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GMP’s for Early Stage Development of New Drug substances and products

The question of how Good Manufacturing Practice (GMP) guidelines should be applied during early stages of development continues to be discussed across the industry and is now the subject of a new initiative by the International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium)—an association of pharmaceutical and biotechnology companies aiming to advance innovation and quality in the development of pharmaceuticals. They have assembled a multidisciplinary team (GMPs in Early Development Working Group) to explore and define common industry approaches and to come up with suggestions for a harmonized approach. Their initial thoughts and conclusions are summarized in Pharm. Technol. 2012, 36 (6), 54–58.

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From an industry perspective, it is common to consider the “early” phase of development as covering phases 1 and 2a clinical studies. During this phase, there is a high…

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CENTANAFADINE

December 27, 2016 9:22 am / Leave a comment

Centanafadine; UNII-D2A6T4UH9C; EB-1020 free base; D2A6T4UH9C; 924012-43-1

CTN SR; EB-1020; EB-1020 SR

WO 2007016155

Molecular Formula:	C₁₅H₁₅N
Molecular Weight:	209.292 g/mol

Phase II Attention-deficit hyperactivity disorder
No development reported Major depressive disorder; Neuropathic pain

Most Recent Events

20 Dec 2016 Neurovance plans a phase III trial for Attention-deficit hyperactivity disorder
27 Jul 2016 Efficacy data from a phase IIb trial in Attention-deficit hyperactivity disorder released by Neurovance
16 Jul 2016 No recent reports of development identified for phase-I development in Attention-deficit-hyperactivity-disorder in Canada (PO)

Originator Euthymics Bioscience
Developer Euthymics Bioscience; Neurovance
Class Azabicyclo compounds; Cyclohexanes; Naphthalenes; Small molecules
Mechanism of Action Adrenergic uptake inhibitors; Dopamine uptake inhibitors; Serotonin uptake inhibitors

Image result for Neurovance

2D chemical structure of 923981-14-0

cas 923981-14-0 hydrochloride

Molecular Formula:	C₁₅H₁₆ClN
Molecular Weight:	245.75 g/mol

(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo(3.1.0)hexane hydrochloride

Centanafadine (INN) (former developmental code name EB-1020) is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) under development by Neurovance in collaboration with Euthymics Bioscience as a treatment for attention deficit hyperactivity disorder (ADHD) that inhibits the reuptake of norepinephrine, dopamine and serotonin with a ratio of 1:6:14, respectively.^[1]^[2]^[3] As of August 2015, it is in phase II clinical trials.[1]

Also claimed is their use for treating attention deficit hyperactivity disorder (ADHD), fragile-X associated disorder, autism spectrum disorder and depression. See WO2015089111, claiming method for treating fragile X-associated disorders, assigned to Neurovance, naming Piskorski, Bymaster and Mckinney. Neurovance, an affiliate of Euthymics Bioscience, is developing centanafadine, a sustained release formulation and a non-stimulant triple reuptake inhibitor, for treating ADHD and is also investigating the drug for treating neuropathic pain.

In June 2015, the drug was reported to be in phase 2 clinical and preclinical development for treating ADHD and neuropathic pain, respectively. Inventors are affiliated with Neurovance.

Attention-deficit hyperactivity disorder (ADHD) is a central nervous system

(CNS) disorder characterized by developmentally inappropriate inattention, hyperactivity, and impulsivity (Buitelaar et al., 2010; Spencer et al., 2007). ADHD is one of the most common developmental disorders in children with 5-10% prevalence (Scahill et al., 2000; Polanczyk et al., 2007). While ADHD was once regarded as only a childhood disorder, it can continue through adolescence and into adulthood. An estimated 2.9-4.4% of the adult population has continuing ADHD (Kessler et al., 2006; Faraone and Biederman, 2005). Major symptoms in adults include inattention, disorganization, lack of concentration and to some extent impulsivity, which result in difficulty functioning, low educational attainment, under achievement in vocational and educational pursuits, and poor social and family relations (Biederman et al, 2006; Barkely et al., 2006).

The exact causes of ADHD are not known, but a dysfunction of the prefrontal cortex and its associated circuitries has been posited as a key deficit in ADHD (Arnsten, 2009). Consistent with this notion is the finding that abnormal catecholaminergic function plays a key role, particularly in prefrontal cortical regions (Arnsten 2009). The

catecholamines norepinephrine (NE) and dopamine (DA) are highly involved in several domains of cognition including working memory, attention, and executive function. Accordingly, these monoamine neurotransmitters are believed to work in concert in modulating cognitive processes.

Pharmacotherapy is a primary form of treatment utilized to reduce the symptoms of ADHD. Stimulants such as methylphenidate and amphetamines are commonly used for ADHD. The major mechanism of action of the stimulants is inhibition of DA and NE transporters. The stimulants are effective against the core symptoms of ADHD and have a response rate of about 70% (Spencer et al. , 2005). However, major concerns about stimulants include risk of abuse, dependency, and diversion as well as potential neurotoxic effects of amphetamines (Berman et al., 2009). The abuse potential of stimulants is particularly problematic in adults because substance abuse is a common co-morbidity with adult ADHD (Levin and Kleber, 1995; Ohlmeier, 2008).

Another major drug used to treat ADHD is atomoxetine, which is a selective norepinephrine reuptake inhibitor. Major advantages of atomoxetine compared to the stimulants is lack of abuse potential, once-daily dosage, and superior treatment of comorbidities such as anxiety and depression. However, atomoxetine has lower efficacy and takes 2-4 weeks for onset of action (Spencer et al., 1998; Newcorn et al., 2008).

Accordingly, there remains a need for effective pharmaceuticals which may be used in the treatment of ADHD and other conditions affected by monoamine neurotransmitters.

PATENT

WO 2007016155

https://www.google.ch/patents/WO2007016155A2?hl=de&cl=en

Reaction Scheme 1 below generally sets forth an exemplary process for preparing l-aryl-3-azabicyclo[3.1.0] hexane analogs from the corresponding 2-bromo-2- arylacetate or 2-chloro-2-arylacetate. The bromo or chloro acetate react with acrylonitrile to provide the methyl 2-cyano-l-arylcyclopropanecarboxylate, which is then reduced to the amino alcohol by reducing agents such as lithium aluminum hydride (LAH) or sodium aluminum hydride (SAH) or NaBH₄ with ZnCl₂. Cyclization of the amino alcohol with SOCl₂ or POCl₃ will provide the l-aryl-3-azabicyclo[3.1.0]hexane. The cyclization of substituted 4-aminobutan-l -ol by SOCl₂ or POCl₃ into the pyrrolidine ring system was reported by Armarego et al, J. Chem. Soc. [Section C: Organic] 19:3222-9, (1971), and in Szalecki et al., patent publication PL 120095 B2, CAN 99:158251. Oxalyl chloride, phosphorous tribromide, triphenylphosphorous dibromide and oxalyl bromide may be used for the same purpose. The methyl 2-bromo-2 -arylacetate or methyl 2- chloro-2-arylacetate may be synthesized from subsituted benzoylaldehyde or methyl-2- arylacetate as shown in Reaction Scheme IA.

Reaction Scheme 1

Reduction

Reagents: (a) NaOMe; (b) LiAIH₄; (c) SOCI₂; (d) POCI₃; (e) NaOH or NH₃ H₂O

Reaction Scheme IA

Reagents: (a) CHCI₃, NaOH; (b) SOCI₂; (c) MeOH; (d) NaBrO₃, NaHSO₃ [00138] Reaction Scheme 2 below illustrates another exemplary process for transforming methyl 2-cyano-l-arylcyclopropanecarboxylate to a desired compound or intermediate of the invention. Hydrolysis of the cyano ester provides the potassium salt which can then be converted into the cyano acid. Reduction and cyclization of the 2- cyano-1-arylcyclopropanecarboxylic acid with LAH or LiAlH(OMe)₃according to the procedure outlined in Tetrahedron 45:3683 (1989), will generate l-aryl-3- azabicyclo[3.1.0]hexane. In addition, the cyano- 1-arylcyclopropanecarboxylic acid can be hydrogenated and cyclized into an amide, which is then reduced to l-aryl-3- azabicyclo[3.1.0]hexane.

Reaction Scheme 2

Hydrolysis

Reagents: (a) NaOMe; (b) KOH; (c) HCI; (d) LiAIH(OMe)₃, or LAH, or SAH, then HCI; (e) H₂/Pd or H₂/Ni

[00139] Reaction Scheme 3 below discloses an alternative exemplary process for converting the methyl 2-cyano-l-arylcyclopropanecarboxylate to a desired compound or intermediate of the invention. The methyl 2-cyano-l-arylcyclopropanecarboxylate is reduced and cyclized into l-aryl-3-aza-bicyclo[3.1.0]hexan-2~one, which is then reduced to l-aryl-3-azabicyclo[3.1.0]hexane [Marazzo, A. et al., Arkivoc 5:156-169, (2004)].

Reaction Scheme 3

Reagents: (a) H₂/Pd or H₂/Ni; (b) B₂H₆ or BH₃ or LAH, then HCI [00140] Reaction Scheme 4 below provides another exemplary process to prepare l-aryl-3-azabicyclo[3.1.0] hexane analogs. Reaction of 2-arylacetonitrile with (+)- epichlorohydrin gives approximately a 65% yield of 2-(hydroxyrnethyl)-l- arylcyclopropanecarbonitrile (85% cis) with the trans isomer as one of the by-products [Cabadio et al., Fr. Bollettino Chimico Farmaceutico 117:331-42 (1978); Mouzin et al., Synthesis 4:304-305 (1978)]. The methyl 2-cyano-l-arylcyclopropanecarboxylate can then be reduced into the amino alcohol by a reducing agent such as LAH, SAH or NaBH₄ with ZnCl₂ or by catalytic hydrogenation. Cyclization of the amino alcohol with SOCl₂ or POCl₃ provides the l-aryl-3-azabicyclo[3.1.0]hexane. The cyclization of substituted 4-aminobutan-l-ol by SOCl₂ or POCl₃ into the pyrrolidine ring system has been reported previously [Armarego et al., J. Chem. Soc. [Section C: Organic] 19:3222-9 (1971); patent publication PL 120095 B2, CAN 99:158251).

ϋv siυjiijJsoLJa

Reaction Scheme 4

Ar CN

ion

Reagents: (a) NaHMDS; (b) LAH or catalytic hydrogenation; (c) SOCl₂; (d) POCI₃; (e) NaOH

[00141] Reaction Scheme 5 provides an exemplary process for synthesizing the

(IR, 5S)-(+)-l-aryl-3-azabicyclo[3.1.0]hexanes. Using (S)-(+)-epichlorohydrin as a starting material in the same process described in Scheme 4 will ensure a final product with 1-R chirality [Cabadio, S. et al, Fr. Bollettino Chimico Farmaceutico 117:331-42 (1978)].

