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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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1R,2S-Methoxamine


1R,2S-methoxamine, also known as L-erythro-methoxamine

CAS 13699-29-1

Benzenemethanol, α-[(1S)-1-aminoethyl]-2,5-dimethoxy-, (αR)-
Benzenemethanol, α-(1-aminoethyl)-2,5-dimethoxy-, [R-(R*,S*)]-
(-)-Methoxamine
Molecular Weight, 211.26, C11 H17 N O3

HYDROCHLORIDE

(1R,2S)-isomer HCl salt of 1 -(2,5-dimethoxyphenyl)-2-amino-1 -propanol also called as (1R, 2S)methoxamine hydrochloride

CAS  16122-04-6

Used as a pressor agent, as a vasoconstrictor, as a nasal decongestant, in ophthalmology and also found very effective in the treatment of faecal incontinence.

treatment of relief of fecal incontinence and anal itch (pruritis ani) , particularly for patients who have had a major bowel resection and reanastomosis .

Anal or fecal incontinence is the inability to voluntarily control the passage of feces or gas through the anus. It may occur either as fecal soiling or as rare episodes of incontinence for gas or watery stools. It is a very distressing condition that can result in self-inflicted social isolation and despair.

Conventional treatments for fecal incontinence include drug therapy to improve stool consistency, such as morphine, loperamide and codeine phosphate to reduce gut motility, and laxatives to soften stools and relieve constipation. Biofeedback training is another treatment which involves muscle strengthening exercises to improve anal canal resting pressure, and squeeze pressure, and to teach symmetry of anal canal function. The most common form of treatment however, is surgical repair, such as the creation of a neo-sphincter which involves grafting on muscle from other parts of the anus, or a colostomy. (Gastroenterology in Practice, Summer 1995, pl8- 21; Dig Dis 1990; 8:179-188; and The New England Journal of Medicine, April 1992, pl002-1004) . In mild cases of anal leakage, the patient will often try and plug the anus with a ball of cotton wall.

In Gut, 1991, 32, p.345-346 it was reported that two thirds of patients with idiopathic faecal incontinence had a decreased anal resting pressure resulting from an abnormal internal sphincter function. In many incontinent patients, the internal anal sphincter was found to be abnormally thin, while others had an external anal sphincter defect. It has also been reported that in vi tro contractile response of the internal anal sphincter to noradrenaline is decreased in incontinence, (Br. J. Surg. 1992, vol 79, August, p829-832; Digestive Diseases and Sciences, vol 38, no. 11, Nov. 1993, pl961-1969) . A further discussion of the innervation and control of the internal anal sphincter and drugs which can increase or decrease the normal anal resting pressure, is discussed in the text book Coloproctology and the Pelvic Floor (Butterworths) , second edition, 1992, at chapter 3 p37-53; Automic Control of Internal Anal Sphincter; and Journal of Clinical Investigation 1990, 86: p424-429.

In Surgery 1990; 107: p311-315 sodium valproate was found to be useful in the treatment of minor incontinence after ileoanal anastomosis.

It has now surprisingly been found that fecal incontinence and anal itch can be resolved by treatment with α adrenergic agonists, nitric oxide synthase inhibitors, prostaglandins F, dopamine, morphine, β-blockers such as propranolol, and 5-Hydroxytryptamine (5-HT) .

This is surprising since it was always thought that once an anal sphincter began functioning abnormally, the patient would require major surgery.

In this way the anal leakage is reduced or eliminated without the patient having to undergo major surgery.

Accordingly in a first aspect of the invention there is provided use of a physiologically active agent selected from an α adrenergic agonist, nitric oxide synthase inhibitor, prostaglandin F, dopamine, morphine, β-blockers, and 5- Hydroxytryptamine in the preparation of a medicament for the treatment or prophylaxis of fecal incontinence or anal itch.

The agents of the invention appear to at least partially treat the incontinence by increasing the resting pressure of the internal anal sphincter. Preferred agents are λ adrenergic agonists, nitric oxide synthase inhibitors, and prostaglandins F.

Examples of suitable aλ adrenergic agonists are nor- adrenalin, methoxamine, but particularly preferred is phenylephrine .

Examples of suitable F prostaglandin are dinoprost and carboprost.

Examples of suitable NO synthase inhibitors are

NG-monnoommeetthhyyll–LL–aarrggiinn:ine (L-NMMA) , and NG-nitro-L-arginine methyl ester ( -NAME)

The medicament can contain a single active agent or a combination of any of the above active agents.

Nitric Oxide (NO) synthase inhibitors such as LNMMA have previously been suggested for the therapeutic treatment of septic shock.

The prostaglandins, along with thromboxanes and leukotrienes are all derived from 20 -carbon polyunsaturated fatty acids and are collectively termed eicosanoids. F prostaglandins are derived in vivo from the endoperoxide prostaglandin H2which is in turn derived from leukotrienes. Clinically, F prostaglandins such as dinoprost and carboprost are used as uterine stimulants in the termination of pregnancy, missed abortion or the induction of labour.

Phenylephrine (an αx adrenergic agonist) is used as a mydriatic in ophthalmology, and as a decongestant , for example, in cold and flu remedies.

However there has been no suggestion to the inventors knowledge of using any of these active agents to treat fecal incontinence or anal itch. As used herein “fecal incontinence” includes all types of anal leakage from minor leakage or ‘spotting’ through moderate leakage, to major instances of faecal incontinence, and includes neurogenic, active, urge and passive incontinence.

More particularly the class of incontinent patients who will benefit most from the present invention are those with idiopathic incontinence and those whose incontinence is at least partly due to a weakness of either the internal or external anal sphincter, especially those with a normal or low maximum anal pressure and a structurally intact internal anal sphincter muscle, such as with an abnormally thin sphincter. However patients with minor structural damage such as a fragmented sphincter would still benefit from the invention. Not only incontinent patients with a damaged or abnormal internal sphincter can be treated, but also patients with a damaged or abnormal external sphincter since the increase in the internal anal resting tone induced by the invention will compensate for a poorly functioning external sphincter.

Another class of patients who particularly benefit from the invention are post-surgical patients who have had major bowel resection and reanastomosis . For example patients with ileoanal pouch (restorative proctocolectomy) , coloanal (with or without colonic pouch) anostomosis, lower anterior resection, and colectomy with ileorectal anastomosis.

The damage to the sphincter could be caused by trauma, such as experienced in child birth, surgical operations, or road traffic accidents. Furthermore it is also believed that incontinence caused by primary internal anal degeneration can also be relieved by the invention.

Anal leakage also often leads to pruritis of the anus and therefore by reducing or eliminating the leakage, the pruritis or anal itch is also relieved or prevented. Furthermore, as a result of the increased anal resting pressure, the patient no longer has the discomfort of distended anal sphincter muscles.

Methoxamine contains two chiral carbons and thus exists in four isomeric forms. Of all the isomeric forms, the studies revealed (1R,2S)- isomer to be therapeutically active.

US patent 2359707 describes the process for the synthesis of racemic β-(2,5-dimethoxy phenyl)-P-hydroxy-isopropyl amine in neutral, acid salt and its derivative from 2,5- dimethoxy propiophenone by treatment with methylnitrite in diethyl ether medium to obtain 2,5-dimethoxy-a-isonitrosopropiophenone hydrochloride. It is further reduced with palladium on carbon to yield β-(2,5-dimethoxyphenyl)-p-ketoisopropylamine hydrochloride and then with platinum black to get p-(2,5-dimethoxyphenyl)-β- hydroxyisopropyl amine hydrochloride. The described process for di-methoxamine HC1 is not cost-effective, due to the use of two expensive catalysts (platinum black and palladium carbon), solvent diethyl ether and involves more number of steps. The other drawback being it is racemic mixture and cannot be used directly as drug. The process described did not specify the quality of the product.

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In US patent 3284490 the processes for racemic N-alkyl derivatives of methoxamine are described from dl-methoxamine.

JP 63165348 describes process for production of optically active l-(2,5- dimethoxyphenyl)-2-aminophenol by resolving racemic compound with the use of optically active L-N-acetylleucine as resolving agent. The disadvantages of the process are less yield, low quality and use of expensive naturally occurring amino acid, which prevents from employing this method on commercial scale.

WO 03/055474 A1 discloses mainly, the use of (1R, 2S)-methoxamine in the treatment of faecal incontinence at low doses without local or systemic side effects when used topically. The patent also described the synthesis of (1R, 2S)-methoxamine, from L- alanine, by protecting the amino group using methylchloroformate, converting carboxy
group of the N-protected alanine into an acid chloride insitu followed by reaction with an amine to produce an N-protected (S)-alanine amide and coupling that compound with a brominated 2,5-dimethoxybenzene in the presence of n-butyllithium or a magnesium based reagent to give (S)-amino-l-(2,5-dimethoxy-phenyl)-l-propanone, the amino group of which is protected .The reduction of the N-protected propanone was carried out using dimethylphenylsilane and the protecting group was removed by treatment with potassium hydroxide. Other method adopted in the patent to isolate (1R,2S)methoxamine is by separation of racemic methoxamine using chiral column.
STR1
The prior art suffers with some of the disadvantages like using n-butyllithium, which is pyrophoric, expensive and causes hazards to commercial scale. Also, the separation of racemic Methoxamine using chiral column mentioned in the patent can be considered for
isolating small quantities of the required isomer for analytical purposes but cannot be adopted on commercial scale for production of the drug.

US Patent 5962737 described stereospecific synthesis of the racemic threo isomers of 2- nitro-1 -phenylpropanols by reacting benzaldehyde derivative with nitroalkane in the presence of a tertiary amine and reducing 2-nitro-l-phenylpropanols with lithium aluminium hydride to 2-amino-l-phenylpropanols. Also described is phase transfer resolution of racemic mixtures of 2-amino-l-phenylpropanol and its derivatives into their optically pure isomers by reacting with the mono alkali metal salt of tartaric acid ester in a two phase system of a hydrocarbon and water. The specification further describes optically pure isomer D-threo 2-amino-( 1 -dialkoxy or alkoxy)phenylpropanol by resolution of dl- threo 2-amino-( 1 -dialkoxy or alkoxy)phenylpropanol by using dibenzoyltartaric acid. The synthesis of the product (lS,2S)-threo 2-amino-(l-dialkoxy or alkoxy) phenyl propanol involves the use of expensive and hazardous chemicals like LAH making the process technically and commercially difficult for implementation.

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Paper

Journal of the American Chemical Society (1984), 106(16), 4629-30

http://pubs.acs.org/doi/pdf/10.1021/ja00328a062

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PATENT

http://www.google.com/patents/EP2275099A1?cl=en

EXAMPLE 3Synthesis of 1R,2S-Methoxamine(S)-N-Methoxycarbonyl alanine

To a stirred solution of L-alanine (300g, 3.37 mol sodium hydroxide (1N, 1800 cm3) at 0°C in an ice bath was added dropwise, over 2 hours, methyl chloroformate (274 cm3, 3.54 mol). The pH of the solution was maintained at 9 by the addition of sodium hydroxide (5N). The reaction mixture was stirred at 0°C for 3 hours whereupon it was acidified to pH 1 by the addition of phosphoric acid solution (15%) and extracted with diethyl ether (5 x 1000 cm3). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to yield the product as a viscous green oil (386 g, 78%). 1H NMR (250 MHz; C2HCl3) 1.48 (3H, d, J7.25, CH3), 3.72 (3 H, s, COCH3), 4.40 (1 H, quintet, J7.25, CH), 5.31 (1 H, bs, NH).

