvovaginal candidiasis (yeast infection) or yeast infections of the skin. For vulvovaginal candidiasis (yeast infection), clotrimazole tablets and creams are inserted into the vagina. Troche or throat lozenge preparations are used for oropharyngeal candidiasis (oral thrush) or prophylaxis against oral thrush in neutropenic patients.
Clotrimazole is usually used 5 times daily for 14 days for oral thrush, twice daily for 2 to 8 weeks for skin infections, and once daily for 3 or 7 days for vaginal infections.[6]
Clotrimazole may be compounded with a glucocorticoid, such as betamethasone, in a topical cream for the treatment of tinea corporis (ringworm), tinea cruris (jock itch) and tinea pedis (athlete’s foot). Although FDA approved, clotrimazole-betamethasone combination cream is not the preferred treatment for dermatophyte infections due to increased side effects from the topical glucocorticoid. Although temporary relief and partial suppression of symptoms may be observed with the combination therapy, glucocorticoids can elicit an immunosuppressive response and rebound effect that results in more severe infection typically requiring systemic antifungal agents to treat the disease. Combination creams are best avoided in order to improve treatment outcome, reduce the possibility of skin atrophy associated with prolonged topical glucocorticoid use, and to limit the cost of treatment. It can be effective in treating chronic paronychia. The preferred treatment of tinea infections is therefore with clotrimazole monotherapy.[7]
Topical and oral clotrimazole can be used in both adults and children.
Additionally, clotrimazole may be used to treat the sickling of cells (related to sickle cell anemia).[8][9]
Small amounts of clotrimazole may be absorbed systemically following topical and vaginal administration. However, this may still be used to treat yeast infections in pregnant women.[10]
Side effects of the oral formulation include itching, nausea, and vomiting. >10% of patients using the oral formulation may have abnormal liver function tests. Side effects include rash, hives, blisters, burning, itching, peeling, redness, swelling, pain or other signs of skin irritation.[1] For this reason, liver function tests should be monitored periodically when taking the oral clotrimazole (troche). When used to treat vulvovaginal candidiasis (yeast infection), <10% of patient have vulvar or vaginal burning sensation. <1% of patients have the following side effects: Burning or itching of penis of sexual partner; polyuria; vulvar itching, soreness, edema, or discharge [6][11][12]
Clotrimazole creams and suppositories contain oil which may weaken latex condoms and diaphragms.[10]
There are no known significant drug interactions with topical clotrimazole. However, with oral (troche) clotrimazole, there are multiple interactions as the medication is a CYP450 enzyme inhibitor, primarily CYP3A4. Thus, any medication that is metabolized by the CYP3A4 enzyme will potentially have elevated levels when oral clotrimazole is used. The prescribing physician should be aware of any medication the patient is taking prior to starting oral clotrimazole. Certain medications should not be taken with oral clotrimazole.[11]
Clotrimazole works by inhibiting the growth of individual Candida or fungal cells by altering the permeability of the fungal cell wall. It binds to phospholipids in the cell membrane and inhibits the biosynthesis of ergosterol and other sterols required for cell membrane production.[12][11] Clotrimazole may be fungistatic (slow fungal growth) or fungicidal (result in fungal cell death).[1]
Clotrimazole (Canesten) antifungal cream
It is available as a generic medication.[1] The wholesale cost in the developing world as of 2014 is 0.20–0.86 USD per 20gm tube of cream.[4]In the United States a course of treatment typically costs less than 25 USD.[5] In 2016 Canesten was one of the biggest selling branded over-the-counter medications sold in Great Britain, with sales of £39.2 million.[13]
syn
CLIP
Fig 4. Open Babel bond-line chemical structure with annotated hydrogens.
Click to toggle size.
Fig 5. 1H NMR spectrum of C22H17ClN2 in CDCL3 at 400 MHz.
Figure 7. 2D 13 C13 C refocused INADEQUATE spectrum of clotrimazole showing intramolecular contacts among 13 C resonances as marked in the molecular structure on the right. The full spectrum is included in the Figure S4. The 2D spectrum was acquired in 17 hr at 106 K on 400 MHz, 384 scans per increment, 2 s recycle delay and 80 t 1 increments of a 27.7 ?s.
2D 13C-13C refocused INADEQUATE spectrum of clotrimazole showing intramolecular contacts among 13C resonances as marked in the molecular structure on the right. The 2D spectrum was acquired in 17 hr at 106 K on 400 MHz.
PATENT
https://patents.google.com/patent/CN105566156A/en
The object of the present invention is to provide a method for synthesizing a pharmaceutical Clotrimazole intermediate o-chlorobenzonitrile, comprising the steps of:
[0004] (i) in a reaction container equipped with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. lmol, aniline (3) 3.6-3 · 9mol, nitromethane burning 310ml, chloro cuprous 1 · 56mol, hook are mixed, controlling the stirring speed 110-160rpm, the solution temperature increased to 110-115 ° C, 3-5h the reaction, the solution temperature increased to 130-135 ° C, the reaction 2-3h, solution temperature increased to 190-195 ° C, the reaction 90-120min, reducing the solution temperature to 15-20 ° C, was added 700 ml of saline solution, sodium bisulfite solution, 130ml, distilled under reduced pressure to collect 130-135 ° C fraction , washed with triethylamine in toluene and recrystallized to give crystals of o-chlorobenzonitrile (1).
[0005] wherein the mass fraction of nitromethane according to step (i) is 60-65%, of the salt solution in step (i) is ammonium nitrate, potassium iodide to any one of the steps of (i) mass fraction of sodium hydrogen sulfite solution was 40-45%, which pressure in the vacuum distillation of step (i) is 1.6-1.7kPa, triethylamine mass fraction of said step (i) is 70-75%, step (i) in toluene of the mass fraction of 90-95%. Throughout the reaction using the following reaction formula:
[0006
[0007 “not as good as Wu Ming 1 point Shi Bian: J Cheng less
A slave I anti Day “* 1, section A, J array low reaction temperature and reaction time, the reaction yield improved.
Detailed ways
[0008] The following examples with reference to specific embodiments of the present invention is further described:
Clotrimazole synthesis kinds drug intermediates of o-chlorobenzonitrile – [0009]
[0010] Example 1:
[0011] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.6111〇1, mass fraction of 60% nitromethane 3,101,111 chloride cuprous 1.56111 〇1, mixing, stirring speed control lOrpm 1, the solution temperature increased to 110 ° C, the reaction 3h, the solution temperature increased to 130 ° C, the reaction 2h, the solution temperature is raised to 190 ° (:, reaction 9011 ^ 11, reducing the solution temperature to 15 ° (:, 7,001,111 ammonium nitrate solution was added, the mass fraction of 40% sodium bisulfite solution was 130ml, 1.6kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 70 washed% triethylamine, 90% toluene to a mass fraction of recrystallized to give crystals of o-chlorobenzonitrile 308.02g, yield 72%.