Reaction Scheme 5

ion

^Ar

H’..

Reagents: (a) NaHMDS; (b) LAH or catalytic hydroge nation; (c) SOCI₂; (d) POCl₃; (e) NaOH j_j

[00142] Reaction Scheme 6 provides an exemplary process to prepare the (1 S,5R)-

(-)-l-aryl-3-azabicyclo[3.1.0]hexanes. Using (R)-(-)-epichlorohydrin as a starting material in the same process described in Scheme 4 will ensure a final product with 1-S chirality [Cabadio, S. et al, Fr. Bollettino Chimico Farmaceutico 117:331-42 (1978)].

Reaction Scheme 6

Ar CN

c or d, Cyclization

Reagents: (a) NaHMDS; (b) LAH or catalytic hydrogenation; (C) SOCI₂; (d) POCI₃; (e) NaOH

[00143] Reaction Scheme 7 provides an alternative exemplary process for transforming the 2-(hydroxymethyl)-l-arylcyclopropanecarbonitrile to a desired compound or intermediate of the invention via an oxidation and cyclization reaction. Utilizing chiral starting materials (+)-epichlorohydrin or (-)-epichlorohydrin will lead to the corresponding (+)- or (-)-enantiomers and corresponding chiral analogs through the same reaction sequences.

Reaction Scheme 7

O Cyclopropanantion Oxidation

Ar CN

CK Ar Ar a HO HO

65% yield, 88% cis O

Hydrogenation

C Cyclization

Reagents: (a) NaNH₂; (b) KMnO₄; (c) H₂/Ni or Pt; (d) B₂H₆ Or BH₃ Or LAH, then HCI

[00144] Reaction Scheme 8 provides an exemplary process for transforming the epichlorohydrin to a desired compound or intermediate of the invention via a replacement and cyclization reaction. The reaction of methyl 2-arylacetate with epichlorohydrin gives methyl 2-(hydroxymethyl)~l~arylcyclopropanecarboxylate with the desired cis isomer as the major product. The alcohol is converted into an OR₃ group such as -O-mesylate, -O- tosylate, -O-nosylate, -O-brosylate, -O-trifluoromethanesulfonate. Then OR₃ is replaced by a primary amine NH₂R₄, where R₄ is a nitrogen protection group such as a 3,4- dimethoxy-benzyl group or other known protection group. Nitrogen protecting groups are well known to those skilled in the art, see for example, “Nitrogen Protecting Groups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981, Chapter 7; “Nitrogen Protecting Groups in Organic Chemistry”, Plenum Press, New York, N.Y., 1973, Chapter 2; T. W. Green and P. G. M. Wuts in “Protective Groups in Organic Chemistry”, 3rd edition, John Wiley & Sons, Inc. New York, N. Y., 1999. When the nitrogen protecting group is no longer needed, it may be removed by methods well known in the art. This replacement reaction is followed by a cyclization reaction which provides the amide, which is then reduced into an amine by a reducing agent such as LAH. Finally the protection group is removed to yield the l-aryl-3- azabicyclo[3.1.0]hexane analogs. Utilizing chiral (S)-(+)-epichlorohydrin as a starting material leads to the (lR,5S)-(+)-l-aryl-3-azabicyclo[3.1.0]hexane analogs with the same reaction sequence. Similarly, the (R)-(-)-epichlorohydrin will lead to the (lS,5R)-(-)-l- aryl-3-azabicyclo[3.1.0]hexane analogs.

Reaction Scheme 8

O Cyclop ro pa nantion

Ar CO₂Me + _C|v Ar Ar

HO R₃O

CO₂Me CO₂Me

Replacement Cyclization

Reagents: (a) NaNH₂; (b) MsCI; (c) R₄NH₂; (d) LAH or SAH or BH₃; (e) HCI

[00145] Reaction Scheme 9 provides an exemplary process for transforming the diol to a desired compound or intermediate of the invention. Reduction of the diester provides the diol which is then converted into an OR₃ group such as -O-mesylate, -O- tosylate, -O-nosylate, -O-brosylate, -O-trifluoromethanesulfonate. Then OR₃ is replaced by a primary amine NH₂R₆, where R₆ is a nitrogen protection group such as a 3,4- dimethoxy-benzyl group or other protection groups known in the art (e.g., allyl amine, tert-butyl amine). When the nitrogen protecting group is no longer needed, it may be removed by methods known to those skilled in the art.

Reaction Scheme 9

X=CI or Br

Deprotection ft* Replacement Cyclization

Reagents: (a) NaOMe; (b) NaBH₄; (c)MsCI; (d) NH₃, then HCI; (e) R₆NH₂; (f) H₂/Pd or acid deprotection, then HCI

[00146] Reaction Scheme 10 provides an exemplary process for resolving the racemic l-aryl-3-aza-bicyclo[3.1.0]hexane to enantiomers. The resolution of amines through tartaric salts is generally known to those skilled in the art. For example, using O,O-Dibenzoyl-2R,3R-Tartaric Acid (made by acylating L(+)-tartaric acid with benzoyl chloride) in dichloroethane/methanol/water, racemic methamphetamine can be resolved in 80-95% yield, with an optical purity of 85-98% [Synthetic Communications 29:4315- 4319 (1999)]. Reaction Scheme 10

Racemate (1 R, 5S)-enantiomer

Racemate (1 S, 5R)-enantiomer

Reagents: (a) L-(-)-DBTA; (b) NaOH, then HCI in IPA; (c) D-(+)-DBTA

[00147] Reaction Scheme 11 provides an exemplary process for the preparation of

3-alkyl-l-aryl-3-azabicyclo[3.1.0]hexane analogs. These alkylation or reductive animation reaction reagents and conditons are generally well known to those skilled in the art.

Reaction Scheme 11

R= Me, Et, Propyl, i-propyl, cyclopropyl, i-butyl, etc.

[00148] Enantiomers of compounds within the present invention can be prepared as shown in Reaction Scheme 12 by separation through a chiral chromatography. Reaction Scheme 12

[00149] Alternatively, enantiomers of the compounds of the present invention can be prepared as shown in Reaction Scheme 13 using alkylation reaction conditions exemplified in scheme 11.

Reaction Scheme 13

[00150] Reaction Scheme 14 provides an exemplary process for preparing some N- methyl l-aryl-3-aza-bicyclo[3.1.0]hexane analogs. The common intermediate N-methyl bromomaleide is synthesized in one batch followed by Suzuki couplings with the various substituted aryl boronic acids. Cyclopropanations are then carried out to produce the imides, which are then reduced by borane to provide the desired compounds.

Reaction Scheme 14

Reagents and conditions: (a) MeNH₂, THF, 10 ⁰C, 1.5 hr; (b) NaOAc, Ac₂O₁ 60 ⁰C, 2 hr; (c) PdCI₂C dppf), CsF, dioxane, 40 ⁰C, 1-6 hr; (d) Me₃SOCI, NaH, THF, 50-65 ⁰C, 2-6 hr; (e) 1M BH₃/THF, O ⁰C; 60 ⁰C 2 hr (f) HCI, Et₂O

[00151] Reaction Scheme 15 provides an additional methodology for producing 1- aryl-3-azabicyclo[3.1.0] hexanes.

Reaction Scheme 15

[00152] Reaction Scheme 16 provides an additional methodology for producing 1- aryl-3-azabicyclo[3.1.0] hexanes. Reaction scheme 16

[00153] Reaction Scheme 17 provides an additional methodology for producing 1- aryl-3-azabicyclo[3.1.0] hexanes.

Reaction Scheme 17

[00154] Reaction Scheme 18 provides an additional methodology for producing 1- aryl-3-azabicyclo[3.1.0] hexanes. Utilizing chiral starting materials (+)-epichlorohydrin or (-)-epichlorohydrin will lead to the corresponding chiral analogs through the same reaction sequences. Reaction Scheme 18

[00155] Reaction Scheme 19 provides an additional methodology for producing 1- aryl-3-azabicyclo[3.1.0] hexanes.

Reaction Scheme 19

R= propyl , butyl, etc.

[00156] Reaction Scheme 20 provides an additional methodology for producing 1- aryl-3-azabicyclo[3.1.0] hexanes.

Reaction Scheme 20

Ac₂O NaOAc, reflux

R= ferf-butyl, etc.

[00157] Reaction Scheme 21 provides an additional methodology for producing 3- and/or 4-subsitituted l-aryl-3-azabicyclo[3.1.0] hexanes. Reaction Scheme 21

(BoC)₂O DCM

R= methyl, etc. -Ar v Ar R₁ = methyl, etc. R- N H HCI

R ^• HCI

[00158] Reaction Scheme 22 provides an additional methodology for producing 3- and/or 4-subsitituted l-aryl-3-azabicyclo[3.1.0] hexanes.

Reaction Scheme 22

(BoC)₂O DCM

1. 2.

R= Ri

[00159] Reaction Scheme 23 provides an additional methodology for producing 3- and/or 2-subsitituted 1 -aryl-3-azabicyclo[3.1.0] hexanes.

Reaction Scheme 23

KBH₄

R = Me, etc. MeOH R₁ = Me, etc.

HCI HCI Ether Ether

[00160] Reaction Scheme 24 provides an additional methodology for producing 2- and/or 3 -substituted l-aryl-3-azabicyclo[3.1.0] hexanes.

Reaction Scheme 24

I) TMSCI; PhMe

Et₃N; NaBH₃CN 2) R₂Li EtOH

[00161] Reaction Scheme 25 provides an additional generic methodology for producing 1 -aryl-3 -azabicyclo[3.1.0] hexanes .

Reaction Scheme 25

Cyolopropanation Ar Reduction ^Ar Cyciization / \

Ar CN + Cl HO. HO

H₂N

^or Protection

[00162] Reaction Scheme 26 provides another generic methodology for producing l-aryl-3-azabicyclo[3.1.0] hexanes.

Reaction Scheme 26

⁰

Reduction Deprotection/ dealkylation

C. Synthesis of various naphthyl and phenyl 3-azabicyclo[3.1.01hexane Hydrochlorides

(1) Synthesis of lS,5R-(-Vl-(l-naphthylV3-azabicyclol3.1.01hexane Hydrochloride as Representative Procedure for (l)-(6).