(S)-N-Methoxycarbonyl alaninedimethylamide

To a stirred solution of MeOC-alanine (227 g, 1.54 mol) and dimethylformamide (DMF) (25 cm3) in dry dichlorourethane (DCM) (2000 cm3) at 0°C was added dropwise oxalyl chloride (146 cm3, 1.62 mol) over a period of 2 hours. The solution was stirred at 0°C until the evolution of gasses ceased whereupon a basic solution of dimethylamine (676 g, 7.70 mol) in NaOH (3 N, 2000 cm3) was added. The aqueous layer was extracted with diethyl ether (2 x 500 cm3) and the combined organic layers dried (MgSO4) and concentrated under reduced pressure to give the product as a white crystalline solid which required no further purification (230 g, 86%). 1H NMR (250 MHz; C2HCl3) 1.33 (3 H, d, J6.75, CH3), 2.99 3 H, s, OCH3) 3.08, (3 H, s, OCH3), 3.66 (3 H, s, COCH3), 4.66 (H, quintet, J7.00, CH), 5.75 (1 H, d, J5.75, NH).

(S)-2-[(Methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanone.

To a THF (1000 cm3) solution of bromo-2,5-dimethoxybenzene (55 g, 0.25 mol) at -20°C under nitrogen was addedn-butyl lithium (100 cm3, 2.5 M in hexanes, 0.25 mol). The mixture was stirred at -20°C for 0.75 hours, whereupon a THF (100 cm3) solution of amide (30 g, 0.17 mol) was added via cannula. The solution was stirred at -20°C for 2 hours and was then allowed to warm to room temperature over 1 hour and quenched by the addition of ammonium chloride solution (700 cm3). The solution was diluted with diethyl ether (1000 cm3) and the organic layer was dried (MgSO4) and concentrated under reduced pressure to give a yellow oil. The product was purified by dry flash chromatography on silica (eluant 4:1 hexane/ethyl acetate then 3:2 hexane/ethyl acetate) to give the product as a white crystalline solid (45 g, 98%). 1H NMR (250 MHz; C2HCl3) 1.36 (3 H, d, J7.0, CH3), 3.70 (3 H, s, COCH3), 3.82 (3 H, s, OCH3), 3.92 (3 H, s, OCH3), 5.43 (1 H, quintet, J 7.3, H-2), 5.80 (1 H, bs, NH), 6.94 (1 H, d, J 9.0, ArH), 7.10 (1 H, dd, J 9.0, 3.3, ArH), 7.32 (1 H, d, J 3.3, ArH).

(1R,2S)-2-[(Methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanol.

To a stirred solution of ketone i.e. (S)-2-[(methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanone (20 g, 74.9 mmol) and dimethylphenyl silane (10.7 g, 78.6 mmol) in dry DCM (500 cm3) at 0°C in an ice bath was added dropwise trithioroacetic acid (TFA) (50 cm3). The solution was stirred at 0°C for 1 h and then quenched by the addition of sodium hydroxide (500 cm3, 1 N). The organic layer was dried and concentrated under reduced pressure to give a yellow oil which solidified on standing. This solid was crystallized from ether/hexane to give the product as a white crystalline solid (15.6 g, 75%).1H NMR (250 MHz; C2HCl3) 1.03 (3 H, d, J7.0, CH3), 3.04 (1 H, d, J4.3, OH), 3.68 (3 H, s, COCH3), 3.78 (3 H, s, OCH3), 3.80 (3 H, s, OCH3), 3.94-3.99 (1 H, m, H-2), 5.05-5.15 (2 H, m, H-1 and NH), 6.72-6.85 (2 H, m, ArH) 6.97 (1 H, d, J 2.0, ArH).

(1,R,2S)-Methoxamine.

To a stirred solution of methoxycarbonyl (MeOC) protected alcohol i.e. (1R,2S)-2-[(methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanol (4.0 g, 14.9 mmol) in methanol (175 cm3) was added a solution of KOH (4.06 g, 72.8 mmol in water (60 cm3). The solution was cooled and acidified with phosphoric acid (15% v/v). The solution was extracted with DCM (2 x 50 cm3) and the aqueous layer basified by the addition of K2CO3. The aqueous layer was extracted with diethyl ether (5 x 50 cm3) and the combined ethereal extracts dried (MgSO4) and concentrated under reduced pressure to give the product as a clear yellow oil (1.9 g, 61%), 1H NMR (250 MHz; C2HCl3) 0.84 (3 H, d, J 7.0, CH3), 3.19-3.22 (1 H, m, H-2), 3.71 (6 H, s, 2 x OCH3), 4.67 (1 H, d, J 5.0, H-1), 6.66-6.72 (2 H, m, ArH), 6.92 (1 H, d, J 2.5, ArH).

(1R, 2S)-Methoxamine hydrochloride.

To an ice cooled solution of (1R,2S)-methoxamine (1.9 g, 9.00 mmol) in anhydrous diethyl ether (30 cm3) was passed a stream of dry HCl gas for 45 mins. The resultant precipitate was filtered by suction, washed with cold diethyl ether and dried under nitrogen to yield the title compound as a white solid. (1.5 g, 68%). 1H NMR (250 MHz; [C2H3]2SO) 0.89 (3 H, d, J 6.8, CH3), 3.37-3.42 (1 H,m,H-2), 3.71 (3 H, s, OCH3), 3.75 (3 H, s, OCH3), 5.12 (1 H, s, H-1), 5.92 (1 H, d, J 4.3, OH), 6.84 (1 H, dd, J 8.8, 3.0, ArH), 6.92-7.00 (2 H, m, ArH); HPLC.

Analytical Method for the Analysis of Methoxamine

The following method was used to analyse methoxamine samples.

Method

  • Column : Cyclobond I RSP 250 x 4.6 mm
    Column temperature : 23°C
    Mobile phase : 0.1% Tetraethylammonium pH 4.1*
    95%v/v
    : Acetonitrile 5%v/v
    Flow rate : 0.6 ml/min
    Solution
    Concentration :
    5 mg/l
    Injection volume : 2.5 µl to 20 µl
    Detection : UV 230 nm
    *Tetraethylammonium acetate pH 4.1 was prepared fresh daily.

Example 2 above allows the complete assignment of the methoxamine isomers as shown below:

Figure imgb0005
Figure imgb0006

PATENT

INDIAN 1020/CHE/2011

BY


The Managing Director of Malladi Drugs & Pharmaceuticals, Prashant Malladi (left), with the Chief Executive Officer, V. N. Gopalakrishnan

V.N Gopalakrishnan

V.N Gopalakrishnan

CEO at Malladi Drugs & Pharmaceuticals Ltd

Prabhakaran Ranganathan

Prabhakaran Ranganathan

Vice President (Operations) at Malladi Drugs and Pharmaceuticals Limited

The present invention further provides an improved process for the preparation of (JS, 2S)-Methoxamine HC1 of formula (6) from (1R, 2S)-methoxamine by treating with acetic anhydride in toluene medium followed by acid hydrolysis and basification to obtain (IS, 2S)-Methoxamine base which is further acidified to form (1S,2S)- Methoxamine HC1 (6).

The present invention further provides an improved process for the preparation of (1R, 2R)-Methoxamine HC1 of formula (5) from its diastereomer (1S, 2R)-methoxamine HC1 of formula (2) by treating with acetic anhydride in toluene medium followed by acid hydrolysis and basification to obtain (1R, 2R)-Methoxamine base which is further acidified to form (1R, 2R)-Methoxamine HC1 (5).

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The following examples illustrate the invention.

EXAMPLES

Example 1
Preparation of l-(2,5-Dimethoxyphenyl)propan-l-one (8)
Aluminium chloride (127.4 g; 0.955 mol) was added to dichloromethane (420 mL) in a round bottomed flask under nitrogen atmosphere. The reaction mixture was cooled to -5 °C; 1,4-dimethoxybenzene (100 g; 0.724 mol) was added slowly within 15-30 minutes. Propionic chloride (87 g; 0.94 mol) dissolved in dichloromethane (245 mL) was added slowly within 2 hours. The reaction mass was allowed to stir for 2 hours and then was quenched in crushed ice (1 kilo) and HC1 (75 mL) at 0 – 5 °C. Separated the layers and the organic layer was washed with 5% sodium hydroxide solution, dried and concentrated (140 g; colorless liquid); Purity by HPLC : 99.04%

Spectroscopic interpretation

The structure of the product, l-(2,5-Dimethoxyphenyl)propan-l-one was confirmed with the help of the following spectroscopic data.

a) IR (cm-1) (KBr)
Aromatic C-H stretch at 3071, aliphatic C – H stretch at 2938, C = O stretch at 1674, benzenoid bands at 1609 and 1584, C – O stretch at 1223, C – H out of plane bending of tri-substituted benzene ring at 814,719.

b) 1H NMR(CDCb, 300 MHz) (δH)
1.16 (3H, t, -CH2-CH3), 3.0 (2H, q, -CH2-CH3), 3.78 (3H, s, -OCH3), 3.85 (3H, s, -OCH3), 6.83 – 7.72 (3H, m, aromatic protons)

c) 13C NMR (CDCb, 300 MHz) (δC)
8.44 (-CH2-CH3), 37.03 (-CH2-CH3), 55.74 (-OCH3), 56.01 (-OCH3), 113.09 – 153.41 (aromatic carbons), 202.96 (C=O)

d) Mass spectrum (ESI, methanol)
[M+Na]+ at m/z 217 (9), [M+H]+ at m/z 195 (100).

Example 2
Preparation of l-(2,5-Dimethoxyphenyl)-2-nitrosopropan-l-one (9) l-(2,5-Dimethoxyphenyl)propan-l-one (100 g; 0.515 mol) was added to dichloromethane (660 mL) in a round bottomed flask under nitrogen atmosphere. Butylnitrite (46.6 g; 0.52 mol) was slowly added in about 30 minutes at 30 – 35 °C. Diethyl ether (60.2 mL) was added to the reaction mixture and dry HC1 gas was purged for about 4 hours at 30 – 35 °C. The reaction mass was maintained for 12 hours and then concentrated under vacuum The residue obtained (60 g; Pale yellow crystalline powder); Purity by HPLC: 99.81%; mp: 104-107 °C

Spectroscopic interpretation

The structure of the product, l-(2,5-Dimethoxyphenyl)-2-nitrosopropan-l-one was confirmed with the help of the following spectroscopic data

a) IR (cm1) (KBr)
O-H stretch at 3250 (broad), aromatic C-H stretch at 3024, aliphatic C – H stretch at 2934, C = O stretch at 1688, C = N stretch at 1645, benzenoid bands at 1589 and 1504, C-O stretch at 1231, C-H out of plane bending of tri-substituted benzene ring at 745,702.

b) 1H NMR(CDCb, 300 MHz) (δh)
2.07 (3H, s, -C-CH3), 3.72 (3H, s, -OCH3), 3.76 (3H, s, -OCH3), 6.84-6.99 (3H, m, aromatic protons), 8.89 (1H, bs, OH)

c) 13C NMR (CDCb, 300 MHz) (δC)
9.16 (-C-CH3), 55.81 (-OCH3), 56.34 (-OCH3), 113.09 – 153.27 (aromatic carbons), 157.07 (C=N-OH); 193.32 (CO)

d) Mass spectrum (ESI, methanol) [M+H]+ at m/z 224 (100)

Example 3
Preparation of dl-erythro-methoxamine HC1 (10)
Raney nickel (50 g); iso-propyl alcohol (250 mL) were added to the autoclave. l-(2,5- Dimethoxyphenyl)-2-nitrosopropan-1 -one (100 g; 0.448 mol) was added slowly at 50 – 55 °C by simultaneously purging the flask with hydrogen at 2-3 Kilo pressure. When hydrogen consumption ceases, the catalyst was filtered and the filtrate was concentrated. iso-Propyl alcohol (200 mL) was added to the concentrated mass followed by acidification with HC1 to obtaindl-erythro-methoxamine HC1 (70 g; white crystalline solid)

Spectroscopic interpretation
The structure of the product, dl-erythro-methoxaxmne HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3409, aromatic C-H stretch at 3010, aliphatic C – H stretch at 2914, HN-H str. at 2574 and 2467, benzenoid bands at 1615 and 1569, C-N stretch at 1279, C-O stretch at 1216, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 812.

b) 1H NMR (DMSO-d6, 300 MHz) (δH)
1.0 (3H,d, -CH-CH3), 3.74 (3H, s, -OCH3), 3.77 (3H, s, -OCH3), 4.89 (1H, q, -CH-CH3),6.1 (1H, d, -CH-OH), 6.87-7.01 (3H, m, aromatic protons), 8.06 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δc)
14.75 (-CH-CH3), 52.12 (-OCH3), 55.70 (-OCH3), 55.70 (-CH-CH3), 67.25 (CH-OH), 111.89 – 153.16 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H)+ at m/z 212 (100), [M-H2O]+ at m/z 194 (56).