[0012] Example 2:
[0013] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.7111〇1, mass fraction of 62% nitromethane 31〇1111, 1.56111〇1 cuprous chloride, mixed, controlling the stirring speed of 130 rpm, the temperature was raised to 112 ° C, the reaction 4h, the solution temperature increased to 132 ° C, the reaction 2h, the solution temperature increased to 192 ° C, the reaction llOmin, reducing the solution temperature to 17 ° C, 700 ml of a solution of potassium iodide was added, the mass fraction of 42% sodium bisulfite solution 130ml, 1.65kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 72% triethylamine washed, recrystallized from toluene to 92% mass fraction, to obtain crystals of o-chlorobenzonitrile 337.96g, yield 79%.
[0014] Example 3:
[0015] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.9111〇1, mass fraction of 65% nitromethane 31〇1111, 1.56111 〇1 cuprous chloride, mixed, controlling stirring speed 160 rpm, temperature was raised to 115 ° C, the reaction 5h, the solution temperature increased to 135 ° C, the reaction 3h, the solution temperature increased to 195 ° C, the reaction 120min, reducing the solution temperature to 20 ° C, was added 700 ml of a solution of ammonium nitrate, 45% mass fraction of sodium bisulfite solution was 130ml, 1.7kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 75% triacetyl amine scrubbing, 95%, recrystallized from toluene to a mass fraction to obtain crystals of o-chlorobenzonitrile 350.80g, yield 82%.
PATENT
https://patents.google.com/patent/US5091540A/en
Clotrimazole, i.e. 1-(o.Cl-α,α-diphenylbenzyl)imidazole, of formula: ##STR1## is a known antimycotic for human use, and a fungicide useful against plant pathogenic fungi.
Methods for its preparation are described in various patents. In particular, U.S. Pat. No. 3,929,820 describes a process starting from chlorophenyldiphenyl methylchloride and imidazole in the presence of a neutralizing agent, such as triethylamine, in a polar organic solvent. The process is strictly limited by the use, as the medium for the reaction in question, of a solvent falling within the given definition, i.e. having a dielectric constant of at least 4.5 and preferably between 15 and 50. In all the examples of the implementation of the process according to the patent in question, acetonitrile (D=37.5) is used as solvent.
EXAMPLE
900 g of benzene and 117.5 g of aluminium chloride are placed in a 2 liter flask fitted with a reflux condenser, stirrer and drying tube.
The mixture is cooled to 0° C. and a solution of 150 g of o.chlorobenzotrichloride in 150 g of benzene is added while maintaining a temperature not exceeding 15° C. The mixture is heated carefully under reflux for 4 hours. HCl is evolved.
The reaction mixture is then cooled to ambient temperature and slowly poured into 300 g of concentrated hydrochloric acid and 800 g of ice, so as not to exceed 25° C. The aqueous layer is then separated and discarded.
The benzene solution is washed with a solution of 230 g of sodium chloride in 800 g of water. The benzene phase is separated and dried over anhydrous sodium sulphate for 1 hour, and then filtered.
45 g of imidazole in 70 g of triethylamine are added to the filtrate and the mixture heated for 3 hours at 45°-50° C. It is then cooled to ambient temperature and 500 g of water are added while stirring. The aqueous layer is separated and discarded, and the benzene phase washed with 200 g of water. The benzene layer is separated and evaporated to dryness under vacuum.
The residue is dissolved in 250 g of ethyl acetate while stirring. 250 g of water are added and the solution titrated to calculate the exact quantity of nitric acid to add.
The solution is cooled to 15° C. and the calculated nitric acid quantity is quickly added. Stirring is halted when precipitation commences, and the system left until precipitation is complete.
The product is centrifuged and washed with 300 g of ethyl acetate and then with 300 g of water.
The moist product is placed into the reaction flask and 300 g of water, 450 g of methylene chloride, 5 g of triethylamine and 110 g of 30% sodium hydroxide are added. The mixture is stirred until a solution forms and the solution then left until the phases separate.
The aqueous phase is washed with 100 g of methylene chloride, and the pooled organic phases are washed twice with 200 g of water each time.
The solution in methylene chloride is treated with YMS decolorizing carbon and filtered, the filter then being washed with methylene chloride which si recovered by distillation. The residue is taken up in 100 g of acetone and redistilled to completely eliminate the methylene chloride.
The residue is taken up in 900 g of acetone and heated to 50° C. to obtain a complete solution. YMS decolorizing carbon and triethylamine are added, the mixture filtered and washed with acetone. Part of the acetone is then removed by distillation, reducing the volume to about 500 c.c. The mixture is cooled to 0° C. and, after five hours, the product is centrifuged and washed with 100 g of acetone. It is dried at 60° C., to obtain 150 g of final product.
/////////////clotrimazole
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Eflornithine, also known as α-difluoromethylornithine (DFMO), is an Active Pharmaceutical Ingredient (API) on the World Health Organization’s list of essential medicines. DFMO is used to treat the second stage of African trypanosomiasis (sleeping sickness). In addition, DFMO is also used to treat opportunistic infections with Pneumocystis carinii pneumonia, a form of pneumonia found in people with a weak immune system suffering from conditions such as acquired immunodeficiency syndrome (AIDS) It has also been explored as chemopreventive agent in cancer therapy with minor success. Today, its main use is to treat excessive facial hair growth on women (hirsutism). The topical cream (Vaniqa) significantly reduces the psychological burden of those affected.\
Eflornithine is a prescription drug indicated in the treatment of facial hirsutism (excessive hair growth). Eflornithine hydrochloride cream for topical application is intended for use in women suffering from facial hirsutism and is sold by Allergan, Inc. under the brand name Vaniqa. Besides being a non-mechanical and non-cosmetic treatment, eflornithine is the only non-hormonal and non-systemic prescription option available for women who suffer from facial hirsutism. Eflornithine for injection against sleeping sickness was manufactured by Sanofi Aventis and sold under the brand name Ornidyl in the USA. It is now discontinued. Eflornithine is on the World Health Organization’s List of Essential Medicines.
Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis (sleeping sickness) and excessive hair growth on the face in women.[1][2] Specifically it is used for the 2nd stage of sleeping sickness caused by T. b. gambiense and may be used with nifurtimox.[1][3] It is used by injection or applied to the skin.[1][2]
Common side effects when applied as a cream include rash, redness, and burning.[2] Side effects of the injectable form include bone marrow suppression, vomiting, and seizures.[3] It is unclear if it is safe to use during pregnancy or breastfeeding.[3] It is recommended typically for children over the age of 12.[3]
Eflornithine was developed in the 1970s and came into medical use in 1990.[4] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] There is no generic version as of 2015 in the United States.[6] In the United States the injectable form can be obtained from the Centers for Disease Control and Prevention.[3] In the 1990s the cost of a course of treatment in Africa was 210 USD.[7] In regions of the world where the disease is common eflornithine is provided for free by the World Health Organization.[8]
https://www.google.com/patents/US4330559
Sleeping sickness, or trypanosomiasis, is treated with pentamidine or suramin (depending on subspecies of parasite) delivered by intramuscular injection in the first phase of the disease, and with melarsoprol and eflornithine intravenous injection in the second phase of the disease. Efornithine is commonly given in combination with nifurtimox, which reduces the treatment time to 7 days of eflornithine infusions plus 10 days of oral nifurtimox tablets.[9]
Eflornithine is also effective in combination with other drugs, such as melarsoprol and nifurtimox. A study in 2005 compared the safety of eflornithine alone to melarsoprol and found eflornithine to be more effective and safe in treating second-stage sleeping sickness Trypanosoma brucei gambiense.[10] Eflornithine is not effective in the treatment of Trypanosoma brucei rhodesiense due to the parasite’s low sensitivity to the drug. Instead, melarsoprol is used to treat Trypanosoma brucei rhodesiense.[11] Another randomized control trial in Uganda compared the efficacy of various combinations of these drugs and found that the nifurtimox-eflornithine combination was the most promising first-line theory regimen.[12]
A randomized control trial was conducted in Congo, Côte d’Ivoire, the Democratic Republic of the Congo, and Uganda to determine if a 7-day intravenous regimen was as efficient as the standard 14-day regimen for new and relapsing cases. The results showed that the shortened regimen was efficacious in relapse cases, but was inferior to the standard regimen for new cases of the disease.[13]
Nifurtimox-eflornithine combination treatment (NECT) is an effective regimen for the treatment of second stage gambiense African trypanosomiasis.[14][15]
After its introduction to the market in the 1980s, eflornithine has replaced melarsoprol as the first line medication against Human African trypanosomiasis (HAT) due to its reduced toxicity to the host.[13] Trypanosoma brucei resistant to eflornithine has been reported as early as the mid-1980s.[13]
The gene TbAAT6, conserved in the genome of Trypanosomes, is believed to be responsible for the transmembrane transporter that brings eflornithine into the cell.[16] The loss of this gene due to specific mutations causes resistance to eflornithine in several trypanosomes.[17] If eflornithine is prescribed to a patient with Human African trypanosomiasis caused by a trypanosome that contains a mutated or ineffective TbAAT6 gene, then the medication will be ineffective against the disease. Resistance to eflornithine has increased the use of melarsoprol despite its toxicity, which has been linked to the deaths of 5% of recipient HAT patients.[13]
The topical cream is indicated for treatment of facial hirsutism in women.[18] It is the only topical prescription treatment that slows the growth of facial hair.[19] It is applied in a thin layer twice daily, a minimum of eight hours between applications. In clinical studies with Vaniqa, 81% percent of women showed clinical improvement after twelve months of treatment.[20] Positive results were seen after eight weeks.[21] However, discontinuation of the cream caused regrowth of hair back to baseline levels within 8 weeks.[22]
Vaniqa treatment significantly reduces the psychological burden of facial hirsutism.[23]
It has been noted that ornithine decarboxylase (ODC) exhibits high activity in tumor cells, promoting cell growth and division, while absence of ODC activity leads to depletion of putrescine, causing impairment of RNA and DNA synthesis. Typically, drugs that inhibit cell growth are considered candidates for cancer therapy, so eflornithine was naturally believed to have potential utility as an anti-cancer agent. By inhibiting ODC, eflornithine inhibits cell growth and division of both cancerous and noncancerous cells.
However, several clinical trials demonstrated minor results.[24] It was found that inhibition of ODC by eflornithine does not kill proliferating cells, making eflornithine ineffective as a chemotherapeutic agent. The inhibition of the formation of polyamines by ODC activity can be ameliorated by dietary and bacterial means because high concentrations are found in cheese, red meat, and some intestinal bacteria, providing reserves if ODC is inhibited.[25] Although the role of polyamines in carcinogenesis is still unclear, polyamine synthesis has been supported to be more of a causative agent rather than an associative effect in cancer.[24]
Other studies have suggested that eflornithine can still aid in some chemoprevention by lowering polyamine levels in colorectal mucosa, with additional strong preclinical evidence available for application of eflornithine in colorectal and skin carcinogenesis.[24][25] This has made eflornithine a supported chemopreventive therapy specifically for colon cancer in combination with other medications. Several additional studies have found that eflornithine in combination with other compounds decreases the carcinogen concentrations of ethylnitrosourea, dimethylhydrazine, azoxymethane, methylnitrosourea, and hydroxybutylnitrosamine in the brain, spinal cord, intestine, mammary gland, and urinary bladder.[25]
Topical use is contraindicated in people hypersensitive to eflornithine or to any of the excipients.[26]
Throughout clinical trials, data from a limited number of exposed pregnancies indicate that there is no clinical evidence that treatment with Vaniqa adversely affects pregnant women or fetuses.[26]
When taken by mouth the risk-benefit should be assessed in people with impaired renal function or pre-existing hematologic abnormalities, as well as those with eighth-cranial-nerve impairment.[27] Adequate and well-controlled studies with eflornithine have not been performed regarding pregnancy in humans. Eflornithine should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus. However, since African trypanosomiasis has a high mortality rate if left untreated, treatment with eflornithine may justify any potential risk to the fetus.[27]
Eflornithine is not genotoxic; no tumour-inducing effects have been observed in carcinogenicity studies, including one photocarcinogenicity study.[28] No teratogenic effects have been detected.[29]
The topical form of elflornithine is sold under the brand name Vaniqa . The most frequently reported side effect is acne (7–14%). Other side effects commonly (> 1%) reported are skin problems, such as skin reactions from in-growing hair, hair loss, burning, stinging or tingling sensations, dry skin, itching, redness or rash.[30]
The intravenous dosage form of eflornithine is sold under the brand name Ornidyl. Most side effects related to systemic use through injection are transient and reversible by discontinuing the drug or decreasing the dose. Hematologic abnormalities occur frequently, ranging from 10–55%. These abnormalities are dose-related and are usually reversible. Thrombocytopenia is thought to be due to a production defect rather than to peripheral destruction. Seizures were seen in approximately 8% of patients, but may be related to the disease state rather than the drug. Reversible hearing loss has occurred in 30–70% of patients receiving long-term therapy (more than 4–8 weeks of therapy or a total dose of >300 grams); high-frequency hearing is lost first, followed by middle- and low-frequency hearing. Because treatment for African trypanosomiasis is short-term, patients are unlikely to experience hearing loss.[30]
No interaction studies with the topical form have been performed.[26]
Figure 1
(A) 3D structure of L-Ornithine
(B) 3D structure of Eflornithine. This molecule is similar to the structure of L-Ornithine, but its alpha-difluoromethyl group allows interaction with Cys-360 in the active site
Eflornithine ODC Reaction Mechanism
Eflornithine is a “suicide inhibitor,” irreversibly binding to ornithine decarboxylase (ODC) and preventing the natural substrate ornithine from accessing the active site (Figure 1). Within the active site of ODC, eflornithine undergoes decarboxylation with the aid of cofactor pyridoxal 5’-phosphate (PLP). Because of its additional difluoromethyl group in comparison to ornithine, eflornithine is able to bind to a neighboring Cys-360 residue, permanently remaining fixated within the active site.[29]
During the reaction, eflornithine’s decarboxylation mechanism is analogous to that of ornithine in the active site, where transamination occurs with PLP followed by decarboxylation. During the event of decarboxylation, the fluoride atoms attached to the additional methyl group pull the resulting negative charge from the release of carbon dioxide, causing a fluoride ion to be released. In the natural substrate of ODC, the ring of PLP accepts the electrons that result from the release of CO2.