[00340] To a stirring solution of ( 1 R,2S)-(2-Aminomethyl-2-( 1 – naphthyl)cyclopropyl)-methanol prepared according to Example XIVB(I) above (3.2 g, 0.014 moles) in 35 niL of dichloroethane (DCE), at room temperature under nitrogen, was added 1.2 niL (0.017 moles, 1.2 eq) of SOCl₂ slowly via syringe while keeping the temperature below 50 ⁰C. (Note: The reaction exotherms from 22 ⁰C to 45 ⁰C) The resulting mixture was stirred for 3.5 h at room temperature after which time, TLC analysis (SiO₂ plate, CH₂Cl₂/MeOH/NH₄OH (10:1:0.1)) showed no starting material remaining. The mixture was quenched with 40 mL of water and the layers were separated. The organic layer was washed with H₂O (2 x 5O mL). The aqueous layers were combined, made basic with ION NaOH to pH = 10 (pH paper) and extracted with 2 x 100 mL of CH₂Cl₂. The combined organics were dried over Na₂SO₄, filtered and concentrated to an oil. The oil was dissolved in MeOH (20 mL), treated with 15 mL of 2M HCl/Et₂O and concentrated in vacuo to a suspension. The slurry was diluted with 25 mL of Et₂O, filtered and washed with 35 mL of Et₂O. The solid product was dried overnight (-29 mmHg, 5O⁰C) to give 1 g (29%) of pure product as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.22 (t, J=7.37 Hz, 1 H), 1.58 (dd, J=6.00, 4.73 Hz, 1 H), 2.03 – 2.10 (m, 1 H), 3.25 – 3.27 (m, 1 H), 3.42 (d, J=I 1.52 Hz, 1 H), 3.64 (d, J=I 1.62 Hz, 1 H), 3.74 – 3.85 (m, 2 H), 7.32 – 7.39 (m, 1 H), 7.40 – 7.48 (m, 2 H), 7.48 – 7.55 (m, 1 H), 7.75 (d, J=8.20 Hz, 1 H), 7.79 – 7.85 (m, 1 H), 8.04 (d, J=8.30 Hz, 1 H), ¹³C NMR (101 MHz, CDCl₃) δ 14.54, 22.43, 30.89, 48.01, 51.89, 123.92, 125.60, 126.24, 126.93, 129.04, 129.17, 133.55, 134.04, LC/MS (m/z M⁺¹) 210.0, [α]_D (c=l, MeOH), = -54.4.

(2) lR,5S-(+)-l-g-naphthyl)-3-azabicvclof3,1.01hexane Hydrochloride

[00341] Yield = 29%; ¹H NMR (400 MHz, METHANOL-^) δ 1.24 – 1.32 (m, 1

H), 1.32 – 1.37 (m, 1 H), 2.23 – 2.31 (m, 1 H), 3.47 (d, J=11.71 Hz, 1 H), 3.66 (d, J=11.71 Hz, 1 H), 3.85 (d, J=11.62 Hz, 1 H), 3.93 (dd, J=11.67, 3.95 Hz, 1 H), 7.46 (dd, J=8.25, 7.08 Hz, 1 H), 7.50 – 7.57 (m, 1 H), 7.57 – 7.65 (m, 2 H), 7.86 (d, J=8.30 Hz, 1 H), 7.89 – 7.95 (m, 1 H), 8.17 (d, J=8.49 Hz, 1 H), ¹³C NMR (101 MHz, METHANOL-^) δ 22.36, 30.65, 30.65, 48.09, 51.99, 123.78, 125.47, 125.89, 126.50, 128.65, 128.88, 133.87, 134.28, LC/MS (m/z M⁺¹ 210.0), [α]_D (c=l, MeOH), = + 55.6.

(4) lR.5S-(+)-l-(2-naphthylV3-azabicvclo[3.1.01hexane Hydrochloride

[00343] Yield = 30%; ¹H NMR (400 MHz, DMSO-J₆) δ 1.14 – 1.23 (m, 1 H), 1.44

– 1.50 (m, 1 H), 2.17 – 2.26 (m, 1 H), 3.36 – 3.43 (m, 1 H), 3.47 – 3.61 (m, 2 H), 3.75 (d, J-11.23 Hz, 1 H), 7.36 (dd, J=8.59, 1.85 Hz, 1 H), 7.42 – 7.53 (m, 2 H), 7.80 (d, J=1.56 Hz, 1 H), 7.82 – 7.90 (m, 3 H), 9.76 (br. s., 1 H), ¹³C NMR (101 MHz, DMSO-J₆) δ 16.41, 24.11, 31.36, 47.50, 49.97, 125.43, 125.76, 126.41, 127.04, 128.07, 128.15, 128.74, 132.39, 133.55, 137.62, ), LC/MS (m/z M⁺¹ 210.1 , [α]_D (c=l, MeOH), = + 66.0.

PATENT

WO 2008013856

https://www.google.com/patents/WO2008013856A2?cl=en

The compound (-^-(S^-dichlorophenylJ-S-azabicyclotS.l.Olhexane and its pharmaceutically acceptable salts have been previously described as agents for treating or preventing a disorder alleviated by inhibiting dopamine reuptake, such as depression (See, US Patent Nos. 6,569,887 and 6,716,868). However, available methods for synthesizing (-)-l-(3₃4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanes and other l-aryl-3-azabicyclo[3.1.0]hexanes are presently limited.

US Patent No. 4,231,935 (Example 37) describes the synthesis of racemic (±)- l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride according to the following scheme.

US Patent Nos. 6,569,887 and 6,716,868 describe the preparation of (-)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane by resolution of racemic (±)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride using a chiral polysaccharide stationary phase. The foregoing methods provide limited tools for producing (-)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0] hexane and other 1-aryl— 3- azabicyclo[3.1.0]hexanes, underscoring a need for additional methods and compositions to produce the compounds.

Example VI Preparation of ClR. 5S)-l-naphthalen-2-yl-3-azabicyclof3.1.0^“|hexane hydrochloride

using Reaction Schemes 1 & 12

A. Synthesis of (IR. 2SV2-Hvdroxymethyl-2-naphthyl- cvclopropancarbonitrile

To a stirring solution of 2-naphthylacetonitrile (50.0 g, 0.299 moles) and (S)-

(+)-epichlorohydrin (36.0 g, 0389 moles) in anhydrous THF (300 mL) at -15 to -20 ⁰C under nitrogen, was added sodium bis (trimethylsilyl)amide (2M in THF, 300 mL, 0.600 moles) slowly via addition funnel while keeping the temperature between -15 ⁰C and —20 °C. After completion of the addition, the mixture was stirred for 3 hours at -15 ⁰C to -20 °C. The reaction mixture was quenched by slow addition of 2M HCl (520 mL) allowing the temperature to rise to 15 ⁰C as the neutralization proceeded. The layers were allowed to settle and the layers were separated. The aqueous layer was extracted once with ethyl acetate (30OmL). The organic portion was washed with brine (4000 mL) dried over sodium sulfate, filtered and concentrated under reduced pressure to provide an orange oil which was used without further purification. B. Synthesis of ((1S, 2R)-2-AminomethvI-2-naphthylen-2-yl cycIopropyD- methanol

To a solution of nitrile in THF (300 mL) was slowly added borane dimethylsulfide (10 M, 60 mL, 0.60 moles) via addition funnel. The reaction temperature was maintained below 60 ⁰C during the addition. After completion of the addition, the reaction was held at 60 ⁰C until the starting nitrile was completely consumed (approximately 2.5 hours). The mixture was cooled below 15 ⁰C and 2M HCl (200 mL) was slowly added maintaining a temperature below 20 ⁰C. The reaction mixture was then heated to 50⁰C for one hour. After the heating period, the reaction was cooled below 30⁰C and isopropyl acetate (200 mL) and water (250 mL) were added. The phases were separated and the organic phase was discarded. Ammonium hydroxide (75 mL) was added and the mixture cooled to 25 ⁰C with stirring. The aqueous phase was extracted with isopropyl acetate (2x 250 mL). The combined organic phases were washed with 5% dibasic sodium phosphate (200 mL) and saturated NaCl (200 mL), dried over sodium sulfate and concentrated. The viscous yellow oil was dissolved in isopropyl acetate (500 mL) and heated to 55 ⁰C with stirring. p-Toluene sulfonic acid monohydrate(54.25 g, 0.285 mole) was added over 5 minutes. A white solid formed as the acid was added. The reaction mixture was slowly cooled to room temperature, filtered and washed with isopropyl acetate. Yielded – 53.7 g white solid 45% (tosylate salt)

C. Synthesis of (IR. 5SM-naphthaIen-2-vI-3-azabicvclo[3.1.01hexane hydrochloride

To a stirring slurry of ((lS,2R)-2-aminomethyl-2-naphthylen-2-yl cyclopropyl)-methanol tosylate (53.7g, 0.134 mole) in isopropyl acetate (350 mL), at room temperature under nitrogen, was added thionyl chloride (11.8 mL, 0.161 moles) slowly via addition funnel while keeping the temperature below 35 ⁰C. The resulting mixture was stirred for 1 hour, after which time, no starting material remained. The mixture was neutralized with the slow addition of 5 N NaOH (160 mL) keeping the temperature below 30 ⁰C. The phases were separated and the aqueous phase was extracted with isopropyl acetate (200 mL). The combined organic extracts were washed with saturated sodium chloride (150 mL), dried over sodium sulfate, filtered and concentrated to 300 mL. The hydrochloride was made directly from this solution by slowly adding HCl in 2-propanol (5-6N, 26 mL). The mixture was stirred for 15 minutes and filtered and washed with isopropyl acetate. The wet cake was slurried in 2-propanol (400 mL) and heated to reflux with stirring under nitrogen for 2 hours. The resulting slurry was allowed to cool and stir at room temperature overnight. The resulting slurry was filtered and washed with 2-propanol. The solid was dried in a vacuum oven at 40⁰C. Yield – 21.1 g, 64.2% ¹H NMR (400 MHz, DMSCW₆) d ppm 1.23 (t) 1.40 (t) 2.21 – 2.28 (m) 3.40 – 3.47 (m) 3.50 – 3.66 (m) 3.74 – 3.82 (m) 7.39 (dd) 7.44 – 7.55 (m) 7.82 (s) 7.84 – 7.92 (m) 9.33 (br. s.) 9.69 (br. s.). LC/MS (m/z M⁺¹ 210)

PATENT

WO 2013019271

https://google.com/patents/WO2013019271A1?cl=en

Example I

Preparation of (lR,5S)-(+)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane

[00108] (lR,5S)-(+)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane may be prepared as follows:

Step 1: Synthesis of [(lS.2R)-2-(aminomethyl)-2-(2-naphthyl^‘)cvclopropyl]methan-l-oK p- toluenesulfonic acid salt [00109] 500g (2.99 mol, 1.0 eq) of 2-naphthylacetonitrile was charged to a 12 L 3- neck round bottom flask equipped with overhead stirrer, addition funnel, thermocouple, nitrogen inlet, cooling bath and drying tube. 3.0 L of tetrahydrofuran was added and stirred at room temperature to dissolve all solids. 360 g (3.89 mol, 1.30 eq) (S)-(+)-epichlorohydrin was added and then the solution was cooled to an internal temperature of – 25 °C. 3.0 L of a 2 molar solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (6.00 mol, 2.0 eq) was added to the reaction mixture via addition funnel at a rate such that the internal temperature of the reaction mixture is maintained at less than -15 °C. After completion of the addition, the mixture was stirred at between -20 °C and -14 °C for 2 hours 15 minutes. Borane- dimethylsulfide complex (750 mL of a 10.0 molar solution, 7.5 mol, 2.5 eq) was then slowly added to the reaction mixture at a rate such that the internal temperature was maintained at less than -5 °C. Upon completion of the borane-dimethylsulfide addition the reaction mixture was heated to an internal temperature of 60 °C and stirred overnight at this temperature. Additional borane-dimethylsulfide complex (75 mL, 0.75 mol, 0.25 eq) was then added and the reaction mixture stirred at 60 °C for 1 hour 45 minutes. The reaction mixture was cooled to room temperature and then quenched by slow addition into pre-cooled (3 °C) 2 molar aqueous hydrochloric acid (5.76 L, 11.5 mol, 3.8 eq) at a rate such that the temperature of the quench solution was maintained at less than 22 °C. The two phase mixture was then heated at an internal temperature of 50 °C for 1 hour followed by cooling to RT. Isopropyl acetate (2.0 L) and water (2.5 L) were added, the mixture agitated, and then the layers were allowed to settle. The upper organic layer was discarded. Aqueous ammonia (750 mL) was added to the aqueous layer which was then extracted with isopropylacetate (2.5 L). The aqueous layer was extracted with isopropylacetate (2.5 L) a second time. The organic extracts were combined and then sequentially washed with a 5% solution of sodium dibasic phosphate in water (2.0 L) followed by saturated brine (2.0 L). The organic layer was then concentrated to a total volume of 5.0 L and then heated to 50 °C. para-Toluene sulfonic acid monohydrate (541 g, 2.84 mol) was then added in portions. During the addition white solids precipitated and a mild exotherm was observed. Upon completion of the addition the mixture was allowed to cool to RT and the solids collected by filtration. The filtercake was washed twice with isopropylacetate, 1.0 L each wash. The filtercake was then dried to a constant weight to give 664.3 g (55% yield) of the desired product as a white solid. Step 2: Synthesis of (5S.lRVl-(2-naphthylV3-azabicvclor3.1.01hexane HC1 salt

[00110] The amine-tosylate salt from step 1 (2037.9 g, 5.10 mol) was suspended in isopropylacetate ( 13.2 L) to give a white slurry in a 50 L 3 -neck RB equipped with an overhead stirrer, thermocouple, addition funnel, nitrogen inlet and drying tube.

Thionylchloride (445 mL, 6.12 mol, 1.20 eq) was then added via addition funnel over one hour 5 minutes. The maximum internal temperature was 24 °C. After stirring for 4 hours 15 minutes 5 molar aqueous sodium hydroxide (6.1 L, 30.5 mol, 5.98 eq) was added via addition funnel at a rate such that the maximum internal temperature was 30 °C. The mixture was then stirred for one hour 15 minutes after which the layers were allowed to settle and the layers were separated. The organic layer was washed with 1 molar aqueous sodium hydroxide (2.1 L). The aqueous layers were then combined and back extracted with isopropyl acetate (7.6 L). The organic layers were combined and washed with saturated aqueous brine (4.1 L). The organic layer was then dried over magnesium sulfate, filtered to remove solids, and then concentrated to a total volume of 4.2 L in vacuo. Hydrogen chloride in isopropyl alcohol (5.7 N, 0.90 L, 5.13 mol, 1 eq) was then added over 50 minutes using an external water/ice bath to keep the internal temperature less than 30 °C. After stirring for 45 minutes the solids were collected by filtration and the filtercake washed two times with isopropyl acetate, 2.3 L each wash. The filtercake was then partially dried and then taken forward to step 3 as a wetcake.

Step 3: Crude (5S.lRVl-(2-naphthyl -3-azabicvclof3.1.01hexane HC1 salt hot slurry in isopropyl alcohol

[00111] The wetcakes from two separate runs of step 2 (total of 4646.6 g starting amine tosylate salt) were combined and suspended in isopropyl alcohol (34.6 L) in a 50 L 3- neck round bottom flask equipped with overhead stirrer, heating mantel, thermocouple, reflux condenser, nitrogen inlet, and drying tube. The slurry was then heated to reflux, stirred for three hours at reflux, and then allowed to cool to room temperature. The solids were collected by filtration and the filtercake washed twice with isopropyl alcohol, 6.9 L each wash. The filtercake was then dried to a constant weight to give 2009.2 g of (5S,1R)-1- (2-naphthyl)-3-azabicyclo[3.1.0]hexane HCl salt (70 % yield from 4646.6 g of amine tosylate salt).

Step 4: Recrvstallization of (5S.lRVl-(2-naDhthvn-3-a2abicvclor3.1.01hexane HCl salt from ethanol to upgrade the enantiomeric excess

[00112] The (5S,lR)-l-(2-naphthyl)-3-azabicyclo[3.1.0]hexane HCl salt from step 3 (2009.2 g, 8.18 mol) was charged to a 50 L 3-neck round bottom flask equipped with an overhead stirrer, heating mantel, reflux condenser, nitrogen inlet, thermocouple, and drying tube. Ethanol (21.5 L of special industrial) was then added and the mixture heated to reflux to dissolve all solids. After dissolution of solids heating was discontinued and the mixture was allowed to cool to room temperature during which time solids reformed. The solids were then collected by filtration and the filtercake washed with ethanol (4.3 L). The filtercake was then dried to a constant weight to give 1434.6 g (71 % yield ) of recrystallized (5S,lR)-l-(2-naphthyl)-3-azabicyclo[3.1.0]hexane HCl salt. Chiral HPLC assay showed an enantiomeric excess of > 99.5 %.

Step 5: Rework to improve color profile

[00113] (5S,lR)-l-(2-naphthyl)-3-azabicyclo[3.1.0]hexane HCl (1405.6 g, 5.72 mol) was charged to a 22 L 3-neck round bottom flask equipped with overhead stirrer, heating mantel, thermocouple, nitrogen inlet and drying tube. Water (14.0 L) was added and the mixture heated to 34 °C to dissolve all solids. The solution was then transferred to a large separatory funnel and teti^ydrofuran (2.8 L) followed by isopropyl acetate (2.8 L) was added. The two phase mixture was agitated and the layers were then allowed to settle. The upper organic layer was discarded. Aqueous ammonia (1.14 L) was then added and the aqueous layer extracted with isopropylacetate (14.0 L). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give an off-white solid. The solid was dissolved in isopropyl alcohol (14.0L) and transferred to a 22 L 3-neck round bottom flask equipped with overhead stirrer, thermocouple, addition funnel, nitrogen inlet and drying tube. Hydrogen chloride in isopropyl alcohol (5.7 N, 175 mL, 1.0 mol) was then added over 10 minutes. Near the end of this addition the formation of solids was evident. The slurry was stirred for 30 minutes then additional hydrogen chloride in isopropanol (840 mL, 4.45 mol) was added over 65 minutes keeping the internal temperature less than 25 °C. The solids were collected by filtration and the filtercake washed twice with isopropyl alcohol, 2.8 L each wash. The filtercake was then dried to a constant weight to give 1277.1 g (91% yield) of the product as an off-white solid.

PATENTS

WO-2016205762

(lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as (+)-l- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, is a compound useful as an unbalanced triple reuptake inhibitor (TRI), most potent towards norepinephrine reuptake (NE), one-sixth as potent towards dopamine reuptake (DA), and one-fourteenth as much towards serotonin reuptake (5- HT). This compound and its utility are disclosed in more detail in U.S. Patent Publication No. 2007/0082940, the contents of which are hereby incorporated by reference in their entirety

Cited Patent	Filing date	Publication date	Applicant	Title
US20050096395 *	Feb 12, 2003	May 5, 2005	Rao Srinivas G.	Methods of treating attention deficit/hyperactivity disorder (adhd)
US20070082940 *	Jul 25, 2006	Apr 12, 2007	Phil Skolnick	Novel 1-aryl-3-azabicyclo[3.1.0]hexanes: preparation and use to treat neuropsychiatric disorders

Reference
1	*	See also references of EP2819516A4

Citing Patent	Filing date	Publication date	Applicant	Title
WO2015089111A1 *	Dec 9, 2014	Jun 18, 2015	Neurovance, Inc.	Novel methods
WO2015102826A1 *	Dec 9, 2014	Jul 9, 2015	Neurovance, Inc.	Novel compositions
US9133159 *	Apr 3, 2013	Sep 15, 2015	Neurovance, Inc.	1-heteroaryl-3-azabicyclo[3.1.0]hexanes, methods for their preparation and their use as medicaments
US9205074	Sep 23, 2014	Dec 8, 2015	Neurovance, Inc.	1-aryl-3-azabicyclo[3.1.0]hexanes: preparation and use to treat neuropsychiatric disorders
US20160303076 *	Dec 9, 2014	Oct 20, 2016	Neurovance, Inc.	Novel methods

References

Jump up^ “3-Neurotransmitters, 1-Molecule: Optimized Ratios”. Neurovance.
Jump up^ “EB-1020, a Non-Stimulant Norepinephrine and Dopamine – Preferring Reuptake Inhibitor for the Treatment of Adult ADHD” (PDF). Neurovance.
Jump up^ Frank P. Bymaster; Krystyna Golembiowska; Magdalena Kowalska; Yong Kee Choi; Frank I. Tarazi (June 2012). “Pharmacological characterization of the norepinephrine and dopamine reuptake inhibitor EB-1020: Implications for treatment of attention-deficit hyperactivity disorder”. Synapse. 66 (6): 522–532. doi:10.1002/syn.21538. PMID 22298359.