Example 4
Preparation of(JR,2S)-Metboxamine HC1 (1) and (1S, 2R)-Methoxamine HC1 (2) dl-erythro-methoxamine HC1 (117g; 0.47 mol) was dissolved in water (350 mL) at 30-35 °C. The clear solution obtained was basified using 50% sodium hydroxide solution. dl-erythro-Methoxaumne (3) was extracted into dichloromethane (150 mL) and concentrated. Mixture of methanol/DMSO (4:1; 1650 mL) was added and the mass was heated to 50 °C. L-(+)-Tartaric acid (71.1g; 0.47mol) was added slowly and the temperature of the mass was further raised to 70 °C for complete dissolution. The mass was cooled to 35 °C and maintained for 48 hours. (IR,2.S)-Methoxamine tartrate complex (80 g) precipitated was filtered. From the filtrate on concentration was obtained (1S,2R)- methoxamine tartrate complex (82 g) (IR,25)-Methoxamine tartrate complex was added to water (250 mL) at 35 °C, basified to 12 – 13 pH with 50% sodium hydroxide solution. Dichloromethane (200 mL) was added and stirred for 30 min. Separated the org layer, dried over sodium sulphate and concentrated completely under vacuum at 45° C. Iso-Propyl alcohol (150 mL) was added, charcaolized and filtered. The clear filtrate was acidified with 20%IPA HC1 to yield (1R, 2S)-Methoxamine HC1 which was filtered and dried (48 g); White crystalline powder; Purity by HPLC : 100%; Chiral purity : 100 %; mp : 172-175 °C; [α]D: -47.94° (c = 2% in MeOH)

Spectroscopic interpretation

The structure of the product, (1R,2S)-Methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3300, aromatic C-H stretch at 3065, aliphatic C-H stretch at 2938, HN-H str. at 2693 and 2580, benzenoid bands at 1609 and 1578, C-N stretch at 1277, C-O stretch at 1217, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 818.

b) 1H NMR (DMSO-d6 300 MHz) (δH)
0.91 (3H,d, -CH-CH3), 3.71 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 5.14 (1H, m, -CH- NH3+), 5.95 (1H, d, -CH-OH), 6.83-7.01 (3H, m, aromatic protons), 8.25 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δC)
II. 44 (-CH-CH3), 49.22 (-OCH3), 55.24 (-OCH3), 55.70 (-CH-CH3), 66.49 (CH-OH),

III. 41 – 153.03 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (15).
(IS, 2i?)-Methoxamine tartrate complex was added to water (275 mL) at 35 °C, basified

to 12 – 13 pH with 50% sodium hydroxide solution. Dichloromethane (250 mL) was added and stirred for 30 min. Separated the organic layer, dried over sodium sulphate and concentrated completely under vacuum at 45 °C. Iso-Propyl alcohol (175 mL) was added, charcaolized and filtered. The clear filtrate was acidified with 20%IPA HC1 to yield (1S, 2R)-Methoxamine HC1 which was filtered and dried (51 g) White crystalline powder; Purity by HPLC : 99.99%; Chiral purity . 100 %; mp . 172-175 °C;[α]D : + 47.9° (c = 2% in MeOH)

Spectroscopic interpretation

The structure of the product, (1S, 2R)-Methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) m (cm1) (KBr)
O-H stretch at 3265, aromatic C-H stretch at 3059, aliphatic C-H stretch at 2997, HN-H str. at 2658 and 2567, benzenoid bands at 1611 and 1587,
C-N stretch at 1294, C-O stretch at 1217, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 818.

b) 1H NMR (DMSO-d6,300 MHz) (δH)
0.91 (3H,d, -CH-CH3), 3.71 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 5.14 (1H, m, -CH- NH3+), 5.97 (1H, d, -CH-OH), 6.83-7.01 (3H, m, aromatic protons), 8.19 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6,300 MHz) (δc)

II. 46 (-CH-CH3), 49.18 (-OCH3), 55.23 (-OCH3), 55.68 (-CH-CH3), 66.45 (CH-OH),

III. 42 – 153.02 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (15).

Example 5
Preparation of dl-threo-methoxamine HC1 (11)
dl-erythro-methoxamine HC1 (120g; 0.48 mol) was dissolved in DM water (500 mL) at 30 – 35 °C and cooled to 10 – 15 °C. The clear solution was basified using 50 % sodium hydroxide solution and extracted in dichloromethane (250 mL). The organic layer was separated and concentrated under vacuum. The residue thus obtained was dissolved in toluene (200 mL) and was added slowly to acetic anhydride (120 g; 1.17mol) at 65 – 70 °C. The reaction mass was maintained under stirring and further cooled to 10 – 20 °C. Conc.Sulphuric acid (57.6g; 0.58mol) was added to the reaction mass slowly by maintaining the reaction mass at 10 – 200 C. The reaction mass was heated to 35 – 400 C for 3 hours and concentrated under vacuum at below 80 °C.

The reaction mass was cooled to 10 – 15 °C and was dissolved in DM water (250 mL). The mass was maintained for 3 h at reflux temperature and again cooled to 10 – 15 °C.

The pH was adjusted to 12 – 13 using 50% sodium hydroxide solution and extracted the d/-threo-Methoxamine base in dichloromethane (250 mL). Separated the organic layer and concentrated under vacuum. The concentrated mass was triturated with iso-Propyl alcohol (150 mL); acidified using 20% HC1 in iso-propyl alcohol. Distilled the iso- propyl alcohol completely to the final traces and acetone (300 mL) was added. The material precipitated, crude dl-threo-methoxamine HC1 was filtered. (85 g) Off white powder; Purity by HPLC: 99.4%; mp: 221-223 °C Spectroscopic interpretation

The structure of the product, di-threo-methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm”1) (KBr)
O-H stretch at 3401, aromatic C-H stretch at 3005, aliphatic C-H stretch at 2924, HN-H str. at 2581 and 2490, benzenoid bands at 1609 and 1578, C-N stretch at 1277, C-0 stretch at 1215, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 802.

b) NMR (DMSO-d6,300 MHz) (δH)
1.2 (3H,d, -CH-CHs), 3.72 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 4.87 (1H, q, -CH-CH3),6.3 (1H, d, -CH-OH), 6.83-6.99 (3H, m, aromatic protons), 8.03 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δC)
14.76 (-CH-CH3), 52.15 (-OCH3), 55.89 (-OCH3), 67.34 (CH-OH), 111.96 – 153.21 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (52).

Example 6
Preparation of (1S,2S)- Methoxamine HC1 (6)
(IR, 2S)-Methoxamine HC1 (120 g; 0.48 mol) was dissolved in DM water (500 mL) at 30 -35 °C and cooled to 10 – 15 °C. The clear solution was basified using 50 % sodium hydroxide solution and extracted in dichloromethane (250 mL). The organic layer was separated and concentrated under vacuum. The residue thus obtained was dissolved in toluene (200 mL) and was added slowly to acetic anhydride (120 g; 1.17 mol) at 65 – 70 °C. The reaction mass was maintained under stirring and further cooled to 10 – 20 °C. Conc.sulphuric acid (57.6 g; 0.58 mol) was added to the reaction mass slowly by maintaining the reaction mass at 10 – 20 °C. The reaction mass was heated to 35 – 40 °C for 3 hours and concentrated under vacuum at below 80 °C.

The reaction mass was cooled to 10-15°C and was dissolved in DM water (250 mL). The mass was maintained for 3 h at reflux temperature and again cooled to 10 – 15 °C. The pH was adjusted to 12-13 using 50% sodium hydroxide solution and extracted the (1S, 2S)-Methoxamine base in dichloromethane (250 mL). Separated the organic layer and concentrated under vacuum The concentrated mass was triturated with iso-Propyl alcohol (150 mL); acidified using 20% HC1 in iso-propyl alcohol. Distilled the iso- propyl alcohol completely to the final traces and acetone (300 mL) was added. The material precipitated, crude (IS, 2S)-methoxamine HC1 was filtered. (86 g); White crystalline powder; Purity by HPLC . 99.8%; Chiral purity : 99.7%; mp : 172-175 °C; [α]D: + 30.739° (c = 2% in MeOH)

Spectroscopic interpretation
The structure of the product, (IS, 2S)-methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3356, aromatic C-H stretch at 3080, aliphatic C-H stretch at 2999, HN-H str. at 2641 and 2583, benzenoid bands at 1611 and 1506, C-N stretch at 1302, C-O stretch at 1229, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 812.

b) 1H NMR (DMSO-d6 300 MHz) (δH)
1.04 (3H,d, -CH-CH3), 3.72 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 4.90 (1H, m, -CH- CH3),6.07 (1H, d, -CH-OH), 6.84-7.01 (3H, d, aromatic protons), 8.15 (3H, bs, HN-H)
The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δC)
14.75 (-CH-CH3), 52.18 (-OCH3), 55.21 (-OCH3), 55.69 (-CH-CH3), 67.32 (CH-OH), 111.38 -153.01 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (48).

Example 7
Preparation of (1R, 2R)-Methoxamine HC1 (5)
(IS, 2R)Methoxamine HC1 (120g; 0.48 mol) was dissolved in DM water (500 mL) at 30 – 35 °C and cooled to 10 – 15 °C. The clear solution was basified using 50 % sodium hydroxide solution and extracted in dichloromethane (250 mL). The organic layer was separated and concentrated under vacuum. The residue thus obtained was dissolved in toluene (200 mL) and was added slowly to acetic anhydride (120 g; 1.17mol) at 65 – 70 °C. The reaction mass was maintained under stirring and further cooled to 10 – 20 °C. Cone.Sulphuric acid (57.6g; 0.58mol) was added to the reaction mass slowly by maintaining the reaction mass at 10 – 20 °C. The reaction mass was heated to 35 – 40 °C for 3 hours and concentrated under vacuum at below 80 °C.