The remaining fluoride atom that resides attached to the additional methyl group creates an electrophilic carbon that is attacked by the nearby thiol group of Cys-360, allowing eflornithine to remain permanently attached to the enzyme following the release of the second fluoride atom and transimination.
Figure 2
Experimental Evidence for Eflornithine End Product[31]
The reaction mechanism of Trypanosoma brucei‘s ODC with ornithine was characterized by UV-VIS spectroscopy in order to identify unique intermediates that occurred during the reaction. The specific method of multiwavelength stopped-flow spectroscopy utilized monochromatic light and fluorescence to identify five specific intermediates due to changes in absorbance measurements.[32] The steady-state turnover number, kcat, of ODC was calculated to be 0.5 s-1 at 4 °C.[32] From this characterization, the rate-limiting step was determined to be the release of the product putrescine from ODC’s reaction with ornithine. In studying the hypothetical reaction mechanism for eflornithine, information collected from radioactive peptide and eflornithine mapping, high pressure liquid chromatography, and gas phase peptide sequencing suggested that Lys-69 and Cys-360 are covalently bound to eflornithine in T. brucei ODC’s active site.[31] Utilizing fast-atom bombardment mass spectrometry (FAB-MS), the structural conformation of eflornithine following its interaction with ODC was determined to be S-((2-(1-pyrroline-methyl) cysteine, a cyclic imine adduct. Presence of this particular product was supported by the possibility to further reduce the end product to S-((2-pyrrole) methyl) cysteine in the presence of NaBH4 and oxidize the end product to S-((2-pyrrolidine) methyl) cysteine (Figure 2).[31]
Figure 3
Active Site of ODC Formed by Homodimerization (Green and White Surface Structures)
(A) Ornithine in the Active Site of ODC, Cys-360 highlighted in yellow
(B) Product of Eflornithine Decarboxylation bound to Cys 360 (highlighted in yellow). The pyrroline ring blocks ornithine from entering the active site
Derived from Grishin, Nick V., et al. “X-ray structure of ornithine decarboxylase from Trypanosoma brucei: the native structure and the structure in complex with α-difluoromethylornithine.” Biochemistry 38.46 (1999): 15174-15184. PDB ID: 2TOD
Eflornithine’s suicide inhibition of ODC physically blocks the natural substrate ornithine from accessing the active site of the enzyme (Figure 3).[29] There are two distinct active sites formed by the homodimerization of ornithine decarboxylase. The size of the opening to the active site is approximately 13.6 Å. When these openings to the active site are blocked, there are no other ways through which ornithine can enter the active site. During the intermediate stage of eflornithine with PLP, its position near Cys-360 allows an interaction to occur. As the phosphate of PLP is stabilized by Arg 277 and a Gly-rich loop (235-237), the difluoromethyl group of eflornithine is able to interact and remain fixated to both Cys-360 and PLP prior to transimination. As shown in the figure, the pyrroline ring interferes with ornithine’s entry (Figure 4). Eflornithine will remain permanently bound in this position to Cys-360. As ODC has two active sites, two eflornithine molecules are required to completely inhibit ODC from ornithine decarboxylation.
Eflornithine was initially developed for cancer treatment at Merrell Dow Research Institute in the late 1970s, but was found to be ineffective in treating malignancies. However, it was discovered to be highly effective in reducing hair growth,[33] as well as in the treatment of African trypanosomiasis (sleeping sickness),[34] especially the West African form (Trypanosoma brucei gambiense).
In the 1980s, Gillette was awarded a patent for the discovery that topical application of eflornithine HCl cream inhibits hair growth. In the 1990s, Gillette conducted dose-ranging studies with eflornithine in hirsute women that demonstrated that the drug slows the rate of facial hair growth. Gillette then filed a patent for the formulation of eflornithine cream. In July 2000, the U.S. Food and Drug Administration (FDA) granted a New Drug Application for Vaniqa. The following year, the European Commission issued its Marketing Authorisation.
The drug was registered for the treatment of gambiense sleeping sickness on November 28, 1990.[35] However, in 1995 Aventis (now Sanofi-Aventis) stopped producing the drug, whose main market was African countries, because it did not make a profit.[36]
In 2001, Aventis and the WHO formed a five-year partnership, during which more than 320,000 vials of pentamidine, over 420,000 vials of melarsoprol, and over 200,000 bottles of eflornithine were produced by Aventis, to be given to the WHO and distributed by the association Médecins sans Frontières (also known as Doctors Without Borders)[37][38] in countries where sleeping sickness is endemic.
According to Médecins sans Frontières, this only happened after “years of international pressure,” and coinciding with the period when media attention was generated because of the launch of another eflornithine-based product (Vaniqa, for the prevention of facial-hair in women),[36]while its life-saving formulation (for sleeping sickness) was not being produced.
From 2001 (when production was restarted) through 2006, 14 million diagnoses were made. This greatly contributed to stemming the spread of sleeping sickness, and to saving nearly 110,000 lives.