External links

Centanafadine – AdisInsight

1 to 9 of 9

Patent ID	Patent Title	Submitted Date	Granted Date
US9205074	1-aryl-3-azabicyclo[3.1.0]hexanes: preparation and use to treat neuropsychiatric disorders	2014-09-23	2015-12-08
US2015148399	Novel 1-Aryl-3-Azabicyclo[3.1.0]Hexanes: Preparation And Use To Treat Neuropsychiatric Disorders	2014-09-23	2015-05-28
US8877798	1-aryl-3-azabicyclo[3.1.0]hexanes: preparation and use to treat neuropsychiatric disorders	2013-05-05	2014-11-04
US2014228421	Methods For Inhibiting Native And Promiscuous Uptake Of Monoamine Neurotransmitters	2013-06-02	2014-08-14
US2014206740	Use Of (1R, 5S)-(+)-(Napthalen-2-yl)-3-Azabicyclo[3.1.0]Hexane In The Treatment Of Conditions Affected By Monoamine Neurotransmitters	2013-06-02	2014-07-24
US8461196	1-aryl-3-azabicyclo[3.1.0]hexanes: preparation and use to treat neuropsychiatric disorders	2012-02-03	2013-06-11
US2009233978	Novel 1-Aryl-3-Azabicyclo[3.1.0]Hexanes: Preparation And Use To Treat Neuropsychiatric Disorders	2009-09-17
US2008058535	METHODS AND COMPOSITIONS FOR PRODUCTION, FORMULATION AND USE OF 1 ARYL-3-AZABICYCLO[3.1.0]HEXANES	2008-03-06
US2007082940	Novel 1-aryl-3-azabicyclo[3.1.0]hexanes: preparation and use to treat neuropsychiatric disorders	2007-04-12

Centanafadine
Legal status

Legal status	Investigational New Drug
Identifiers
IUPAC name [show]
CAS Number	924012-43-1
PubChem (CID)	16095349
ChemSpider	17253639
Chemical and physical data
Formula	C₁₅H₁₅N
Molar mass	209.28 g/mol
3D model (Jmol)	Interactive image
SMILES C1=C(C=CC2=CC=CC=C12)[C@@]34C[C@@H]3CNC4

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

///////CENTANAFADINE, PHASE 2, UNII-D2A6T4UH9C, EB-1020, D2A6T4UH9C, 924012-43-1, CTN SR, EB-1020, EB-1020 SR,

C1C2C1(CNC2)C3=CC4=CC=CC=C4C=C3

Happy New Year's Eve from Google!

Niraparib; MK 4827

December 22, 2016 1:59 pm / 1 Comment on Niraparib; MK 4827

ChemSpider 2D Image | Niraparib | C19H20N4O

MK-4827,(S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxaMide

Niraparib; MK 4827; MK4827

UNII:HMC2H89N35

Antineoplastic, Poly(ADP-ribose) Polymerase Inhibitors

1038915-60-4 CAS, free form

1038915-64-8 CAS HYDROCHLORIDE

1613220-15-7 cas TOSYLATE MONOHYDRATE

Figure imgf000023_0001

1038915-73-9 TOSYLATE

1038915-73-9 TOSYLATE

MK-4827(Niraparib) tosylate is a selective inhibitor of PARP1/PARP2 with IC50 of 3.8 nM/2.1 nM; with great activity in cancer cells with mutant BRCA-1 and BRCA-2; >330-fold selective against PARP3, V-PARP and Tank1.
IC50 value: 3.8 nM/2.1 nM( PARP1/2) [1]
Target: PARP1/2
in vitro: MK-4827 displays excellent PARP 1 and 2 inhibition with IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibits PARP activity with EC(50) = 4 nM and inhibits proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) in the 10-100 nM range [1].
in vivo: MK-4827 is well tolerated in vivo and demonstrates efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer [1]. In addition, MK-4827 strongly enhances the effect of radiation on a variety of human tumor xenografts, both p53 wild type and p53 mutant. The enhancement of radiation response is observed in clinically relevant radiation-dose fractionation schedules. The therapeutic window during which time MK-4827 interacts with radiation lasts for several hours. These biological attributes make translation of this therapeutic combination treatment feasible for translation to the treatment of a variety of human cancers [2].

[1]. Jones P, et al. Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem. 2009 Nov 26;52(22):7170-85.

[2]. Wang L, et al. MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation. Invest New Drugs. 2012 Dec;30(6):2113-20.

MERCK

TESARO

An inhibitor of poly (ADP-ribose) polymerase (PARP) with potential antineoplastic activity. PARP Inhibitor MK4827 inhibits PARP activity, enhancing the accumulation of DNA strand breaks and promoting genomic instability and apoptosis. The PARP family of proteins detect and repair single strand DNA breaks by the base-excision repair (BER) pathway. The specific PARP family member target for PARP inhibitor MK4827 is unknown. (NCI Thesaurus)

Niraparib (originally MK-4827)^[1] is an orally active^[2] small molecule PARP inhibitor being developed (by Tesaro) to treat ovarian cancer.

It is an inhibitor of PARP1 and PARP2.^[3]

Niraparib is due to be submitted for FDA approval (for maintenance therapy in ovarian cancer) later in 2016.^[4]

Chemically, MK-4827 is C₁₉H₂₀N₄O^[5] (ignoring a possible tosylate group).^[6]

A 2012 study found that PARP inhibitors exhibit cytotoxic effects not based solely on their enzymatic inhibition of PARP, but by their trapping of PARP on damaged DNA, and the strength of this trapping activity was ordered niraparib >> olaparib >> veliparib.^[7]

MEDICINAL CHEMISTRY APPROACH

The Medicinal Chemistry approach to compound 1 is shown in Scheme ABOVE. The racemic piperidine 2 was accessed by reduction of the 3-aryl pyridine 3 and then resolved by salt formation with tartaric acid. Protection of the piperidine nitrogen in enantiomerically upgraded piperidine 2 and condensation with aldehyde 4 afforded imine 5 which, after displacement of the nitro group with sodium azide, underwent a thermally promoted cyclisation to afford the 2-aryl indazole 6. Conversion of the ester functionality to a primary amide and deprotection afforded the active pharmaceutical ingredient (API) as the hydrochloride salt. A final chiral HPLC purification was then required to upgrade the enantiomeric purity to >98% ee, followed by lyophilization to give the desired compound 1 as an amorphous HCl salt.

NMR CD3OD

Clinical trials

It has undergone a phase III trial for ovarian cancer.^[8] It is reported that the primary endpoint (progression-free survival, PFS) was met.^[4] Patients with and without a BRCA mutation both showed longer PFS.^[4]

As of June 2016 seven clinical trials have been registered for MK-4827.^[9]

PAPER

http://pubs.acs.org/doi/abs/10.1021/op400233z

Process Development of C–N Cross-Coupling and Enantioselective Biocatalytic Reactions for the Asymmetric Synthesis of Niraparib

Cheol K. Chung *†, Paul G. Bulger *†, Birgit Kosjek†, Kevin M. Belyk†, Nelo Rivera†, Mark E. Scott‡, Guy R. Humphrey†, John Limanto†, Donald C. Bachert§, and Khateeta M. Emerson§

^† Department of Process Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States

^‡ Department of Medicinal Chemistry, Merck & Co., Inc., Boston, Massachusetts 02115, United States

^§ Department of Chemical Process Development and Commercialization, Merck & Co., Inc., Rahway, New Jersey 07065, United States

Org. Process Res. Dev., 2014, 18 (1), pp 215–227

DOI: 10.1021/op400233z

*E-mail: cheol_chung@merck.com., *E-mail: paul_bulger@merck.com

This article is part of the Transition Metal-Mediated Carbon-Heteroatom Coupling Reactions special issue.

Abstract

Process development of the synthesis of the orally active poly(ADP-ribose)polymerase inhibitor niraparib is described. Two new asymmetric routes are reported, which converge on a high-yielding, regioselective, copper-catalyzed N-arylation of an indazole derivative as the late-stage fragment coupling step. Novel transaminase-mediated dynamic kinetic resolutions of racemic aldehyde surrogates provided enantioselective syntheses of the 3-aryl-piperidine coupling partner. Conversion of the C–N cross-coupling product to the final API was achieved by deprotection and salt metathesis to isolate the desired crystalline salt form.

PAPER

http://pubs.acs.org/doi/full/10.1021/op2000783

Development of a Fit-for-Purpose Large-Scale Synthesis of an Oral PARP Inhibitor

Debra J. Wallace *†, Carl A. Baxter†, Karel J. M. Brands†, Nadine Bremeyer†, Sarah E. Brewer†, Richard Desmond‡, Khateeta M. Emerson†, Jennifer Foley‡, Paul Fernandez§, Weifeng Hu⊥, Stephen P. Keen†, Peter Mullens†, Daniel Muzzio§, Peter Sajonz‡, Lushi Tan‡, Robert D. Wilson†, George Zhou§, and Guoyue Zhou⊥

Global Process Chemistry, Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, U.K.

Global Process Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, United States

Department of Chemical Process Development and Commercialization, Merck and Co., Rahway, New Jersey, 07065, USA

WuXi APPTec (Shanghai) Pharmaceutical Co. Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China

Org. Process Res. Dev., 2011, 15 (4), pp 831–840

DOI: 10.1021/op2000783

debra_wallace@merck.com.

Abstract

Compound (1) a poly(ADP-ribose)polymerase (PARP) inhibitor has been made by a fit-for-purpose large-scale synthesis using either a classical resolution or chiral chromatographic separation. The development and relative merits of each route are discussed, along with operational improvements and extensive safety evaluations of potentially hazardous reactions.

as tosylate H20

1613220-15-7 cas

Free form 1038915-60-4

2-[4-(3S)-3-Piperidinylphenyl]-2H-indazole-7-carboxamide
Niraparib
Jones, Philip; Journal of Medicinal Chemistry 2009, V52(22), P7170-7185
MK-4827

(S)-2-(4-(Piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide Tosylate Monohydrate 1

………………. The solid was collected and dried in vacuo at 40 °C to afford 1 as the tosylate monohydrate salt (797 g, 86%, >99 wt %, >99%ee) as a tan-coloured solid.

Mp = 144 °C. ¹H NMR (600 MHz, CD₃OD) δ 8.95 (1H, s), 8.15 (1H, dd, J = 7.1, 1.2 Hz), 8.02 (2H, m), 8.00 (1H, dd, J = 8.3, 1.2 Hz), 7.72 (2H, m), 7.49 (2H, m), 7.25 (1H, dd, J = 8.3, 7.1 Hz), 7.22 (2H, d, J = 8.0 Hz), 3.49–3.43 (2H, m), 3.16–3.04 (3H, m), 2.34 (3H, s), 2.09–2.05 (2H, m), 1.96–1.82 (2H, m).

¹³C NMR (150.9 MHz, CD₃OD) δ 169.7, 148.1, 143.7, 143.0, 141.9, 140.5, 131.8, 130.0, 129.8, 127.3, 127.1, 125.4, 124.2, 123.3, 122.4, 50.2, 45.2, 41.1, 30.9, 24.0, 21.4.