The reaction mass was cooled tol0-15°C and was dissolved in DM water (250 mL). The mass was maintained for 3 h at reflux temperature and again cooled to 10 – 15 °C. The pH was adjusted to 12-13 using 50% sodium hydroxide solution and extracted the (IR, 2i?)-Methoxamine base in dichloromethane (250 mL). Separated the organic layer and concentrated under vacuum. The concentrated mass was triturated with iso-Propyl alcohol (150 mL); acidified using 20% HC1 in iso-propyl alcohol Distilled the iso- propyl alcohol completely to the final traces and acetone (300 mL) was added. The material precipitated, crude (1R, 2R)-methoxamine HC1 was filtered. (90 g) White crystalline powder; Purity by HPLC: 99.1%, Chiral purity. 100%; mp: 172-175 °C;[α]D: -29.04° (c – 2% in MeOH)

Spectroscopic interpretation

The structure of the product, (1R, 2R)methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3356, aromatic C-H stretch at 3078, aliphatic C-H stretch at 2999, HN-H str. at 2619 and 2500, benzenoid bands at 1611 and 1508, C-N stretch at 1302, C-O stretch at 1229, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 812.

b) 1H NMR(DMSO-d6 300 MHz) (δH)
I. 04 (3H,d, -CH-CHa), 3.72 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 4.90 (1H, m, -CH- CH3),6.07 (1H, d, -CH-OH), 6.83-7.01 (3H, d, aromatic protons), 8.13 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6 300 MHz) (δe)
II. 41 (-CH-CH3), 52.16 (-OCH3), 55.22 (-OCH3), 55.70 (-CH-CH3), 67.32 (CH-OH), III. 39-153.15 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (44).

PATENT

http://www.google.com/patents/US8491931

(1,R,2S)-Methoxamine

To a stirred solution of methoxycarbonyl (MeOC) protected alcohol i.e. (1R,2S)-2-[(methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanol (4.0 g, 14.9 mmol) in methanol (175 cm3) was added a solution of KOH (4.06 g, 72.8 mmol in water (60 cm3). The solution was cooled and acidified with phosphoric acid (15% v/v). The solution was extracted with DCM (2×50 cm3) and the aqueous layer basified by the addition of K2CO3. The aqueous layer was extracted with diethyl ether (5×50 cm3) and the combined ethereal extracts dried (MgSO4) and concentrated under reduced pressure to give the product as a clear yellow oil (1.9 g, 61%), 1H NMR (250 MHz; C2HCl3) 0.84 (3H, d, J 7.0, CH3), 3.19-3.22 (1H, m, H-2), 3.71 (6H, s, 2×OCH3), 4.67 (1H, d, J 5.0, H-1), 6.66-6.72 (2H, m, ArH), 6.92 (1H, d, J 2.5, ArH).

(1R,2S)-Methoxamine hydrochloride

To an ice cooled solution of (1R,2S)-methoxamine (1.9 g, 9.00 mmol) in anhydrous diethyl ether (30 cm3) was passed a stream of dry HCl gas for 45 mins. The resultant precipitate was filtered by suction, washed with cold diethyl ether and dried under nitrogen to yield the title compound as a white solid. (1.5 g, 68%). 1H NMR (250 MHz; [C2H3]2SO) 0.89 (3H, d, J 6.8, CH3), 3.37-3.42 (1H,M,H-2), 3.71 (3H, s, OCH3), 3.75 (3H, s, OCH3), 5.12 (1H, s, H-1), 5.92 (1H, d, J 4.3, OH), 6.84 (1H, dd, J 8.8, 3.0, ArH), 6.92-7.00 (2H, m, ArH); HPLC.

//1R,2S-methoxamine

RACEMIC

Methoxamine
Title: Methoxamine
CAS Registry Number: 390-28-3
CAS Name: a-(1-Aminoethyl)-2,5-dimethoxybenzenemethanol
Additional Names: a-(1-aminoethyl)-2,5-dimethoxybenzyl alcohol; 2-amino-1-(2,5-dimethoxyphenyl)-1-propanol; b-hydroxy-b-(2,5-dimethoxyphenyl)isopropylamine; b-(2,5-dimethoxyphenyl)-b-hydroxyisopropylamine; 2,5-dimethoxynorephedrine
Molecular Formula: C11H17NO3
Molecular Weight: 211.26
Percent Composition: C 62.54%, H 8.11%, N 6.63%, O 22.72%
Literature References: a1-Adrenergic agonist. Prepn: Baltzly et al., US 2359707 (1944 to Burroughs Wellcome). Metabolism: A. Klutch, M. Bordun, J. Med. Chem. 10, 860 (1967). Clinical pharmacology: N. T. Smith, C. Whitcher, Anesthesiology 28, 735 (1967); P. D. Snashall et al., Clin. Sci. Mol. Med. 54, 283 (1978). HPLC determn in plasma: I. A. Al-Meshal et al., J. Liq. Chromatogr. 12, 1589 (1989). Therapeutic use: P. M. C. Wright et al., Anesth. Analg. 75, 56 (1992); L. Cabanes et al., N. Engl. J. Med. 326, 1661 (1992). Comprehensive description: A. M. Al-Obaid, M. M. El-Domiaty, Anal. Profiles Drug Subs. 20, 399-431 (1991).
Derivative Type: Hydrochloride
CAS Registry Number: 61-16-5
Trademarks: Vasoxine (Burroughs Wellcome); Vasoxyl (Burroughs Wellcome); Vasylox (Burroughs Wellcome)
Molecular Formula: C11H17NO3.HCl
Molecular Weight: 247.72
Percent Composition: C 53.33%, H 7.32%, N 5.65%, O 19.38%, Cl 14.31%
Properties: Crystals, mp 212-216°. pKa (25°C) 9.2. Very sol in water: One gram dissolves in 2.5 ml water, in 12 ml ethanol. Practically insol in ether, benzene, chloroform. pH of a 2% aq soln between 4.5 and 5.5.
Melting point: mp 212-216°
pKa: pKa (25°C) 9.2
Therap-Cat: Antihypotensive.
Keywords: a-Adrenergic Agonist; Antihypotensive.

Dasotraline, ダソトラリン


Inline image 1

ChemSpider 2D Image | Dasotraline | C16H15Cl2NDasotraline.svgDasotraline.png
(1R,4S)-4-(3,4-Dichlorphenyl)-1,2,3,4-tetrahydro-1-naphthalinamine
1-Naphthalenamine, 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-, (1R,4S)- [ACD/Index Name]
4D28EY0L5T
675126-05-3 [RN]
9885
SEP-225289
UNII:4D28EY0L5T
(1R,4S)-N-DESMETHYL SERTRALINE
(1R,4S)-trans-norsertraline
(1R,4S)-trans-norsertraline|SEP-225289
Dasotraline; 675126-05-3; UNII-4D28EY0L5T; (1R,4S)-trans-Norsertraline; Norsertraline, (1R,4S)-trans-; SEP-225289
ダソトラリン
SEP-225289; SEP-289, DSP-225289

Dasotraline,  SEP-225289, DSP-225289  

1R,4S Transnorsertraline

Generic Name:Dasotraline
Synonym: SEP-225289
Chemical Name:(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine

4(S)-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1(R)-ylamine hydrochloride
CAS Number:675126-05-3, Cas of THE DRUG SUBSTANCE hydrochloride is 675126-08-6
Indication:Attention deficit hyperactivity disorder (ADHD)
Drug Company:Sunovion Pharmaceuticals. Inc. in phase 2 as on sept 2014, Sunovion Pharmaceuticals Inc.

http://www.yaopha.com/2014/09/10/chemical-structures-of-drugs-in-clinical-pipeline-snapshot-sep-2014-yaopha%E4%B8%B4%E5%BA%8A%E8%8D%AF%E7%89%A9%E5%8C%96%E5%AD%A6%E7%BB%93%E6%9E%84%E5%BF%AB%E8%AE%AF/

PRONUNCIATION da soe tra’ leen
THERAPEUTIC CLAIM Treatment of attention deficit hyperactivity
disorder (ADHD)
CHEMICAL NAMES
1. 1-Naphthalenamine, 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-, (1R,4S)-
2. (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine

MOLECULAR FORMULA C16H15Cl2N
MOLECULAR WEIGHT 292.2

SPONSOR Sunovion Pharmaceuticals. Inc.
CODE DESIGNATION SEP-225289
CAS REGISTRY NUMBER 675126-05-3
UNII 4D28EY0L5T
WHO NUMBER 9885

SEP-225289 is an antidepressant which had been in early clinical trials at Sepracor (now Sunovion Pharmaceuticals) for the treatment of major depressive disorder (MDD). In 2010, the company discontinued development of the compound for this indication. At present, phase II clinical trials are under way for the treatment of attention deficit/hyperactivity disorder (ADHD). In preclinical studies, the drug has been shown to be a potent and balanced reuptake inhibitor of serotonin, norepinephrine and dopamine (SNDRI). A drug candidate with a triple mechanism of action as such may provide a broader spectrum of therapy than currently marketed antidepressants.

Recently, drug candidates for blocking the monoamine reuptake transporters have sparked considerable interest in the pharmaceutical industry for treatment of central nervous system disorders. Various candidates are in clinical evaluation in addition to numerous others at the preclinical stage. Sertraline 2 is a selective serotonin reuptake inhibitor (SSRI), marketed by Pfizer as Zoloft for depression. (1R,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride 1 is structurally similar to sertraline 2 and is currently under investigation for a number of potential central nervous system disorder indications at Sepracor.

Figure

ABOUT SERTRALINE

Sertraline2DACS2.svg

Sertraline-A-3D-balls.png
(1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine

SERTRALINE

Clinicians recognize a distinction among central nervous system illnesses, and there have been many schemes for categorizing mental disorders. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed., Text Revision, (hereinafter, the “DSM-IV-TR™”), published by the American Psychiatric Association, and incorporated herein by reference, provides a standard diagnostic system upon which persons of skill rely. According to the framework of the DSM-IV-TR™, the CΝS disorders of Axis I include: disorders diagnosed in childhood (such as, for example, attention deficit disorder or “ADD” and attention deficit / hyperactivity disorder or “ADHD”) and disorders diagnosed in adulthood. CΝS disorders diagnosed in adulthood include

(1) schizophrenia and psychotic disorders; (2) cognitive disorders;(3) mood disorders; (4) anxiety related disorders; (5) eating disorders; (6) substance related disorders; (7) personality disorders; and (8) “disorders not yet included” in the scheme.

Of particular interest to the present invention are adulthood disorders of DSM-IN-TR™ categories (1) through (7) and sexual disorders, currently classified in category (8). Mood disorders of particular interest include depression, seasonal affective disorder and bipolar disorder. Anxiety related disorders of particular interest are agoraphobia, generalized anxiety disorder, phobic anxiety, obsessive compulsive disorder (OCD), panic disorder, acute stress disorder, posttraumatic stress disorder, premenstrual syndrome, social phobia, chronic fatigue disorder, perimenopause, menopause and male menopause.

In general, treatment for psychoses, such as schizophrenia, for example, is quite different than treatment for mood disorders. While psychoses are treated with D2 antagonists such as olanzapine (the “typical” and “atypical” antipsychotics), mood disorders are treated with drugs that inhibit the neuronal reuptake of monoamines, in particular, serotonin (5-HT), norepinephrine (ΝE) and dopamine (DA).

[005] Common therapeutic agents for mood disorders include, but are not limited to, selective serotonin reuptake inhibitors (SSRI’s), including fluoxetine, citalopram, nefazodone, fluvoxamine, paroxetine, and sertraline.

Sertraline, whose chemical name (lS,4S)-c/5 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-Ν-methyl-l-napthalenamine, is approved for the treatment of depression by the United States Food and Drug Administration, and is available under the trade name ZOLOFT® (Pfizer Inc., NY, NY, USA). In the human subject, sertraline has been shown to be metabolized to (lS,4S)-c« 4- (3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-napthalenamine, also known as desmethylsertraline or norsertraline. Desmethylsertraline has been described as “not contributing significantly to the serotonergic action of sertraline” Ronfield et al, Clinical Pharmacokinetcs, 32:22-30 (1997). Reports from Hamelin et al, Clinical Pharmacology & Therapeutics, 60:512 (1996) and Serebruany et al, Pharmacological Research, 43:453-461 (2001), have stated that norsertraline is “neurologically inactive”. These statements appear to be based on results observed in serotonin-induced syndrome and ptosis in mouse models in vivo, whereas the original Pfizer research papers suggested on the basis of data in vitro that desmethylsertraline was a selective serotonin uptake inhibitor. Koe et al, JPET, 226:686-700 (1983). Sanchez et al, Cellular and Molecular Neurobiology, 19: 467 (1999), speculated that despite its lower potency, desmethylsertraline might play a role in the therapeutic effects of sertraline but, there is presently no evidence in the literature to support this theory.