Vaniqa is a cream, which is white to off-white in colour. It is supplied in tubes of 30 g and 60 g in Europe.[30] Vaniqa contains 15% w/w eflornithine hydrochloride monohydrate, corresponding to 11.5% w/w anhydrous eflornithine (EU), respectively 13.9% w/w anhydrous eflornithine hydrochloride (U.S.), in a cream for topical administration.
Ornidyl, intended for injection, was supplied in the strength of 200 mg eflornithine hydrochloride per ml.[39]
In 2000, the cost for the 14-day regimen was US $500; a price that many in countries where the disease is common cannot afford.[13]
Vaniqa, granted marketing approval by the US FDA, as well as by the European Commission[40] among others, is currently the only topical prescription treatment that slows the growth of facial hair.[19] Besides being a non-mechanical and non-cosmetic treatment, it is the only non-hormonal and non-systemic prescription option available for women who suffer from facial hirsutism.[18] Vaniqa is marketed by Almirall in Europe, SkinMedica in the USA, Triton in Canada, Medison in Israel, and Menarini in Australia.[40]
Ornidyl, the injectable form of eflornithine hydrochloride, is licensed by Sanofi-Aventis, but is currently discontinued in the US.[41]
Clip
Scalable Continuous Flow Process for the Synthesis of Eflornithine Using Fluoroform as Difluoromethyl Source
The development of a scalable telescoped continuous flow procedure for difluoromethylation of a protected amino acid with fluoroform (CHF3, R-23) gas and subsequent high temperature deprotection to provide eflornithine, an important Active Pharmaceutical Ingredient (API), is described. Eflornithine is used for the treatment of sleeping sickness and hirsutism, and it is on the World Health Organization’s list of essential medicines. Fluoroform is produced in large quantities as a side product in the manufacture of polytetrafluoroethylene (PTFE, Teflon). Fluoroform is an ozone-benign and nontoxic gas, but its release into the environment is forbidden under the Kyoto protocol owing to its high global warming potential. The existing manufacturing route to eflornithine uses chlorodifluoromethane (CHClF2, R-22) which will be phased out under the Montreal protocol; therefore, the use of the fluoroform presents a viable cost-effective and more sustainable alternative. The process parameters and equipment setup were optimized on laboratory scale for the two reaction steps to improve product yield and scalability. The telescoped flow process utilizing fluoroform gas was operated for 4 h to afford the target molecule in 86% isolated yield over two steps with a throughput of 24 mmol/h.
1hydrochloride monohydrate as colorless powder. (17.05 g, 72.3 mmol, 86% yield). Mp. 228 °C;
1H NMR (300.36 MHz, D2O): δ = 6.46 (t, 2JHF = 52.8 Hz, 1H), 3.05 (t,3JHH = 7.6 Hz, 2H), 2.25–1.97 (m, 2H), 1.96–1.79 (m, 1H), 1.76–1.59 (m, 1H) ppm.
13C NMR (75 MHz, D2O): δ = 167.8 (d, 3JCF = 6.4 Hz), 114.0 (dd, 1JCF = 249.7 Hz, 1JCF = 247.0 Hz), 64.5 (dd, 2JCF = 20.4 Hz, 2JCF = 18.7 Hz), 38.8 (d, 3JCF = 7.3 Hz), 31.6 (d, 4JCF = 3.2 Hz), 20.8 ppm.
19F NMR (282 MHz, D2O): δ = −126.28 (dd, 2JFF = 283.5 Hz, 2JHF = 52.4 Hz), – 131.76 (dd, 2JFF = 283.5 Hz, 2JHF = 52.4 Hz) ppm.
 |
|
 |
|
| Clinical data | |
|---|---|
| Trade names | Vaniqa, others |
| Synonyms | α-difluoromethylornithine or DFMO |
| AHFS/Drugs.com | Monograph |
| License data |
|
| Pregnancy category |
|
| Routes of administration |
intravenous, topical |
| ATC code | |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Bioavailability | 100% (Intravenous) Negligible (Dermal) |
| Metabolism | Not metabolised |
| Elimination half-life | 8 hours |
| Excretion | Kidneys |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C6H12F2N2O2 |
| Molar mass | 182.17 g·mol−1 |
| 3D model (JSmol) | |
/////////////ZQN1G5V6SR, эфлорнитин , إيفلورنيثين , 依氟鸟氨酸 , Eflornithine, エフロルニチン
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Pirlindole (Lifril, Pyrazidol) is a reversible inhibitor of monoamine oxidase A (RIMA) which was developed and is used in Russia as an antidepressant.[1]:337 It is structurally and pharmacologically related to metralindole.
Biovista is investigating BVA-201, a repurposed oral formulation of pirlindole mesylate, for the potential treatment of multiple sclerosis
SYN 1
SYN 2
PAPER
Khimiko-Farmatsevticheskii Zhurnal (1986), 20(3), 300-3.
PATENT
U.S.S.R. (1986), SU 276060
PAPER
Sudebno-meditsinskaia ekspertiza (1989), 32(4), 49-50
PAPER
Journal of Pharmaceutical and Biomedical Analysis
https://www.sciencedirect.com/science/article/abs/pii/S0731708598002131
PATENT
claiming method for resolving racemic mixture of pirlindole hydrochloride into enantiomerically pure (S)-pirlindole and/or (R)-pirlindole,
Pirlindole, 2, 3, 3a, 4, 5, 6-hexahydro-lH-8-methyl-pyrazine
[3, 2, 1-j , k] carbazole, is a tetracyclic compound of the formula I
(I)
Pirlindole is a reversible monoamine oxidase A inhibitor being up to date useful as a medicament in the treatment of depression.
Pirlindole has an asymmetric carbon atom which implies that there are two enantiomers, (S) -pirlindole and (R) -pirlindole .
The state of the art teaches several methods for the enantiomeric separation of pirlindole. For example, The Journal of Pharmaceutical and Biomedical Analysis, 18(1998) 605- 614, “Enantiomeric separation of pirlindole by liquid chromatography using different types of chiral stationary phases”, Ceccato et al, discloses the enantiomeric separation of pirlindole by liquid chromatography (LC) using three different chiral stationary phases.
Further, The Journal of Pharmaceutical and Biomedical Analysis 27(2002) 447-455, “Automated determination of pirlindole enantiomers in plasma by on-line coupling of a pre-column packed with restricted access material to a chiral liquid chromatographic column”, Chiap et al., discloses the use of a pre-column packed with restricted access material for sample clean up coupled to a column containing a cellulose based chiral stationary phase for separation and quantitative analysis of the enantiomers .