PAPER

Discovery of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors

Philip Jones *, Sergio Altamura, Julia Boueres, Federica Ferrigno, Massimiliano Fonsi, Claudia Giomini, Stefania Lamartina, Edith Monteagudo, Jesus M. Ontoria, Maria Vittoria Orsale, Maria Cecilia Palumbi, Silvia Pesci, Giuseppe Roscilli, Rita Scarpelli, Carsten Schultz-Fademrecht, Carlo Toniatti and Michael Rowley

IRBM/Merck Research Labs Rome, Via Pontina km 30,600, 00040 Pomezia, Italy

J. Med. Chem., 2009, 52 (22), pp 7170–7185

DOI: 10.1021/jm901188v, http://pubs.acs.org/doi/abs/10.1021/jm901188v

*To whom correspondence should be addressed. Current address: Department of Medicinal Chemistry, Merck Research Labs Boston, Avenue Louis Pasteur 33, Boston, MA 02115-5727. Phone: +1-617-992-2292. Fax: +1-617-992-2405. E-mail: philip_jones@merck.com.

Abstract

We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC₅₀ = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC₅₀ = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC₅₀ in the 10−100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.

PATENT

https://www.google.com/patents/WO2014088983A1?cl=en

Image result for niraparib

EXAMPLE 1

The following Example 1 describes synthesis of the compound 2-{4-[(3S)-Piperidin enyl}-2H-indazole-7-carboxamide:

2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate 1

Scheme

1.1 Acylation

2- crystalline

A mixture of succinic anhydride 1 (110 g) and bromobenzene (695 mL) was cooled to below 5°C then added A1C1₃ (294 g). The slurry was allowed to warm to RT and then aged until the reaction was complete judged by HPLC. The reaction mixture was then transferred slowly into a cold HC1 solution resulting in the formation of a white precipitate. The white slurry was filtered through a fritted funnel rinsing with H₂0. To the off-white product was added MTBE and extracted with aq. NaOH. The aqueous layer was cooled in an ice bath. Concentrated HC1 was added drop wise to adjust the solution pH to 1 , resulting in the formation of a white slurry. The slurry was collected on a fritted funnel, rinsed with H₂0, and dried under vacuum with a N₂ sweep at RT to give the target compound (265 g, 93% corrected yield) as a white powder.

1.2 Esterification

A mixture of the acid 2 (205 g), IPA (4 L) and cone. H₂S0₄ (2.13 mL / 3.91 g) was heated to a gentle reflux until the reaction was complete judged by HPLC. The solution was then cooled to RT and concentrated to a volume of 350-400 mL. The residue was dissolved in

MTBE (1.2 L), washed with aq. Na₂C0₃ followed by water. After dried over MgS0₄ , the filtrate was solvent-switched into heptane. The slurry was then filtered, and the cake was washed with cold heptane. After drying under vacuum, the target compound (223.5 g, 93% corrected yield) was obtained as a white powder.

1.3 Epoxidation

A mixture of Me₃SOI (230 g) and DMSO (300 mL) was added KOt-Bu (113 g) followed by DMSO (300 mL). The mixture was aged for a further 1.5 hr. In a separate flask, ketone 3 (230 g) was dissolved in a mixture of THF (250 mL) and DMSO (150 mL), and the resulting solution was added drop wise to the ylide solution. The mixture was aged for 2 hr at RT, added hexanes (1 L), and then quenched by the addition of ice-water (600 mL). The layers were cut, and the organic layer was washed with water then with brine. The slightly cloudy yellow organic layer was dried over Na₂S0₄ and filtered through a fritted funnel. Product solution assay was 176.1 g (76%> assay yield). This solution was carried forward into the rearrangement step. 1.4 Epoxide rearrangement and bisulfite formation

5 – not isolated

A solution of crude epoxide 4 (assay 59.5 g) in hexanes was solvent switched into PhMe, and added ZnBr₂ (10.7 g). When the rearrangement was complete judged by HPLC, the slurry was filtered through a fritted funnel. The clear filtrate was washed with 10% aq. NaCl and then stirred with a solution of sodium bisulfite (NaHS0₃, 24.7 g) in H₂0 (140 mL) vigorously at RT for 3 hr. The cloudy aqueous layer was separated and washed with heptanes. By 1H-NMR assay, the aqueous solution contained 71.15 g bisulfite adduct 6 (30.4 wt % solution, 90%) yield from crude epoxide 4). This solution was used directly in the subsequent transaminase step.

1.5 Transaminase DKR

45 C, inert, 40-46 hrs 7

100 g/L as 17.16 wt % aq solution 99.3% ee

85-87% yield

To a cylindrical Labfors reactor was charged pyridoxal-5 -phosphate (1.4 g, 5.66 mmol), 452 ml 0.2 M borate buffer pH 10.5 containing 1M iPrNH₂, 52 g transaminase (SEQ ID NO: 180), and 75 ml DMSO, and the resulting mixture was warmed to 45°C. The pH was controlled at pH 10.5 using 8 M aq iPrNH₂. To this was added dropwise a mixture of 17.16 wt% aq solution of ester bi-sulfite 6 (147.2 g, 353 mmol) and 219 ml DMSO under N₂ atmosphere. When the reaction was complete judged by HPLC, the reaction mixture was cooled and extracted with 1 volume of 3:2 IPA:IPAc. The aq/rag layer was extracted again with 1 volume of 3:7 IPATPAc. The organic layer was washed with brine at pH >9. Assay yield in solution was 78 g (87%); 99.3% ee. After dried over MgS0₄, and filtered through a fritted funnel, the crude solution was concentrated under vacuum flushing with IP Ac to remove IPA. The resulting slurry was concentrated to a final volume of -200 mL, cool to below 0°C, and filtered to collect the solid. The cake was washed with ice-cold IPAc and dried at RT under vacuum to give the desired product (84% corrected yield, 99.3 LCAP) as a white powder. 1.6. Reduction of amide

(S)-3-(4-bromophenyl)piperidine

The lactam 7 can be reduced to form the i eridine 8 as described below:

7 – crystalline

A mixture of lactam 7 (10.25 g at 97.5 wt %) in THF (100 mL) was cooled to < 10°C, and added NaBH₄ (4.47 g). EtOH (6.89 mL) was then added slowly over 20 min. The slurry was aged for an additional 1 hr at 2°C after which BF₃ THF (13.03 mL) was added over 1 hr. The slurry was slowly warmed to RT and aged until complete conversion judged by HPLC. The reaction was then cooled to < 5°C then slowly quenched with MeOH (7.96 mL), added HC1 (9.69 mL), then the reaction was heated to 45°C until decomplexation of product-borane complex was complete, as indicated by LC assay. The reaction was cooled, diluted with IPAc (75 mL) and water (80 mL), and then pH was adjusted with aqueous NH₄OH to pH 8. The organic layer was separated, added 75 mL water, then pH adjusted to 10.5 with 50 wt % NaOH. The layers were separated and the organic layer was washed with brine. After solvent-switched to IPAc, LC Assay yield was 9.1g; 95.9%.

1.7 Tosylate salt formation The tosylate salt of the piperidine 8 can be formed as described below:

The crude piperidine 8 free base in IPA was heated to ~40°C. TsOH H₂0 solids was added portion-wise. The slurry was warmed to 50°C and held at that temperature for 2 h, and then slowly cooled to RT and aged overnight. Supernatant concentration was measured to be 2.5 g/ml (free base concentration). The solids were filtered and washed with IP Ac (3×15 mL) and dried at RT. Isolated solides: 14.85 g, 96% corrected isolated yield.

1.8 Boc protection

The piperi ine 8 tosylate salt can be protected as described below:

To a stirred slurry of the tosylate salt of piperidine 8 (25.03 g, 60.6 mmol) in MTBE (375 ml) was added NaOH (aq. 1.0 N, 72.7 ml, 72.7 mmol) at RT. To the mixture, (BOC)₂0 (13.36 ml, 57.6 mmol) was added slowly over 3 min. The resulting mixture was stirred for 4.5 hr at RT, and then the aqueous layer was separated. The MTBE layer was washed with water (100 ml X 2). The organic layer was filtered, and DMAC (100 ml) was added to the filtrate and

concentrated under vacuum. Product assay: 21.86 g, quantitative yield.

1.9 Terf-Butylamide Formation

N-(tert-butyl)- 1 H-indazole-7-carboxamide

10 11

Indazole-7-carboxylic acid 10 (50.3 g, 295 mmol) was dissolved in DMF, and added CDI (59.1 g, 354 mmol) at RT. After 1.5hr, tert-butylamine (62.5 ml, 589 mmol) was added to the reaction mixture. The resulting reaction mixture was warmed to 40 °C until complete

conversion, then cooled to RT. Water (600 ml) was added dropwise causing the mixture to form a thick slurry. Solid was collected by filtration and washed with 10% DMF in water (250 ml) followed by water. The solid was dried under vacuum. Beige solid: 55.31 g, 86%> isolated yield.

1.10 Carbon-Nitrogen Coupling

(S)-tert-butyl 3-(4-(7-(tert-butylcarbamoyl)-2H-indazol-2-yl)phenyl)piperidine- 1 -carboxylate

A mixture of the protected piperidine 9 (113 g, 18.23 wt%, 60.6 mmol) in DMAc (160 mL), compound 11 (13.82 g, 63.6 mmol), and K₂CO₃ (25.6 g, 182 mmol) was degassed by bubbling nitrogen. To the mixture was added CuBr (0.444 g, 3.03 mmol) and 8- hydroxyquinoline 12 (0.889 g, 6.06 mmol), and the resulting mixture was warmed to 110°C until complete conversion. The reaction mixture was then cooled, filtered through a pad of Celite, and rinsed with DMAc (100 ml). The filtrate was warmed to 35°C and added citric acid aqueous solution (10%) dropwise to form a light green slurry. After cooled to room temperature, the slurry was filtered, and the cake was washed with DMAc/Water (2/1, 150ml) followed by copious amount of water. The solid was dried under vacuum with nitrogen. Net weight: 27.24g. LC assay: 26.77g, 98.3 wt %. Assay yield: 93.6%.

1.11 Double deprotection

To compound 13 (20.0 g, 41.2 mmol) was added MSA (60 ml) and o-xylene (40 ml), and the the reaction mixture was warmed to 40°C until the complete conversion judged by HPLC. The reaction mixture was cooled to RT and added water (140 ml) slowly maintaining the temperature < 25°C. When the water addition was completed, the organic layer was removed, and the aq. layer was washed with toluene. The aqueous layer was filtered through a glass funnel, and the filtrate was added an aqueos solution of TsOH (11.77g in 23.5 ml) slowly at RT causing a thick slurry to form. Solid was collected by filtration, washed with water, and dried under vacuum. The titled compound was obtained as a white powder. Net weight: 20.6 g. LC assay: 20.0 g, 97.3 wt %. Assay yield: 95.2%.