] The primary clinical use of sertraline is in the treatment of depression. In addition, United States Patent 4,981,870 discloses and claims the use of sertraline and norsertraline, as well as (lR,4S)-trans 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-N-methyl-l-napthalenamine and (lS,4R)-trαra 4-(3 ,4- dichlorophenyl)- 1 ,2,3 ,4-tetrahydro-N-methyl- 1 -napthalenamine for the treatment of psychoses, psoriasis, rheumatoid arthritis and inflammation. The receptor pharmacology of the individual (1S,4R) and (1R,4S) enantiomers of trα«5 4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l -napthalenamine is described by Welch et al, J. Med. Chem., 27:1508-1515 (1984). Summary of the Invention

It has now been discovered that {\R,4S)-trans 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-l-napthalenamine (P) and (lS,4R)-tra«_ 4-(3 ,4- dichlorophenyl)- 1,2,3, 4-tetrahydro-l-napthalenamine (Q) are useful in the treatment of CNS-related disorders that are modulated by monoamine activity, and produce diminished side effects as compared to the current standards of treatment. Treatable CNS disorders include, but are not limited to, mood disorders {e.g., depression), anxiety disorders {e.g., OCD), behavioral disorders {e.g., ADD and ADHD), eating disorders, substance abuse disorders and sexual function disorders. The compounds are also useful for the prophylaxis of migraine.

Compounds P and Q are represented by the formulae:

Figure imgf000005_0001

In one aspect, the present invention relates to a method for treating CNS disorders, which involves the administration of a therapeutically effective amount of P or Q, or a pharmaceutically acceptable salt of either.

In another aspect, the invention relates to trans- 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-l-napthalenamine of the formula (PQ):

NH2

Figure imgf000006_0001

(PQ)

Skeletal formulae of chlorprothixene and tametraline, from which sertraline was derived

Norsertraline, sertraline’s chief active metabolite

………………………………………..

PATENT

http://www.google.com/patents/US20090149549

(Scheme 2).

Figure US20090149549A1-20090611-C00025

In a preferred embodiment, the compound prepared by the route of Scheme 2 is (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine. Even more preferred is the preparation of the compound substantially free of its cis isomer.

Example 1

Synthesis of N—((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1-yl)acetamide (3)1.1. Synthesis of Oxime 2

A suspension formed from a mixture of (S)-tetralone 1 (56.0 g, 0.192 mol), hydroxylamine hydrochloride (14.7 g, 0.212 mol), and sodium acetate (17.4 g, 0.212 mol) in methanol (168 mL) was heated to reflux for 1 to 5 hours under a N2atmosphere. The progress of the reaction was monitored by HPLC. After the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was diluted with toluene (400 mL) and 200 mL water. The organic layer was separated and washed with an additional 200 mL water. The organic layer was concentrated and dried to give crude solid oxime 2 (58.9 g, 100%), m. p. 117-120° C.

1H NMR (400 MHz, CDCl3) δ (ppm) 9.17 (br, 1H, OH), 7.98 (m, 1H), 7.36 (d, 1H, J=8.0 Hz), 7.29 (m, 2H), 7.20 (d, 1H, J=2.4 Hz), 6.91 (m, 2H), 4.11 (dd, 1H, J=7.2 Hz, 4.4 Hz), 2.82 (m, 2H), 2.21 (m, 1H), 2.08 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 154.94, 144.41, 140.40, 132.83, 130.92, 130.82, 130.68, 130.64, 129.98, 129.38, 128.12, 127.64, 124.48, 44.52, 29.51, 21.27.

1.2. Synthesis of Enamide 3

The solution of the crude oxime 2 (59 g, 0.193 mol) in toluene (500 mL) was purged with N2 for 30 min. Et3P (25 g, 0.212 mol) was charged. After stirring for 10 min, acetic anhydride (21.6 g, 20 mL, 0.212 mol) was added. The reaction mixture was refluxed for 8 to 13 h. Progress of the reaction was monitored by HPLC. The reaction mixture was cooled to room temperature. 6N NaOH (aq) (86 mL, 0.516 mol) and 1.0 M (n-Bu)4NOH in methanol (1.0 mL) were added. The hydrolysis was complete in about 2 to 4 h. The organic layer was separated and diluted with EtOAc (300 mL) and 2-BuOH (30 mL). The diluted organic solution was washed with 1% HOAc (aq) solution (300 mL) and DI water (3×300 mL) and concentrated to about 350 mL of a slurry in vacuo. The slurry was diluted with heptane (100 mL) and 2-BuOH (4 mL) and heated to reflux to form a clear solution. Heptane (50 to 200 mL) was slowly added until a cloudy solution formed. The suspension was slowly cooled to rt. The product was filtered out, washed with 30% toluene and 70% heptane (3×100 mL) solution and dried in a vacuum oven to give 56.9 g white solid (enamide 3, 89% yield), m. p. 167-168° C.

(S)-Tetralone 1 (50.0 g, 0.172 mol) was slurried in methanol (150 mL) with hydroxylamine hydrochloride (13.1 g, 0.189 mol) and sodium acetate (15.5 g, 0.189 mol). The resulting suspension was heated to reflux for 2 to 6 h under an inert atmosphere with progress monitored by HPLC. On completion, the mixture was cooled to 25° C., diluted with toluene (300 mL) and quenched with 1.7 N NaOH (100 mL). The mixture was concentrated in vacuo under reduced pressure, the aqueous layer removed and the organic layer washed further with DI water (100 mL). Further toluene (300 mL) was charged to the vessel and water removed by azeotropic distillation. Once at ambient temperature, n-Bu3P (47.1 mL, 0.183 mol) was charged to the reactor, followed by acetic anhydride (32.5 mL, 0.344 mol). The reaction was heated to reflux and monitored by HPLC. After 20-24 h, the reaction was cooled to ambient temperature and quenched with 6 N NaOH (120 mL). This mixture was allowed to react for 2 to 6 h before the aqueous layer was removed. The organic phase was washed with DI water (100 mL). Concentration of the mixture in vacuo, cooling to room temperature and diluting with isopropanol (50 mL) was done prior to addition of heptane to assist with crystallization. An initial charge of heptane (50 mL) was followed by an additional 650 mL. Aging of the slurry followed by filtration, washing (4×100 mL heptane) and drying yielded a light yellow solid (enamide 3, 44.1 g, 77%).

1H NMR (400 MHz, CDCl3) δ (ppm) 7.35 (d, 1H, J=8.4 Hz), 7.26 (m, 3H), 7.17 (m, 1H), 7.05 (dd, 1H, J=8.0, 1.6 Hz), 7.00 (br, 1H), 6.87 (m, 0.82H, 82% NH rotamer), 6.80 (br, 0.18H, 18% NH rotamer), 6.31 (t, 0.82H, J=4.8 Hz, 82% H rotamer), 5.91 (br, 0.18H, 18% H rotamer), 4.12 (br, 0.18H, 18% H rotamer), 4.03 (t, 0.82H, J=8.0 Hz, 82% H rotamer), 2.72 (m, 1H), 2.61 (ddd, 1H, J=16.8, 8.0, 4.8 Hz), 2.17 (s, 2.46H, 82% CH3 rotamer), 1.95 (s, 0.54H, 18% CH3 rotamer). 100 MHz13CNMR (CDCl3) δ 169.3, 143.8, 137.7, 132.3, 131.8, 131.4, 130.5, 130.3, 130.2, 128.8, 128.1, 127.8, 127.2, 123.8, 122.5, 121.2, 117.5, 42.6, 30.3, 24.1.

Example 2Synthesis of N-((1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (4)

The enamide 3 (24 g, 72 mmol) was slurried in degassed isopropanol (200 mL). The resulting slurry was transferred to the appropriate reactor. Prior to the addition of the catalyst solution, the content of the reactor was purged with nitrogen. A solution of (R,R)-MeBPE(COD)RhBF4 catalyst (20.1 mg, 0.036 mmol, 0.05 mol %) in isopropanol (IPA) (100 mL) was added to the reactor. The content was cooled to 0° C. and purged with nitrogen three times. The reactor was then purged with hydrogen and pressurized to 90 psig. The reaction was aged with agitation at 0° C. for 7.5 h and conversion was monitored by the hydrogen uptake. The content was then warmed to RT and hydrogen was vented. After purging with nitrogen, the contents were drained. The reaction mixture was heated to 50° C. and filtered through a pad of Celite. The clear orange solution was concentrated to ˜50% volume (150 mL) and diluted with toluene (5.9 g, 5 wt %). The suspension was heated to 65° C. and water (14.7 mL) was added dropwise to form a cloudy solution. The slurry was slowly cooled to −10° C. and aged for 30 minutes. The solid was filtered and washed with cold IPA (2×45 mL). The cake was dried under vacuum at 45° C. overnight to afford 20.0 g (83% yield) of trans acetamide 4 (>99% de).

1H NMR (CDCl3) 400 MHz δ 7.34 (dd, 2H, J=7.9, 2.4 Hz), 7.23 (t, 1H, J=7.5 Hz), 7.15 (m, 2H), 6.85 (dd, 1H, J=8.2, 2.0 Hz), 6.82 (d, 1H, J=7.7 Hz), 5.72 (d, 1H, J=8.4 Hz), 5.31 (dd, 1H, J=13.2, 8.1 Hz), 4.10 (dd, 1H, J=7.0, 5.9 Hz), 2.17 (m, 2H), 2.06 (s, 3H), 1.87 (m, 1H). 1.72 (m, 1H); 13C NMR (CDCl3) 100 MHz δ 169.7, 146.9, 138.8, 137.7, 132.6, 130.8, 130.6, 130.5, 130.3, 128.4, 128.3, 127.9, 127.4, 47.9, 44.9, 30.5, 28.4, 23.8.

Example 3

Synthesis of (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine Hydrochloride (5)

A solution of trans-acetamide 4 (9.0 g, 26.9 mmol), n-propanol (45 mL) and 5M hydrochloric acid (45 mL) was refluxed for approximately 48 h (90-93° C.). During this time, the reaction temperature was maintained at ≧90° C. by periodically collecting the distillate until the reaction temperature was >92° C. Additional n-propanol was added periodically to maintain the solution at its original volume. After the hydrolysis was complete, the solution was slowly cooled to 0° C., resulting in a slurry, which was aged for one hour at 0° C. The reaction mixture was filtered, and the cake was washed with 1:1 methanol/water (20 mL), followed by t-butyl methyl ether (20 mL). The wet-cake was dried under vacuum at 45 to 50° C. to afford 7.0 g of the amine hydrochloride 5 (80% yield).

1H NMR (DMSO-d6) δ 1.81-1.93 (m, 2H), 2.12-2.21 (m, 1H), 2.28-2.36 (m, 1H), 4.28 (t, 1H, J=6.8), 4.59 (br.s, 1H), 6.84 (d, 1H, J=7.6), 7.05 (dd, 1H, J=8.4, 1.6), 7.25 (t, 1H, J=7.6), 7.32 (t, 1H, J=7.6), 7.37 (d, 1H, J=1.6), 7.56 (d, 1H, J=8.4), 7.76 (d, 1H, J=7.2), 8.80 (br.s, 3H);

13C NMR (DMSO-d6) 147.4, 138.9, 133.6, 131.0, 130.5, 130.4, 130.1, 129.0, 128.9, 128.4, 128.2, 126.8, 47.9, 43.1, 27.8, 25.2.