According to the prior art, Chirality 11:261-266 (1999) all attempts to obtain the enantiomers of pirlindole by selective crystallization with optically active acids failed, and it was only possible to obtain at laboratory scale (few grams) as hydrochloride salt, using derivatization technique in conjunction with preparative chromatography.
The characteristics of the process disclosed in the state of the art limit in a definitive way, its implementation on an industrial or semi-industrial scale due to the necessity to use a separation by chromatography on a large scale which makes the process very costly, difficult to implement and with poor reproducibility. .
EXAMPLE 7
(R) -Pirlindole mesylate
Starting from 10 g of (R) -pirlindole (S) -mandelate obtained in Example 1 and following the procedure described in Example 5 using methanesulfonic acid as pharmaceutical acceptable acid, ,
7.4 g (0.023 mole) of (R) -pirlindole mesylate were obtained (yield = 85.2% ). Chiral HPLC (enantiomeric purity = 98.0%).
XAMPLE 9
(S) -pirlindole mesylate
Starting from 10 g of (S) -pirlindole (R) -mandelate obtained in Example 2 and following the procedure described in Example 6 using methanesulfonic acid as pharmaceutical acceptable acid, 6.8 g (0.021 mole) of (S) -pirlindole mesylate were obtained (yield = 77.8%). Chiral HPLC (enantiomeric purity = 98.0%).
PATENT
Process for the preparation of pirlindole . useful for treating depression.
Pirlindole (8-methyl-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole) of formula I
Compound Formula I
also described as Pyrazidole™ represents a new class of original tetracyclic antidepressants, the pyrazinocarbazole derivatives. The drug was synthesized and characterized at the end of the 1960s and was marketed as an anti-depressant in 1975. Current clinical trials have demonstrated to be a highly effective short-acting and safe drug.
[0003] Pirlindole is a selective, reversible inhibitor of MAO-A. In-vitro evidence suggest the catalytic oxidation of Pirlindole into dehydro-pirlindole by MAO-A. Dehydro-pirlindole may be a more potent slowly reversible inhibitor of MAO-A and this might explain the persistence of MAO-A inhibition in-vivo (MAO-The mother of all amine oxidases, John P.M. Finberg et al. 1998, Springer).
[0004] Pirlindole chemical structure is composed of one stereogenic centre which indicates the existence of two enantiomers, the ( ?)-Pirlindole and the (S)-Pirlindole.
[0005] Although Pirlindole pharmacological data and the clinical use were performed on the racemate, recently there have been increasing interest in the pharmacological profile of each enantiomer (WO 2015/171005 Al).
[0006] International patent publication WO 2015/171003A1 filed 9th May 2014 discloses a resolution of racemic pirlindole into optically active pirlindole. The Resolution-Racemization-Recycle (RRR) synthesis described involves derivatization by preparation of pairs of diastereomers in the form of salts from an optically active organic acid. These diastereomers can be separated by conventional techniques such as crystallisation. Although it is a very efficient procedure to prepare laboratorial scale or pre-clinical batch of (/?)- or (S)-Pirlindole, it is not economically convenient at an industrial scale because the process relies on Pirlindole racemate as the starting material.
[0007] Andreeva et al. (Pharmaceutical Chemistry 1992, 26., 365-369) discloses the first isolation of Pirlindole enantiomers in isolated form. ( ?)-Pirlindole of formula II
was isolated as an hydrochloride salt from a racemic base by the fractional crystallization of racemic pirlindole salt with (+)-camphor-10-sulfonic acid. (S)-Pirlindole formula III
was also isolated as an hydrochloride salt although via asymmetric synthesis from the 6-methyl-2,3,4,9-tetrahydro-lH-carbazol-l-one IV
[0008] Compound of formula IV was reacted with chiral auxiliary (S)-(-)-a-methylbenzylamine to afford asymmetric (S)-6-methyl-N-(l-phenylethyl)-2,3,4,9-tetrahydro-lH-carbazol-l-imine V
[0009] Compound of formula V was subjected to stereoselective reduction with sodium borohydride in ethanol. According to Andreeva et al. the reaction might occur through directed intramolecular hydride transfer after formation of a complex between compound of formula V and reducing agent to afford (S)-6-methyl-N-((S)-l-phenylethyl)-2,3,4,9-tetrahydro-lH-carbazol-l-amine VI
[0010] Compound of formula VI is reacted with ethylene glycol ditosylate by ethylene bridge formation under alkaline conditions to yield (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole VII.
[0011] Alkaline agent is sodium hydride (NaH), in the presence of dimethyl sulfoxide (DMSO) or dimethylformamide (DMF).
[0012] The ratio between alkaline agent, compound of formula VI and ethylene glycol ditosylate is 1.2:1:1.
[0013] The cyclization reaction occurs at room temperature for a period of 4.5 hours. [0014] Compound of formula VII was subjected to catalytic hydrogenolysis conditions to afford the desired hydrochloride salt of compound of formula III.
[0015] The hydrogenolysis reaction was catalysed by Palladium on charcoal (Pd content 0.1 g, 9 mol%) and was conducted in methanol. The conversion of compound of formula VII into compound of formula III was performed under a hydrogen pressure of 1.8-2.0 MPa at 22 °C for a period of 17h.
[0016] The work-up conditions for the hydrogenolysis reaction involved neutralization with ammonia solution followed by benzene recrystallization. The hydrochloride salt of compound of formula III was formed from addition of hydrochloric acid to a solution of free base in ethanol.
[0017] The process yielded (S)-Pirlindole hydrochloride with a final yield of 10% with respect to the intermediate VI.
[0018] The mixture of sodium hydride with DMSO generates dimsyl anion. This anion is very often used in laboratory scale, but because it is unstable its use on large scale should be under specific precautions. Dimsyl anion decomposition is exotermic. It is reported that dimsyl anion decomposition starts even at 20 °C, and above 40 °C it decomposes at an appreciable rate (Lyness, W. I. et ai, U.S. 3,288,860 1966, CI. 260-607).
[0019] The mixture of DMF and sodium hydride is reported in ‘Sax & Lewis’s Dangerous Properties of Industrial Materials’ to give a violent reaction with ignition above 50 °C. Buckey, J. et ai, Chem. Eng. News 1982, 60(28), 5, describes the thermal runaway of a pilot plant reactor containing sodium hydride and DMF from 50 °C. Accelerated Rate Calorimetry (ARC) tests showed exothermic activity as low as 26 °C. Similar behaviour was also seen with DMA. De Wall, G. et ai, Chem. Eng. News 1982, 60(37), 5, reports a similar incident, wherein runaway started at 40 °C, and rose 100 °C in less than 10 minutes, boiling off most of the DMF.