EXAMPLE 2

The following Example 2 describes synthesis of the trifluoromethylacetate salt of compound 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide:

2.1 Cumylamide Formation

N-(2-phenylpropan-2-yl)- 1 H-indazole-7-carboxamide

10 1 5

To the indazole-7-carboxylic acid 10 (400 mg, 2.47 mmol) in tetrahydrofuran (9.9 mL), was sequentially added HATU (1.13 g, 2.96 mmol), DIPEA (2.15 mL, 12.3 mmol), and cumylamine (500 mg, 3.70 mmol) at 50°C. The reaction was stirred overnight before being concentrated and loaded directly onto a silica column, eluting with 10-30% EtOAc/hexane. The product was collected and concentrated to afford the desired product as a colorless solid (557 mg, 81% yield).

2.2 Carbon-Nitrogen Coupling

-butyl 3-(4-(7-((2-phenylpropan-2-yl)carbamoyl)-2H-indazol-2-yl)phenyl)piperidine- carboxylate

15 16

A sealed vial containing the indazole-7-carboxamide 15 (50 mg, 0.18 mmol), copper(I) iodide (2.6 mg, 0.014 mmol), potassium phosphate tribasic (80 mg, 0.38 mmol), and aryl bromide 9 (73.1 mg, 0.215 mmol) was evacuated and backfilled with argon (x3). Trans-N,N’- dimethylcyclohexane-l,2-diamine (11.3 μΐ,, 0.072 mmol), and toluene (179 μΐ) were then added successively and the sealed vial was heated at 110 °C overnight. The vial was then cooled and toluene (0.30 mL) was added to the slurry. Crude LC/MS indicated >20: 1 selectivity for the desired indazole isomer. The crude product was purified by loading directly onto a Biotage Snap 10G silica column, eluting with 5-50% EtOAc/hexane. The product was collected and concentrated to afford the desired product as a colorless solid (78 mg, 81% yield).

2.3 Double deprotection

(5)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide trifluoromethylacetate salt

16 17

To the piperidine-l-carboxylate 16 (45 mg, 0.084 mmol), was added triethylsilane (267 μί, 1.67 mmol) and TFA (0.965 mL, 12.5 mmol) at 25°C. The reaction was stirred for 4 hours and the reaction was concentrated in vacuo, and purified by mass triggered reverse phase HPLC (acetonitrile: water, with 0.1% TFA modifier). Lyphilization gave the desired product as the TFA salt and as a white solid (31 mg, 85% yield). HRMS (ESI) calc’d for Ci₉H₂iN₄0 [M+H]⁺: 321.1710, found 321.1710.

EXAMPLE 3

Following the conditions used in sections 2.1 and 2.2 of Example 2, this Example 3 shows regioselective N2 arylation of compound 9 using various amide protecting groups. The indazole-7-carboxylic acid 10 was reacted with various amines to generate a protected amide.

The amide protecting groups are indicated by the R group in Table 2. The amide coupling yield is provided in Table 2. The Cu-mediated carbon-nitrogen coupling of this indazole to compound 9 was then tested to determine if regioselective N2 arylation was possible. The arylation yield is also provided in Table 2. The data shows that various amide protecting groups on the indazole intermediate are suitable to generate efficient regioselective N2 arylation of compound 9.

PATENT

WO 2008084261

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=3F0FFB4E6F55421A36EDCCB09D1D1B6E.wapp1nC?docId=WO2008084261&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

The present invention relates to amide substituted indazoles which are inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), previously known as poly(ADP-ribose)synthase and poly(ADP-ribosyl)transferase. The compounds of the present invention are useful as monotherapies in tumors with specific defects in DNA-repair pathways and as enhancers of certain DNA-damaging agents such as anticancer agents and radiotherapy. Further, the compounds of the present invention are useful for reducing cell necrosis (in stroke and myocardial infarction), down regulating inflammation and tissue injury, treating retroviral infections and protecting against the toxicity of chemotherapy.
Poly(ADP-ribose) polymerase (PARP) constitute a super family of eighteen proteins containing PARP catalytic domains (Bioessays (2004) 26:1148). These proteins include PARP-1, PARP-2, PARP-3, tankyrase-1, tankyrase-2, vaultPARP and TiPARP. PARP-I, the founding member, consists of three main domains: an amino (N)-terminal DNA-binding domain (DBD) containing two zinc fingers, the automodification domain, and a carboxy (C)-terminal catalytic domain.
PARP are nuclear and cytoplasmic enzymes that cleave NAD⁺ to nicotinamide and ADP-ribose to form long and branched ADP-ribose polymers on target proteins, including
topoisomerases, histones and PARP itself (Biochem. Biophys. Res. Commun. (1998) 245:1-10).

Poly(ADP-ribosyl)ation has been implicated in several biological processes, including DNA repair, gene transcription, cell cycle progression, cell death, chromatin functions and genomic stability.
The catalytic activity of PARP-I and PARP-2 has been shown to be promptly stimulated by DNA strand breakages (see Pharmacological Research (2005) 52:25-33). In response to DNA damage, PARP-I binds to single and double DNA nicks. Under normal physiological conditions there is minimal PARP activity, however, upon DNA damage an immediate activation of PARP activity of up to 500-fold occurs. Both PARP-I and PARP-2 detect DNA strand interruptions acting as nick sensors, providing rapid signals to halt transcription and recruiting the enzymes required for DNA repair at the site of damage. Since radiotherapy and many chemotherapeutic approaches to cancer therapy act by inducing DNA damage, PARP inhibitors are useful as chemo- and radiosensitizers for cancer treatment. PARP inhibitors have been reported to be effective in radio sensitizing hypoxic tumor cells (US 5,032,617, US
5,215,738 and US 5,041,653).
Most of the biological effects of PARP relate to this poly (ADP-ribosyl)ation process which influences the properties and function of the target proteins; to the PAR oligomers that, when cleaved from poly(ADP-ribosyl)ated proteins, confer distinct cellular effects; the physical association of PARP with nuclear proteins to form functional complexes; and the lowering of the cellular level of its substrate NAD⁺ (Nature Review (2005) 4:421-440).
Besides being involved in DNA repair, PARP may also act as a mediator of cell death. Its excessive activation in pathological conditions such as ischemia and reperfusion injury can result in substantial depletion of the intercellular NAD⁺, which can lead to the impairment of several NAD⁺ dependent metabolic pathways and result in cell death (see Pharmacological Research (2005) 52:44-59). As a result of PARP activation, NAD⁺ levels significantly decline. Extensive PARP activation leads to severe depletion OfNAD⁺ in cells suffering from massive DNA damage. The short half-life of poly(ADP-ribose) results in a rapid turnover rate, as once poly(ADP-ribose) is formed, it is quickly degraded by the constitutively active poly(ADP-ribose) glycohydrolase (PARG). PARP and PARG form a cycle that converts a large amount OfNAD⁺ to ADP-ribose, causing a drop OfNAD⁺ and ATP to less than 20% of the normal level. Such a scenario is especially detrimental during ischemia when deprivation of oxygen has already drastically compromised cellular energy output. Subsequent free radical production during reperfusion is assumed to be a major cause of tissue damage. Part of the ATP drop, which is typical in many organs during ischemia and reperfusion, could be linked to NAD⁺ depletion due to poly(ADP-ribose) turnover. Thus, PARP inhibition is expected to preserve the cellular energy level thereby potentiating the survival of ischemic tissues after insult. Compounds which are inhibitors of PARP are therefore useful for treating conditions which result from PARP mediated cell death, including neurological conditions such as stroke, trauma and Parkinson’s disease.
PARP inhibitors have been demonstrated as being useful for the specific killing of BRCA-I and BRCA-2 deficient tumors {Nature (2005) 434:913-916 and 917-921; and Cancer Biology & Therapy (2005) 4:934-936).
PARP inhibitors have been shown to enhance the efficacy of anticancer drugs
{Pharmacological Research (2005) 52:25-33), including platinum compounds such as cisplatin and carboplatin {Cancer Chemother Pharmacol (1993) 33:157-162 and MoI Cancer Ther (2003) 2:371-382). PARP inhibitors have been shown to increase the antitumor activity of
topoisomerase I inhibitors such as Irinotecan and Topotecan (MoI Cancer Ther (2003) 2:371-382; and Clin Cancer Res (2000) 6:2860-2867) and this has been demonstrated in in vivo models (J Natl Cancer Inst (2004) 96:56-67).
PARP inhibitors have been shown to restore susceptibility to the cytotoxic and antiproliferative effects of temozolomide (TMZ) (see Curr Med Chem (2002) 9:1285-1301 and Med Chem Rev Online (2004) 1:144-150). This has been demonstrated in a number of in vitro models (Br J Cancer (1995) 72:849-856; Br J Cancer (1996) 74:1030-1036; MoI Pharmacol (1997) 52:249-258; Leukemia (1999) 13:901-909; GUa (2002) 40:44-54; and Clin Cancer Res (2000) 6:2860-2867 and (2004) 10:881-889) and in vivo models (Blood (2002) 99:2241-2244; Clin Cancer Res (2003) 9:5370-5379 and J Natl Cancer Inst (2004) 96:56-67). PAPR inhibitors have also been shown to prevent the appearance of necrosis induced by selective Λ3 -adenine methylating agents such as MeOSC>2(CH2)-lexitropsin (Me-Lex) {Pharmacological Research (2005) 52:25-33).
PARP inhibitors have been shown to act as radiation sensitizers. PARP inhibitors have been reported to be effective in radiosensitizing (hypoxic) tumor cells and effective in preventing tumor cells from recovering from potentially lethal {Br. J. Cancer (1984) 49(Suppl. VI):34-42; and Int. J. Radial Bioi. (1999) 75:91-100) and sub-lethal {Clin. Oncol. (2004) 16(l):29-39) damage of DNA after radiation therapy, presumably by their ability to prevent DNA strand break rejoining and by affecting several DNA damage signaling pathways.
PARP inhibitors have also been shown to be useful for treating acute and chronic myocardial diseases (see Pharmacological Research (2005) 52:34-43). For instance, it has been demonstrated that single injections of PARP inhibitors have reduced the infarct size caused by ischemia and reperfusion of the heart or skeletal muscle in rabbits. In these studies, a single injection of 3-amino-benzamide (10 mg/kg), either one minute before occlusion or one minute before reperfusion, caused similar reductions in infarct size in the heart (32-42%) while 1,5-dihydroxyisoquinoline (1 mg/kg), another PARP inhibitor, reduced infarct size by a comparable degree (38-48%). These results make it reasonable to assume that PARP inhibitors could salvage previously ischemic heart or reperfusion injury of skeletal muscle tissue {PNAS (1997) 94:679-683). Similar findings have also been reported in pigs {Eur. J. Pharmacol. (1998) 359:143-150 and Ann. Thorαc. Surg. (2002) 73:575-581) and in dogs (Shock. (2004) 21:426-32). PARP inhibitors have been demonstrated as being useful for treating certain vascular diseases, septic shock, ischemic injury and neurotoxicity {Biochim. Biophys. Actα (1989) 1014:1-7; J Clin. Invest. (1997) 100: 723-735). Oxygen radical DNA damage that leads to strand breaks in DNA, which are subsequently recognized by PARP, is a major contributing factor to such disease states as shown by PARP inhibitor studies (J Neurosci. Res. (1994) 39:38-46 and PNAS (1996) 93:4688-4692). PARP has also been demonstrated to play a role in the
pathogenesis of hemorrhagic shock {PNAS (2000) 97:10203-10208).
PARP inhibitors have been demonstrated as being useful for treatment of inflammation diseases (see Pharmacological Research (2005) 52:72-82 and 83-92).
It has also been demonstrated that efficient retroviral infection of mammalian cells is blocked by the inhibition of PARP activity. Such inhibition of recombinant retroviral vector infections has been shown to occur in various different cell types (J Virology, (1996)
70(6): 3992-4000). Inhibitors of PARP have thus been developed for use in anti- viral therapies and in cancer treatment (WO 91/18591).
In vitro and in vivo experiments have demonstrated that PARP inhibitors can be used for the treatment or prevention of autoimmune diseases such as Type I diabetes and diabetic complications {Pharmacological Research (2005) 52:60-71).
PARP inhibition has been speculated as delaying the onset of aging characteristics in human fibroblasts {Biochem. Biophys. Res. Comm. (1994) 201(2):665-672 and Pharmacological Research (2005) 52:93-99). This may be related to the role that PARP plays in controlling telomere function (Nature Gen., (1999) 23(l):76-80).
The vast majority of PARP inhibitors to date interact with the nicotinamide binding domain of the enzyme and behave as competitive inhibitors with respect to NAD⁺(Expert Opin. Ther. Patents (2004) 14:1531-1551). Structural analogues of nicotinamide, such as benzamide and derivatives were among the first compounds to be investigated as PARP inhibitors.
However, these molecules have a weak inhibitory activity and possess other effects unrelated to PARP inhibition. Thus, there is a need to provide potent inhibitors of the PARP enzyme.
Structurally related PARP inhibitors have previously been described. WO 1999/59973 discloses amide substituted benzene rings fused to 5 membered heteroaromatic rings;
WO2001/85687 discloses amide substituted indoles; WO 1997/04771, WO 2000/26192, WO 2000/32579, WO 2000/64878, WO 2000/68206, WO 2001/21615, WO 2002/068407, WO 2003/106430 and WO 2004/096793 disclose amide substituted benzo imidazoles; WO
2000/29384 discloses amide substituted benzoimidazoles and indoles; and EP 0879820 discloses amide substituted benzoxazoles.
It has now surprisingly been discovered that amide substituted indazoles of the present invention exhibit particularly high levels of inibition of the activity of poly(ADP-ribose)polymerase (PARP). Thus the compounds of the present invention are particularly useful as inhibitors of PARP-I and/or PARP-2. They also show particularly good levels of cellular activity, demonstrating good anti-proliferative effects in BRCAl and BRCA2 deficient cell lines.