INTERMEDIATE

Example 5 Catalytic Asymmetric Hydrogenation of the Enamide 3 Using (R,S,R,S)-MePenn Phos(COD)RhBF4 as the Catalyst

As shown in Scheme 4, the enamide 3 was subjected to homogeneous catalytic asymmetric hydrogenation in the presence of a chiral catalyst, H2, and a solvent. In this example the catalyst was derived from the complex of the transition metal rhodium with the chiral phosphine ligand, (1R,2S,4R,5S)—P,P-1,2-phenylenebis {(2,5-endo-dimethyl)-7-phosphabicyclo[2.2.1]heptane}(R,S,R,S-MePennPhos). The hydrogenations were carried out at a substrate concentration of about 0.12 M to about 0.24 M of compound 3.

Figure US20090149549A1-20090611-C00043

………………………………………..

Koenig, Stefan G.; Vandenbossche, Charles P.; Zhao, Hang; Mousaw, Patrick; Singh, Surendra P.; Bakale, Roger P.
Organic Letters, 2009 ,  vol. 11,  2  pG . 433 – 436

http://pubs.acs.org/doi/abs/10.1021/ol802482d

Abstract Image

Imidoyl chlorides, generated from secondary acetamides and oxalyl chloride, can be harnessed for a selective and practical deprotection sequence. Treatment of these intermediates with 2 equiv of propylene glycol and warming enables the rapid release of amine hydrochloride salts in good yields. Notably, the reaction conditions are mild enough to allow for a swift deprotection with no observed epimerization of the amino center.

Supporting Information             A Facile Deprotection of Secondary Acetamides

http://pubs.acs.org/doi/suppl/10.1021/ol802482d/suppl_file/ol802482d_si_001.pdf

(1R,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride – Compound 1, Scheme 1 / Table 3, entry 1A:

decomp. > 290 °C.

1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 3H), 7.71 (d, 1H, J = 7.7 Hz), 7.53 (d, 1H, J = 8.1 Hz), 7.34 (s, 1H),
7.29 (m, 1H), 7.22 (m, 1H), 7.01 (d, 1H, J = 8.1 Hz), 6.81 (d, 1H, J = 7.7 Hz), 4.56 (s,
1H), 4.26 (s, 1H), 2.26 (m, 1H), 2.15 (m, 1H), 1.83 (m, 2H).

13C NMR (100 MHz, DMSO-d6) δ 147.3, 138.8, 133.5, 130.9, 130.5, 130.4, 130.0, 128.9, 128.8, 128.3, 128.1,
126.7, 47.8, 43.0, 27.7, 25.1.

NMR  GRAPHS GIVEN

Inline image 1

13 C NMR

Inline image 2

………………………………………..

Jerussi, T. P.; Fang, Q. K.; Currie, M. G. PCT Int. Appl. WO 2004042669 A1 200440325, 2004.

http://www.google.com/patents/WO2004024669A1?cl=en

Figure

The discovery route involved preparation of (S)-tetralone (4S)-3 from racemic tetralone(4RS)-3 via chromatographic separation of sulfinyl imine (Rs,4RS)-5 diastereomers, followed by hydrolysis. The sulfinyl imine isomers were generated by condensation with (R)-tert-butylsulfinamide ((R)-TBSA), (Rs)-4, in the presence of titanium ethoxide. The yield of sulfinyl imine diastereomer (Rs,4S)-5 was ∼15% after chromatographic purification. The low recovery yield was due to chromatographic loss and the instability of compound 5 on silica gel. The resulting (S)-tetralone (4S)-3 was converted to N-formyl amine (1RS,4S)-6 as a mixture of two diastereomers that were again separated by chromatography to afford the desired diastereomer(1R,4S)-6 in 17% yield over two steps. (1R,4S)-trans-norsertraline 1 was obtained after the acidic hydrolysis of (1R,4S)-6 in 71% yield. The overall yield of this route was less than 2% and involved two chromatographic purifications, making it impractical for an efficient large-scale synthesis of 1.

Jerussi, T. P.; Fang, Q. K.; Currie, M. G. PCT Int. Appl. WO 2004042669 A1 200440325, 2004.http://www.google.com/patents/WO2004024669A1?cl=en

……………………………………………

PAPER

Development of a large-scale stereoselective process for (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride
Org Process Res Dev 2007, 11(4): 726

http://pubs.acs.org/doi/abs/10.1021/op7000589

Abstract Image

A convenient, multikilogram-scale, stereoselective process for the synthesis of (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride 1 is described. The key steps involve synthesis of sulfinyl imine (Rs,4S)-5 from (S)-tetralone (4S)-3 and (R)-tert-butylsulfinamide (Rs)-4, and its stereoselective reduction with 9-BBN to produce the (1R)-amine center of 1. The process has been scaled up to multikilogram scale and gives 1 in an overall yield of >50% with a chemical purity of 99.7 A% by HPLC and stereochemical purity of >99.9% by chiral HPLC.

(1R,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-ylamine HCl (1).
 
1H NMR (400 MHz, DMSO-d6) δ 1.81−1.93 (m, 2H), 2.12−2.21 (m, 1H), 2.28−2.36 (m, 1H), 4.28 (t, 1H, J = 6.8 Hz), 4.59 (br s, 1H), 6.84 (d, 1H, J = 7.6 Hz), 7.05 (dd, 1H, J = 8.4, 1.6 Hz), 7.25 (t, 1H, J = 7.6 Hz), 7.32 (t, 1H, J = 7.6 Hz), 7.37 (d, 1H, J = 1.6 Hz), 7.56 (d, 1H, J = 8.4 Hz), 7.76 (d, 1H, J = 7.2 Hz), 8.80 (br s, 3H).
 
13C NMR (100 MHz, DMSO-d6) δ 147.4, 138.9, 133.6, 131.0, 130.5, 130.4, 130.1, 129.0, 128.9, 128.4, 128.2, 126.8, 47.9, 43.1, 27.8, 25.2.
 
Anal. Calcd for C16H15Cl2N:  C, 58.47; H, 4.91; N, 4.26; Cl, 32.36. Found:  C, 58.44; H, 4.79; N, 4.21; Cl, 32.53.

……………………………………………………………..

WO 2004024669

http://www.google.com/patents/WO2004024669A1?cl=en

Preparation of compounds of the present invention is illustrated below in Scheme 1 and its accompanying narrative.

Figure imgf000007_0001

[0015] In the compound

Figure imgf000008_0001

of Scheme 1,

R is R,° , wherein R1, R2 and R3 are each independently alkyl. In a preferred embodiment of the compounds, R is tert-butyl.

[0016] N-[4-(3 ,4-dichlorophenyl)- 1 ,2,3 ,4-tefrahydronaphthalen- 1 -yl]formamide, the intermediate in the synthesis shown in Scheme 1 , exists in four stereoisomeric forms:

Figure imgf000008_0002

C (1S,4S) D (1R.4R) [0017] When N-[4-(3 ,4-dichlorophenyl)- 1 ,2,3,4-tetrahydronaρhthalen-l – yl]formamide is synthesized from achiral starting materials via non- stereoselective syntheses, all four isomers will be produced. The mixture can be readily separated into a racemic cis diastereomer and a racemic trans diastereomer by means, such as recrystallization or chromatography on achiral media, that rely on chemical and physical differences.

[0018] The trans diastereomer, represented as E below, is a 1 :1 mixture of A and B. When E is hydrolyzed, PQ is produced; when A is hydrolyzed, P is produced; when B is hydrolyzed, Q is produced. The cis diastereomer, represented as F below, is a 1 : 1 mix of C and D.

Figure imgf000009_0001

E = A + B F = C + D

……………………………………………………………………………………………

WO 2007006003

http://www.google.com/patents/WO2007006003A2?cl=en

Figure imgf000027_0001

Scheme 3

Production (lR,4S)-4-(3,4-dichloro-phenyl)-l,2,3,4-tetrahydro-naphthalen-l-ylamine HCl from 4-(S)-(3,4-dichloro-phenyl)-3,4-dihydro-2H-naphthalen-l-one.

Figure imgf000031_0001

(S)-(3,4-Dichloro-phenyl)-3,4- (1 R,4S)-4-(3,4-Dichloro-phenyl)-1 ,2,3,4-tetrahydro- d ιhydro-2H-naphthalen-1 -one naphthalen-1 -ylamine; [0080] Charge 4-(S)-(3,4-dichloro-phenyl)-3,4-dihydro-2H-naρhthalen-l-one (1 kg, 3.4 mol) and (R)-tert-butylsulphinamide (TBSA, 464 g, 3.8 mol) to a suitable reactor and dissolved in about 7 L THF. Add a 20%wt solution of Titanium ethoxide in ethanol (about 7.8 kg, 6.9 mol) and heat the mixture to about 70 0C for about 24h. The reaction is monitored by HPLC, and after the reaction is complete, cool the mixture to room temperature and added a 24% wt aqueous solution of NaCl to the mixture. The resultant slurry was filtered and washed multiple times with about 1 L total of ethyl acetate. The mother liquors and washes were concentrated to a minimum volume. The aqueous phase was extracted with about 5 L of ethyl acetate and evaporated to dryness.

[0081] The contents were then dissolved in about 7 L of THF and cooled to about —10 0C. About 9 kg, (~5 mol) of a 0.5 M solution of 9-borabicycIononane (9-BBN) in THF, was added slowly (about 3h) and the mixture was stirred at 0 0C until reaction completion. A 6N HCl/methanol (~2L) was added to the mixture and stirred until the hydrolysis reaction was complete. After neutralization with about 2 L of 6N aqueous NaOH, the mixture was distilled to remove THF and the residue (aqueous phase) was extracted twice with methyl t- butyl ether (2x6L). The organic phase was then washed with water. The organic phase was concentrated, then cooled to 00C followed by addition of 2N HCl in methyl t-butyl ether (3 L). The product slowly precipitated as the HCl salt during the addition. The slurry was filtered and washed with methyl t-butyl ether (2x2L). The product was dried under vacuum at about 45°C to afford about 850 g of Re-Crystallization of crude (lR,4S)-4-(3,4-dichloro-phenyl)- 1,2,3,4-tetrahydro-naphthalen-l-ylamine HCl.

[0082] The resulting (lR,4S)-4-(3,4-dichloro-phenyl)-l,2,3,4-tetrahydro- naphthalen-1-ylamine HCl (85Og) was charged to a suitable reactor and about 30 L of denatured ethanol was added. The mixture was heated to reflux, the volume was reduced to about 50% via distillation, and then cooled to 50°C. About 30 L of Hexane was added to the slurry to complete the product crystallization and then the slurry was cooled to about 00C. The product was isolated by filtration, the cake was washed with about 2 L of ethanol/hexane (1/3 v/v) and then about 2 L of ethyl acetate, followed by about 3 L of hexane. The wet cake was dried under vacuum at about 45°C to afford 630 g of product.

[0083] Another alternative process for preparation of compound P is presented below.