[0020] There exists a need for safe, industrial- and eco-friendly processes for the preparation of Pirlindole enantiomers. These facts are disclosed in order to illustrate the technical problem addressed by the present disclosure.
[0068] In an embodiment, the preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole, compound of formula VII was carried out as follow.
[0069] In an embodiment, in a 2 L three necked round bottomed flask equipped with magnetic stirrer, ethylene glycol ditosylate (73 g, 197 mmol) and DMI (240 mL) were loaded. To the resulting clear solution, NaH (60% suspension in mineral oil, 15.8 g, 394 mmol) was added carefully. To the resulting suspension a solution of VI ((S)-6-methyl-N-((S)-l-phenylethyl)-2,3,4,9-tetrahydro-lH-carbazol-l-amine) (30 g, 98.5 mmol) in DMI (60 mL) was added dropwise at 60 °C. The mixture was stirred for 1 h at 60 °C. The mixture was cooled down to room temperature, then MeOH was added slowly with ice-water cooling. A white precipitation appeared, and the resulting suspension was stirred and then filtered. The filtered product was washed with water-MeOH. The product was dried under vacuum to give 24.9 g of compound of formula VII (75.2 mmol, yield: 76%). Purity >99.9area% (HPLC).
[0070] In an embodiment, the preparation of hydrochloride salt of (S)-Pirlindole, compound of formula III, was performed as follow.
[0071] In an embodiment, the free amine VII ((S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole) (8,32 g, 25 mmol) was dissolved in DCM (42 mL) and excess of HCI in MeOH (42 mL) was added. The solvents were evaporated under reduced pressure to dryness to give a yellow oil. The residue was dissolved in MeOH (120 mL) and was added to the dispersion of Pd/C (1,74 g, -50% water) in MeOH (20 mL). The reaction mixture was stirred at 50 °C under a 750 KPa (7.5 bar) pressure of hydrogen for 5h. After completion (HPLC) the suspension was filtered through a celite pad, and the filter cake was washed with MeOH. The pH of the resulting solution was checked (<3) and it was evaporated to give the crude hydrochloride salt of compound of formula III. To the crude material iPrOH was added and the suspension was allowed to stir at reflux. The suspensions were filtered, and the product was dried under vacuum to give the hydrochloride salt of (S)-Pirlindole, compound of formula III (5.11 g, 19.5 mmol, yield: 77%). Purity > 99.5% (HPLC). Enantiomeric purity 99.5% (Chiral HPLC). MS (ESI): m/z 227.2 (M+H)+.
PATENT
Process for the preparation of piperazine ring for the synthesis of pyrazinocarbazole derivatives, such as the antidepressant pirlindole .
Pirlindole hydrochloride is the compound represented in formula I
[0003] It is the common name of 8-methyl-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole hydrochloride which is an active pharmaceutical ingredient marketed with the name Pyrazidol™. The compound is effective as an anti-depressant agent.
[0004] Pirlindole chemical structure belongs to the pyrazinocarbazole group. It is composed of one stereogenic centre which anticipate the existence of two enantiomers, the ( ?)-Pirlindole of formula II and the (S)-Pirlindole of formula III.
[0005] Although Pirlindole pharmacological data and the clinical use were performed on the racemate, recently there have been increasing interest in the pharmacological profile of each enantiomer (WO 2015/171005 Al).
[0006] The document WO 2015/171003Al(Tecnimede group) filed 9th May 2014 discloses a resolution of racemic pirlindole into optically active pirlindole. The Resolution-Racemization-Recycle (RRR) synthesis described involves derivatization by preparation of pairs of diastereomers in the form of salts from an optically active organic acid. These diastereomers can be separated by conventional techniques such as crystallisation. Although it is a very efficient procedure to prepare laboratorial scale or pre-clinical batch of (/?)- or (S)-Pirlindole, it is not economically convenient at an industrial scale because the process relies on Pirlindole racemate as the starting material.
[0007] Processes to prepare Pirlindole involve the formation of a piperazine ring. The state of the art discloses different processes for piperazine ring formation but they are generally a multistep approach, and they are hampered by low yields, expensive reagents, or are reported as unsuccessful (Roderick et al. Journal of Medicinal Chemistry 1966, 9, 181-185).
[0008] The first asymmetric synthesis of Pirlindole enantiomers described by Andreeva et al. (Pharmaceutical Chemistry 1992, 26, 365-369) discloses a one-step process to prepare pyrazinocarbazole piperazine ring system from a tetrahydrocarbazole-amine. The process discloses a very low yield (23.8 %) and employs the use of sodium hydride (NaH) in the presence of dimethyl sulfoxide (DMSO) or dimethyl formamide (DMF), both conditions described as generating exothermic decomposition that can cause reaction ignition or reaction thermal runaway.
[0009] The mixture of sodium hydride with DMSO generates dimsyl anion. This anion is very often used in laboratory scale, but because it is unstable its use on large scale should be under specific precautions. The dimsyl anion decomposition is exothermic. It is reported that dimsyl anion decomposition starts even at 20 °C, and above 40 °C it decomposes at an appreciable rate (Lyness et al. US 3288860).
[0010] The mixture of DMF and sodium hydride is reported in Sax & Lewis’s Dangerous Properties of Industrial Materials to give a violent reaction with ignition above 50 °C. Buckey et al., (Chemical & Engineering News, 1982, 60(28), 5) describes the thermal runaway of a pilot plant reactor containing sodium hydride and DMF from 50 °C. Accelerated Rate Calorimetry (ARC) tests showed exothermic activity as low as 26 °C.
Similar behaviour was also seen with DMA. De Wall et al. (Chem. Eng. News, 1982, 60(37), 5) reports a similar incident, wherein runaway started at 40 °C, and rose 100 °C in less than 10 minutes, boiling off most of the DMF.
[0011] An alternative process for the preparation of a piperazine ring system of a pyrazinocarbazole derivative can involve the formation of a lactam ring in a three steps approach:
1. N-acylation reaction;
2. intramolecular indole acetamide cyclisation to afford a lactam ring;
3. lactam reduction.
[0012] Intramolecular indole chloroacetamide cyclization to yield a lactam ring has been described by Bokanov et al. (Pharmaceutical Chemistry Journal 1988, 23, 12, 1311-1315) particularly in the non-enantioselective synthesis of pyrazinocarbazolone derivatives. Bokanov et al. did not describe the lactam reduction into a piperazine ring.
[0013] Intramolecular indole chloroacetamide cyclization to yield a lactam ring has also been described both by Rubiralta et al. (Journal of Organic Chemistry 54, 23, 5591-5597) and Bennasar, et al. (Journal of Organic Chemistry 1996., 61, 4, 1239-1251), as an unexpected outcome of a photocyclization reaction. The lactam conversion was low (<11% yield).