[0084] 4-(S)-(3,4-dichloro-phenyl)-3,4-dichloro-2H-naphthalen-l-one (4.11 kg) and (R)-tert-butylsulphinamide (TBSA, 1.9 kg) were charged to a suitable reactor and dissolved in 29 L THF. A 20%wt solution of titanium ethoxide in ethanol (31.6 kg) was added and the mixture was heated to 70 °C with stirring. The reaction is monitored by HPLC, and after the reaction was complete (20-24 h) the mixture was cooled to room temperature and added to 20 L of a 24 wt% aqueous solution of NaCl. The resultant slurry was filtered and washed 3 times with ethyl acetate (4.1 L). The mother liquors and washes were concentrated to a minimum volume. The aqueous phase was extracted with about 20 L of a 1 :1 mix of ethyl acetate and toluene. The organic phases were combined and concentrated to half volume to give a solution of 2. A purified sample of 2 was analyzed: m.p. 104 0C, 1HNMR (400 MHz, CDCl3) δ (ppm) 8.23 (dd, IH, J= 7.9, 0.9 Hz), 7.38 (ddd, IH, J= 14.7, 7.3, 1.5 Hz), 7.37 (d, IH, J= 8.4 Hz), 7.33 (d, IH, J= 7.7 Hz), 7.17 (d, IH, J= 1.8 Hz), 6.93 (d, IH, J= 7.7 Hz), 6.89 (dd, IH, J= 8.4, 2.2 Hz), 4.18 (dd, IH, J= 7.3, 4.8 Hz), 3.36 (ddd, IH, J= 17.5, 8.8, 4.4 Hz), 2.93 (ddd, IH, J= 17.6, 8.3, 4.2 Hz), 2.33 (m, IH), 2.15 (m, IH), 1.34 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 175.8, 144.2, 142.7, 132.6, 130.8, 130.7, 129.7, 128.1, 127.6, 127.4, 57.8, 44.3, 31.1, 29.4, 22.8. HRMS calc for C20H2ICl2NOS 394.0799, found 394.0767.

[0085] The solution of imine (2) was cooled to -10 0C and 36.3 kg of a 0.5 M solution of 9-borabicyclononane (9-BBN) in THF, was added slowly (over 3h) and the mixture was stirred at 0 0C until reaction completion. A 4N HCl/methanol (8 L) was added to the mixture and stirred until the hydrolysis reaction was complete. After neutralization with about 15 kg of 6N aqueous NaOH (pH 8), the mixture was distilled to remove THF and methanol. The residue (aqueous phase) was extracted twice with methyl t-butyl ether (2 x 16L). The organic phase was then washed with water. The organic phase was concentrated, then cooled to 00C followed by addition of 2N HCl in methyl t- butyl ether (5.4 kg). The product precipitated as the HCl salt. The slurry was filtered, washed with methyl t-butyl ether (2 x 8L) and dried under vacuum at 450C to afford about 3.73 kg of crude (lR,4S)-4-(3,4-dichloro-phenyl)-l,2,3,4- tetrahydro-naphthalen-1-ylamine HCl (compound P).

A purified sample of P was analyzed:  NOTE P IS DASOTRALINE

m.p. 152 – 154 0C,

1H NMR (400 MHz, CDCl3) δ (ppm) 7.58 (d, IH, J= 7.7 Hz), 7.29 (m, 2H), 7.18 (br. t, IH, J= 7.5 Hz), 7.09 (d, IH, J= 1.8 Hz), 6.87 (d, IH, J= 7.7 Hz), 6.80 (dd, IH, J= 8.3, 2.0 Hz), 4.65 (dd, IH, J= 4.4, 4.4 Hz), 4.15 (t, IH, J= 5.5 Hz), 3.30 (d, IH, J= 3.7 Hz), 2.35 (m, IH), 1.95 (m, IH), 1.85 (m, IH), 1.75 (m, IH), 1.23 (s, 9H).

13C NMR (100 MHz, CDCl3) δ 147.1, 138.4, 138.0, 132.6, 130.8, 130.6, 130.5, 129.8, 128.3, 127.9, 55.8, 53.3, 44.0, 28.2, 27.7, 22.9.

HRMS calc for C20H23Cl2NOS 396.0956, found 396.0968.

[0086] The crude (lR,4S)-4-(3,4-dichloro-phenyl)-l,2,3,4-tetrahydro- naphthalen-1-ylamine HCl (3.63 kg) was charged to a suitable reactor and 128 L of denatured ethanol was added. The mixture was stirred at reflux and polish filtered. The volume was reduced to about 50% via distillation, and then cooled to 500C. 80 L of heptane was added to the slurry to complete the product crystallization and then the slurry was cooled to -5 °C. The product was filtered, the cake was washed twice with 5.7 L of ethanol/heptane (1/1 v/v) and then washed with 6 L of hexane. The wet cake was dried under vacuum at about 45°C to afford 2.57 kg of product. The product had a chemical purity of 99.65 A% and a diastereomeric purity in excess of 99%

…………………………………………………………………………

PATENT

WO 2011069032

http://www.google.com/patents/WO2011069032A2?cl=en

Transnorsertraline, i. e. , (1 R,4S)-trans-4-(3 ,4-dichlorophenyl)- 1 ,2,3 ,4-tetrahydro- 1 – naphthalenamine and (lS,4R)-trans-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l- naphthalenamine are described in, for example, U.S. Patent No. 7,087,785 B2 (“the ‘785 patent”; incorporated herein by reference in its entirety), have the following chemical structures, respectively:

Figure imgf000002_0001

Uses of transnorsertraline in the treatment, prevention, or management of affective disorders and other various CNS disorders are also disclosed in the ‘785 patent. Such disorders include, but are not limited to, depression, mood disorders, anxiety disorders, behavioral disorders, eating disorders, substance abuse disorders, and sexual function disorders.

ref

A Randomized, Double-Blind, Parallel-Group, Multicenter Efficacy and Safety Study of SEP-225289 Versus Placebo in Adults With Attention Deficit Hyperactivity Disorder (ADHD) (NCT01692782)
ClinicalTrials.gov Web Site 2012, September 27

Characterization of the electrophysiological properties of triple reuptake inhibitors on monoaminergic neurons
Int J Neuropsychopharmacol 2011, 14(2): 211

PET evaluation of serotonin and dopamine transporter occupancy associated with administration of SEP-225289
Biol Psychiatry 2010, 67(9, Suppl. 1): Abst 102
[65th Annu Meet Soc Biol Psychiatry (SOBP) (May 20-22, New Orleans) 2010]

Koenig, Stefan G.; Vandenbossche, Charles P.; Zhao, Hang; Mousaw, Patrick; Singh, Surendra P.; Bakale, Roger P.
Organic Letters, 2009 ,  vol. 11, (2)  pg 433 – 436

Thalen, Lisa K.; Zhao, Dongbo; Sortais, Jean-Baptiste; Paetzold, Jens; Hoben, Christine; Baeckvall, Jan-E.
Chemistry – A European Journal, 2009 ,  vol. 15, ( 14)  pg. 3403 – 3410

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US20060257475 * Aug 17, 2006 Nov 16, 2006 Boehringer Ingelheim International Gmbh Stable Sertraline Hydrochloride Formulation and Method
US20080280993 * Jul 15, 2008 Nov 13, 2008 Sepracor Inc. Treatment of CNS Disorders With trans 4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-1-Napthalenamine
Dasotraline is a serotoninnorepinephrine and dopamine reuptake inhibitor (SNDRI) that is under investigation for the treatment of Binge Eating Disorder, Adult Attention Hyperactivity Disorder, Attention Deficit Hyperactivity Disorder, and Adult Attention Deficit Hyperactivity Disorder

Dasotraline (INN)[1] (former developmental code name SEP-225,289) is a serotonin-norepinephrine-dopamine reuptake inhibitor(SNDRI) that is under development by Sunovion for clinical use.[2][3][4][5] In 2017, the U.S. Food and Drug Administration accepted Sunovion’s New Drug Application for review for the treatment of ADHD;[6] the NDA for dasotraline is expected to be decided by the end of August 2018.[7] The drug is no longer being developed for major depressive disorder (MDD), but is still under investigation for the treatment of attention-deficit hyperactivity disorder (ADHD) and eating disorders.[8][9] Structurally, dasotraline is a stereoisomer of desmethylsertraline, which is an active metabolite of the marketed selective serotonin reuptake inhibitor (SSRI) antidepressantsertraline (Zoloft) and an SNDRI similarly.

Side Effects

In phase I trials for ADHD, test subjects reported the following side effects:[10][11]

Syn1

SYN2

Clip

https://patents.google.com/patent/US20150196502

Transnorsertraline, i.e., (1R,4S)-trans-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine and (1S,4R)-trans-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine are described in, for example, U.S. Pat. No. 7,087,785 B2 (“the ‘785 patent”; incorporated herein by reference in its entirety), have the following chemical structures, respectively:

Figure US20150196502A1-20150716-C00001

Uses of transnorsertraline in the treatment, prevention, or management of affective disorders and other various CNS disorders are also disclosed in the ‘785 patent. Such disorders include, but are not limited to, depression, mood disorders, anxiety disorders, behavioral disorders, eating disorders, substance abuse disorders, and sexual function disorders.

2.2 Salts and Polymorphic Forms
Whether crystalline or amorphous, potential solid forms of a pharmaceutical compound include single-component and multiple-component solids. Single-component solids consist essentially of the pharmaceutical compound in the absence of other compounds. Variety among single-component crystalline materials may potentially arise, e.g., from the phenomenon of polymorphism, wherein multiple three-dimensional arrangements exist for a particular pharmaceutical compound (see, e.g., S. R. Byrn et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette).
Solid forms such as salts, crystal forms, e.g., polymorphic forms of a compound are known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, fractability, and compressibility of the compound as well as the safety and efficacy of drug products based on the compound, (see, e.g., Knapman, K. Modern Drug Discoveries, 2000: 53).
The importance of studying polymorphs was underscored by the case of ritonavir, an HIV protease inhibitor that was formulated as soft gelatin capsules. About two years after the product was launched, the unanticipated precipitation of a new, less soluble polymorph in the formulation necessitated the withdrawal of the product from the market until a more consistent formulation could be developed (see S. R. Chemburkar et al., Org. Process Res. Dev., (2000) 4:413-417). Thus, the preparation of solid forms is of great importance in the development of a safe, effective, stable and marketable pharmaceutical compound.
New salts and polymorphic forms of transnorsertraline can further the development of formulations for the treatment, prevention or management of CNS diseases.
hydrochloride salt of transnorsertraline exists as a monohydrate.

Paper

Chemistry – A European Journal (2009), 15(14), 3403-3410.

A Chemoenzymatic Approach to Enantiomerically Pure Amines Using Dynamic Kinetic Resolution: Application to the Synthesis of Norsertraline

Dynamic transformation: A racemization catalyst and the enzyme Candida antarcticalipase B (CALB) were combined in a one‐pot dynamic kinetic resolution (DKR) of primary amines, which were transformed to their corresponding amides in up to 95 % yield and >99 % ee. This chemoenzymatic DKR was also applied to the synthesis of norsertraline (see scheme).

Racemization catalyst 5 c and the enzyme Candida antarctica lipase B were combined in a one‐pot dynamic kinetic resolution (DKR) of primary amines in which a wide range of amines were transformed to their corresponding amides in up to 95 % isolated yield and >99 % ee. The DKR protocol was applicable with either isopropyl acetate or dibenzyl carbonate as the acyl donor. In the latter case, release of the free amine from the carbamate products was carried out under very mild conditions. The racemization of (S)‐1‐phenylethylamine with several different Ru catalysts was also evaluated. Catalyst 5 c, of the Shvo type, was able to selectively racemize amines and was also compatible with the reaction conditions used for DKR. A racemization study of three different amines with varying electronic properties was also performed. Competitive racemization of a 1:1 mixture of the deuterated and non‐deuterated amine was carried out with 5 c and a primary kinetic isotope effect was observed for all three amines, providing support that the rate‐determining step is β‐hydride elimination. The chemoenzymatic DKR protocol was applied to the synthesis of norsertraline (16) by using a novel route starting from readily available 1,2,3,4‐tetrahydro‐1‐naphthylamine (1 o)………https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fchem.200802303&file=chem_200802303_sm_miscellaneous_information.pdf

Synthesis of (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-aminehydrochloride(NorSertraline, (1R,4S)-16)

1 H NMR (400 MHz, CD3OD) δ = 7.54 – 7.50 (m, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.40 (td, J = 3.7 Hz, 1.3 Hz, 1H), 7.33 (td, J = 3.7 Hz, 1.3 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.02-6.97 (m, 2H), 4.68 (dd, 1H), 4.33 (dd, 1H), 2.44 – 2.22 (m, 2H), 2.01 – 1.88 (m, 2H).