[0014] Lactam reduction of a pyrazinone into piperazine ring systems is disclosed both by Aubry et al. (Biorganic Medicinal Chemistry Letters 2007, 17, 2598-2602) and Saito et al. (Tetrahedron 1995, 51, 30, 8213-8230) in the total synthesis of alkaloid natural products.
[0015] There exists the need for improved processes for the preparation of piperazine ring derivatives in particular enantioselective processes for the preparation of pyrazinocarbazole intermediates precursors of Pirlindole enantiomers compounds of formula II and III.
Example 1 – Preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-3a,4,5,6-tetrahydro-lH-pyrazino[3,2,l-jk]carbazol-2(3H)-one – Formula IV
[00106] In an embodiment, the preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-3a,4,5,6-tetrahydro-lH-pyrazino[3,2,l-jk]carbazol-2(3H)-one (Formula IV) was carried out as follows. To the solution of VI (S)-6-methyl-N-((S)-l-phenylethyl)-2,3,4,9-tetrahydro-lH-carbazol-l-amine (30 g, 98.5 mmol) in toluene (300 mL), 50 % (w/v) aqueous NaOH (79 g) was added dropwise at 0-5 °C, then the solution of chloroacetyl
chloride (12 mL, 148 mmol, 1.5 equiv.) in toluene (15 mL) was added dropwise at 0-5 °C. The mixture was stirred at 0-5 °C for approximately 2.5 h, and additional chloroacetyl chloride (12 mL, 148 mmol, 1.5 equiv.) in toluene (15 mL) was added dropwise at 0-5 °C. The mixture was stirred at 0-5 °C for approximately 1.5 h. Water was added to the reaction mixture keeping the temperature below 5 °C. The phases were separated, and the aqueous phase was extracted with toluene. The organic phase was treated with 2M aqueous HCI. The resulting suspension was filtered. The filtered solid was identified as the HCI salt of VI, which can be liberated and driven back to the chloroacetylation step. The phases of the mother liquor were separated, and the aqueous phase was extracted with toluene. The organic phase was dried over Na2S04, filtered and concentrated under reduced pressure to about 350 mL as a solution in toluene. The toluene solution of the crude product compound of formula X was reacted in the next step.
[00107] In an embodiment, in the same reaction vessel to the toluene solution of crude intermediate obtained in previous step were added TBAB (0.394 g, 1.22 mmol, 1 w/w% for the theoretical yield of prev. step) and 50 % (w/v) aqueous NaOH (8.1 g, 10 equiv.). The reaction mixture was stirred for 1 h at 65 °C, while the reaction was complete. Water was added to the mixture at 0 °C, and the phases were separated, the organic phase was washed with aqueous HCI, and with water, then dried over Na2S04, filtered and evaporated to give 32.87 g of compound IV (S)-8-methyl-3-((S)-l-phenylethyl)-3a,4,5,6-tetrahydro-lH-pyrazino[3,2,l-jk]carbazol-2(3H)-one (yield: 97% for the two steps) as a brown solid. The crude product was reacted in the next step without further purification.
Example 2 – Preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole _ Formula V
[00108] In an embodiment, the preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole (Formula V) was performed as follows. To the stirred solution of 32.87 g of IV, (S)-8-methyl-3-((S)-l-phenylethyl)-3a,4,5,6-tetrahydro-lH-pyrazino[3,2,l-jk]carbazol-2(3H)-one (95.4 mmol) in dry THF (170 mL) 66 mL solution of sodium bis(2-methoxyethoxy)aluminium hydride in toluene (70 w/w%, 237 mmol, 2.5 equiv.) was added dropwise. The reaction mixture was warmed to 40 °C, and the end of the addition the mixture was stirred at 50 °C until the total consumption of the starting material. Additional 22 mL of sodium bis(2-methoxyethoxy)aluminium hydride solution (70 w/w%, 79 mmol, 0.8 equiv.) was added dropwise. After completion the mixture was cooled to room temperature and 5% aqueous NaOH was added carefully. Water and DCM were added to the mixture, the phases were separated, and the aqueous phase was extracted with DCM. The organic phase was dried over Na2S04, filtered and the solvent was evaporated to get a brown solid (28.8 g). This crude product was dissolved in DCM and MeOH was added. White solid precipitated. The solid was filtered and washed with MeOH to give V (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-j‘k]carbazole 14.6 g (yield: 46%) as an off-white cotton-like solid.
Example 3 – Preparation of (S)-Pirlindole Hydrochloride – Formula III
[00109] In an embodiment, the preparation of (S)-Pirlindole hydrochloride III was carried out as follows. The free amine V ((S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a, 4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole) (8.32 g, 25 mmol) was dissolved in DCM (42 mL) and excess of HCI in MeOH (42 mL) was added. The solvents were evaporated under reduced pressure to dryness to give a yellow oil. The residue was dissolved in MeOH (120 mL) and was added to the dispersion of Pd/C (1.74 g, -50% water) in MeOH (20 mL). The reaction mixture was stirred at 50 °C under 750 KPa (7.5 bar) pressure of hydrogen for 5h. After completion (HPLC) the suspension was filtered through a celite pad, and the filter cake was washed with MeOH. The pH of the resulting solution was checked (<3) and it was evaporated to give the crude hydrochloride salt of compound of formula III. To the crude material iPrOH was added and the suspension was allowed to stir at reflux. The suspensions were filtered, and the product was dried under vacuum to give the hydrochloride salt of (S)-Pirlindole, compound of formula III (5.11 g, 19.5 mmol, yield: 77%). Purity > 99.5% (HPLC). Enantiomeric purity 99.5% (Chiral HPLC). MS (ESI): m/z 227.2 (M+H)+.
[00110] Table 1. Comparative yields
http://www.biomedsearch.com/nih/Pirlindole-in-treatment-depression-meta/21053988.html
General References
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| Clinical data | |
|---|---|
| Trade names | Pirazidol |
| Routes of administration |
Oral |
| ATC code |
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| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Bioavailability | 20–30% |
| Protein binding | 95% |
| Metabolism | hepatic |
| Onset of action | 2 to 8 hours |
| Elimination half-life | 185 hours |
| Excretion | urine (50–70%), feces (25–45%) |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C15H18N2 |
| Molar mass | 226.32 g/mol |
| 3D model (JSmol) | |
//////////////Pirlindole, Lifril, Pyrazidol, 60762-57-4, DEPRESSION
CC1=CC2=C(C=C1)N3CCNC4C3=C2CCC4
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