13C NMR (101 MHz, CD3OD) δ = 146.8, 138.9, 132.5, 131.9, 130.6, 130.3, 130.2, 130.0, 128.9, 128.3, 127.7, 127.3, 48.8, 43.5, 27.8, 24.9.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013151877&recNum=109&docAn=US2013034529&queryString=EN_ALL:nmr%20AND%20PA:(Bristol-Myers%20Squibb)%20&maxRec=4406

PATENT

ApplicationPriority dateFiling dateRelationTitle
PCT/US2010/0588312009-12-042010-12-03DivisionFormulations, salts and polymorphs of transnorsertraline and uses thereof
US2013135131702013-01-092013-01-09Division
US156319092009-12-042017-06-23ContinuationFormulations, salts and polymorphs of transnorsertraline and uses thereof
US266864092009-12-042009-12-04US Provisional Application
PCT/US2010/0588312009-12-042010-12-03Formulations, salts and polymorphs of transnorsertraline and uses thereof
US2013135131702013-01-092013-01-09US Provisional Application
US146053342009-12-042015-01-26Formulations, salts and polymorphs of transnorsertraline and uses thereof
US146053342015-01-26Formulations, salts and polymorphs of transnorsertraline and uses thereof
US156319092017-06-23Formulations, salts and polymorphs of transnorsertraline and uses thereof

References

  1. Jump up^ “International Nonproprietary Names for Pharmaceutical Substances (INN)” (PDF). WHO Drug Information. WHO. 27 (4). 2013. Retrieved 4 November 2014.
  2. Jump up^ Chen, Zhengming; Skolnick, Phil (2007). “Triple uptake inhibitors: therapeutic potential in depression and beyond”. Expert Opinion on Investigational Drugs16 (9): 1365–77. doi:10.1517/13543784.16.9.1365PMID 17714023.
  3. Jump up^ DeLorenzo, C.; Lichenstein, S.; Schaefer, K.; Dunn, J.; Marshall, R.; Organisak, L.; Kharidia, J.; Robertson, B.; Mann, J. J.; Parsey, R. V. (2011). “SEP-225289 Serotonin and Dopamine Transporter Occupancy: A PET Study”Journal of Nuclear Medicine52 (7): 1150–5. doi:10.2967/jnumed.110.084525PMC 3856248Freely accessiblePMID 21680689.
  4. Jump up^ Ziegler, L.; Küffer, G.; Euler, E.; Wilhelm, K. (1990). “Arthrographische Darstellung von Ganglien im Handbereich” [Arthrographic imaging of ganglions of the hand]. RöFo (in German). 153 (2): 143–6. doi:10.1055/s-2008-1033352PMID 2168068.
  5. Jump up^ Guiard, B.; Chenu, F.; El Mansari, M.; Blier, P. (2009). “P.1.c.059 Electrophysiological properties of the triple reuptake inhibitor SEP 225289 on monoaminergic neurons”. European Neuropsychopharmacology19: S285. doi:10.1016/S0924-977X(09)70419-5.
  6. Jump up^ “Sunovion Announces FDA Acceptance for Review of New Drug Application for Dasotraline for the Treatment of ADHD” (Press release). Marlborough, Massachusetts: Sunovion. Business Wire. November 10, 2017. Retrieved 2018-05-01.
  7. Jump up^ “Pipeline Report: Brand Drugs” (PDF). Welldyne. February 2018. pp. 1, 4. Retrieved 1 May 2018.
  8. Jump up^ Clinical trial number NCT02276209 for “Dasotraline Adult ADHD Study” at ClinicalTrials.gov
  9. Jump up^ http://adisinsight.springer.com/drugs/800023450[full citation needed]
  10. Jump up^ Koblan, Kenneth S; Hopkins, Seth C; Sarma, Kaushik; Jin, Fengbin; Goldman, Robert; Kollins, Scott H; Loebel, Antony (2015). “Dasotraline for the Treatment of Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial in Adults”Neuropsychopharmacology40 (12): 2745–52. doi:10.1038/npp.2015.124PMC 4864650Freely accessiblePMID 25948101.
  11. Jump up^ http://www.additudemag.com/adhdblogs/19/11101.html[full citation needed]

Further reading

Liming Shao Patent
  • US application 2007203111, Shao L, Wang F, Malcolm SC, Hewitt MC, Bush LR, Ma J, Varney MA, Campbell U, Engel SR, Hardy LW, Koch P, Campbell JE, “Cycloalkylamines as monoamine reuptake inhibitors”, published 2007-08-30, assigned to Sepracor Inc.
Asymmetry Patent
  • US patent 7129378, Han X, Krishnamurthy D, Senanayake CH, Lu Z-H, “Method of preparing amine stereoisomers”, published 2005-07-28, assigned to Apsinterm LLC
Dasotraline
Dasotraline.svg
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C16H15Cl2N
Molar mass 292.20 g·mol−1
3D model (JSmol)
Patent ID

Title

Submitted Date

Granted Date

US2017266133 METHODS AND COMPOSITIONS OF DASOTRALINE FOR TREATMENT OF ADHD
2015-05-12
US2017266134 DOSAGE OF DASOTRALINE AND METHOD FOR TREATMENT OF ADHD
2015-05-12
Patent ID

Title

Submitted Date

Granted Date

US2015196502 FORMULATIONS, SALTS AND POLYMORPHS OF TRANSNORSERTRALINE AND USES THEREOF
2015-01-26
2015-07-16
US2013065904 Combinations of Eszopiclone and Trans 4-(3, 4-Dichlorophenyl)-1, 2, 3, 4-Tetrahydro-N-Methyl-1-Napthalenamine or Trans 4-(3, 4-Dichlorophenyl)-1, 2, 3, 4-Tetrahydro-1-Napthalenamine, and Methods of Treatment of Menopause and Mood, Anxiety, and Cognitive Disorders
2012-11-09
2013-03-14
US9072699 TREATMENT OF CNS DISORDERS WITH trans 4-(3, 4-DICHLOROPHENYL)-1, 2, 3, 4-TETRAHYDRO-1-NAPTHALENAMINE
2014-01-10
2014-05-08
US8329950 Process for preparation of trans 4-(3, 4-Dichlorophenyl)-1, 2, 3, 4-tetrahydro-1Napthalenamine
2012-01-25
2012-12-11
US2006128993 Treatment of CNS disorders with trans 4-(3, 4-dichlorophenyl)-1, 2, 3, 4-tetrahydro-1-napthalenamine and its formamide
2006-06-15
Patent ID

Title

Submitted Date

Granted Date

US8097760 PREPARATION OF CHIRAL AMIDES AND AMINES
2009-06-11
2012-01-17
US9498452 Treatment of CNS disorders with trans 4-(3, 4-dichlorophenyl)-1, 2, 3, 4-tetrahydro-1-naphthalenamine
2015-06-01
2016-11-22
US8344030 Treatment of CNS disorders with trans 4-(3, 4-dichlorophenyl)-1, 2, 3, 4-tetrahydro-1-napthalenamine
2012-02-03
2013-01-01
US8134029 Treatment of CNS Disorders With trans 4-(3, 4-Dichlorophenyl)-1, 2, 3, 4-Tetrahydro-1-Napthalenamine
2010-11-18
2012-03-13
US7589237 Treatment of CNS Disorders With trans 4-(3, 4-Dichlorophenyl)-1, 2, 3, 4-Tetrahydro-1-Napthalenamine
2008-11-13
2009-09-15
Patent ID

Title

Submitted Date

Granted Date

US2012077818 COMPOSITIONS COMPRISING TRANSNORSERTRALINE AND SEROTONIN RECEPTOR 1A AGONISTS/ANTAGONISTS AND USES THEREOF
2010-05-12
2012-03-29
US2016016891 PREPARATION OF CHIRAL AMIDES AND AMINES
2015-05-18
2016-01-21
US2014057990 PREPARATION OF CHIRAL AMIDES AND AMINES
2013-08-01
2014-02-27
US9199946 PYRIMIDINONE CARBOXAMIDE INHIBITORS OF ENDOTHELIAL LIPASE
2013-03-29
2015-03-05
US8524950 Preparation of chiral amides and amines
2011-12-21
2013-09-03
Patent ID

Title

Submitted Date

Granted Date

US2008293726 Combinations of Eszopiclone and Trans 4-(3, 4-Dichlorophenyl)-1, 2, 3, 4-Tetrahydro-N-Methyl-1-Napthalenamine or Trans 4-(3, 4-Dichlorophenyl)-1, 2, 3, 4-Tetrahydro-1-Napthalenamine, and Methods of Treatment of Menopause and Mood, Anxiety, and Cognitive Disorders
2008-11-27
US7105699 Treatment of CNS disorders with trans 4-(3, 4-dichlorophenyl)-1, 2, 3, 4-tetrahydro-1-napthalenamine and its formamide
2006-01-19
2006-09-12
US2017157067 TREATMENT OF CNS DISORDERS WITH trans 4-(3, 4-DICHLOROPHENYL)-1, 2, 3, 4-TETRAHYDRO-1-NAPHTHALENAMINE
2016-10-20
US2014315910 Combinations of Eszopiclone and Trans 4-(3, 4-Dichlorophenyl)-1, 2, 3, 4-Tetrahydro-N-Methyl-1-Napthalenamine or Trans 4-(3, 4-Dichlorophenyl)-1, 2, 3, 4-Tetrahydro-1-Napthalenamine, and Methods of Treatment of Menopause and Mood, Anxiety, and Cognitive Disorders
2014-06-27
2014-10-23
US2007282007 TREATMENT OF PAIN DISORDERS WITH trans 4-(3, 4-DICHLOROPHENYL)-1, 2, 3, 4-TETRAHYDRO-1-NAPHTHALENAMINE AND ITS FORMAMIDE
2007-12-06
Patent ID

Title

Submitted Date

Granted Date

US8658700 Treatment of CNS disorders with trans 4-(3, 4-dichlorophenyl)-1, 2, 3, 4-tetrahydro-1-napthalenamine
2012-12-04
2014-02-25
US8957114 Formulations, salts and polymorphs of transnorsertraline and uses thereof
2010-12-03
2015-02-17
US7790772 Treatment of CNS Disorders With trans 4-(3, 4-Dichlorophenyl)-1, 2, 3, 4-Tetrahydro-1-Napthalenamine
2009-11-26
2010-09-07
US7423179 Treatment of CNS disorders with trans 4-(3, 4-dichlorophenyl)-1, 2, 3, 4-tetrahydro-1-napthalenamine
2006-09-28
2008-09-09
US7087785 Treatment of CNS disorders with trans 4-(3, 4-dichlorophenyl)-1, 2, 3, 4-tetrahydro-1-napthalenamine and its formamide
2004-05-13
2006-08-08

//////////ダソトラリン, SEP-225289,  SEP-289, DSP-225289, Dasotraline, 675126-05-3, UNII-4D28EY0L5T, (1R,4S)-trans-Norsertraline, Norsertraline

C1CC(C2=CC=CC=C2C1C3=CC(=C(C=C3)Cl)Cl)N

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