The present invention provides compounds of formula I:

Scheme 1

A procedure to synthesize derivatives of those compounds of this invention is shown in scheme 1, whereby the substituted 2H-indazoles are prepared using a synthetic route similar to that described in WO 2005/066136. Following initial conversion of the 2-nitro-3-methyl-benzoic acid derivative into the corresponding ester, radical bromination of the methyl group using reagents like N-bromosuccinimide and benzoyl peroxide yields the key benzyl bromide derivative. Oxidation of this benzylic bromide to the corresponding benzaldehyde can be accomplished for instance using 7V-methylmorpholine-7V-oxide and molecular sieves. Following the condensation of the aldehyde with an amine, ring closure can be accomplished by treating the key intermediate with sodium azide at elevated temperature to introduce the final nitrogen atom and the resultant extrusion of nitrogen to furnish the indazole ring. A base such as lutidine can also be added to this reaction. Final conversion of the ester to the primary amide yields the desired derivatives. This can be accomplished either by heating the ester in an ammonia solution or by conversion to the corresponding carboxylic acid and then amide coupling.

R^x = C_1-6alkyl
Oxidation
e.g. NMMO, mol sieves

NH₃, THF or MeOH,
70⁰C sealed tube, or
NaOH or KOH, NH₃, HATU
or TBTU, DIPEA, DMF, RT
Scheme 1

Scheme 2
A variation of schemes 1 is shown below in scheme 2 and allows the introduction of substituents onto the indazole cores. When the required nitrobenzoic acid derivatives are not commercial available they can be prepared through nitration of the corresponding benzoic acid derivatives, for instance using potassium nitrate in concentrated sulphuric acid. Synthetic manipulations as decribed above allow the formation of the corresponding aniline which can either be cyclised to the indazole by firstly acetylation of the indazole and cyclisation with sodium nitrite in concentrated HCl acid at O⁰C. Alternatively, the aniline can be diazonitised with nitrosium tetrafluoroborate and the corresponding diazonium tetrafluoroborate salt decomposed at elevated temperatures to the corresponding dilfluorobenzene derivative by a Schiemann reaction
(Caution). Following the synthetic sequence as described in scheme 1 allows oxidation of the benzylic methyl group to the corresponding aldehyde and elaboration of the desired indazole derivatives by coupling with a (hetero)anilide and cyclisation with sodium azide.

Nitration Esterifi cation
KNO₃, cone. e.g. AcCI, MeOH,

Reduction
H₂, Pd/C

Scheme 2 Scheme 3
An alternative procedure involves functionalisation of the indazole at a late stage as shown in scheme 3. Here the indazole ester is first converted to the corresponding carboxamide and the subjected to nucleophilic aromatic substitution of the appropriate fluoro(hetero)aromatic bromide. This allows the preparation of a bromide derivative that can be cross coupled under Suzuki coupling conditions, for instance using tri(tert-butyl)phosphine and Pd2(dba)₃ as catalysts in the presence of a base, such as sodium carbonate. Conversion to the desied piperidine moiety is then accomplished by a Fowler reaction using an acyl chloride, such as CBz-Cl and a reducing agent such as NaBH₄. Final hydrogenation reaction can yield the corresponding piperidine derivatives.

Suzuki coupling

Scheme 3

PATENT

WO 2009087381

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009087381&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PATENT CITATIONS

Cited Patent	Filing date	Publication date	Applicant	Title
US8071623 *	Jan 8, 2008	Dec 6, 2011	Instituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa	Amide substituted indazoles as poly(ADP-ribose)polymerase(PARP) inhibitors
US8129377 *	Sep 29, 2005	Mar 6, 2012	Mitsubishi Tanabe Pharma Corporation	6-(pyridinyl)-4-pyrimidone derivates as tau protein kinase 1 inhibitors
US20100286203 *	Jan 8, 2009	Nov 11, 2010	Foley Jennifer R	Pharmaceutically acceptable salts of 2–2h-indazole-7-carboxamide

* Cited by examiner

NON-PATENT CITATIONS

Reference
1	*	CHUNG ET AL.: “Process Development of C-N Cross-Coupling and Enantioselective Biocatalytic Reactions for the Asymmetric Synthesis of Niraparib.“, ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 18, no. 1, 2014, pages 215 – 227, XP055263728
2	*	JONES ET AL.: “Discovery of 2-(4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide ( MK -4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors.“, JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, no. 22, 2009, pages 7170 – 7185, XP055263725
3	*	WALLACE ET AL.: “Development of a Fit-for-Purpose Large-Scale Synthesis of an Oral PARP Inhibitor.“, ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 15, no. 4, 2011, pages 831 – 840, XP055263721

* Cited by examiner

REFERENCED BY

Citing Patent	Filing date	Publication date	Applicant	Title
WO2016025359A1 *	Aug 10, 2015	Feb 18, 2016	Merck Sharp & Dohme Corp.	Processes for the preparation of a bace inhibitor

References

Jump up^ “PARP Inhibitors in Oncology. Chemosensitizers or Single-Agent Therapeutics?” (PDF). July 2009.
Jump up^ A Phase III Trial of Niraparib Versus Physician’s Choice in HER2 Negative, Germline BRCA Mutation-positive Breast Cancer Patients (BRAVO)
Jump up^ “PARP inhibitor, MK-4827, shows anti-tumor activity in first trial in humans”. 17 Nov 2010.
^ Jump up to:^a ^b ^c Tesaro’s PARP ovarian cancer drug hits PhIII goal; prepares to file. June 2016
Jump up^ MK-4827 @ pubchem
Jump up^ MK-4827
Jump up^ Murai, Junko, et al. “Trapping of PARP1 and PARP2 by clinical PARP inhibitors.” Cancer research 72.21 (2012): 5588-5599.
Jump up^ AbbVie takes PARP inhibitor into third phase III trial. June 2014
Jump up^ Niraparib studies

Patent ID	Patent Title	Submitted Date	Granted Date
US2015299167	Regioselective N-2 Arylation of Indazoles	2013-12-03	2015-10-22
US8889707	Treatment of addiction	2013-02-07	2014-11-18
US2013184342	METHODS AND COMPOSITIONS FOR TREATMENT OF CANCER AND AUTOIMMUNE DISEASE	2013-03-13	2013-07-18
US2012035244	PARP1 TARGETED THERAPY	2012-02-09
US8071623	Amide substituted indazoles as poly(ADP-ribose)polymerase(PARP) inhibitors	2008-07-10	2011-12-06
US2010286203	PHARMACEUTICALLY ACCEPTABLE SALTS OF 2–2H-INDAZOLE-7-CARBOXAMIDE	2010-11-11

Niraparib

Clinical data
Routes of administration	By mouth
Legal status
Legal status	US: Investigational
Identifiers
IUPAC name [show]
CAS Number	1038915-60-4
PubChem (CID)	24958200
ChemSpider	24531930
UNII	HMC2H89N35
ChEMBL	CHEMBL1094636
Chemical and physical data
Formula	C19H20N4O
Molar mass	320.394 g/mol
3D model (Jmol)	Interactive image
SMILES c1cc2cn(nc2c(c1)C(=O)N)c3ccc(cc3)[C@@H]4CCCNC4

EMA issues new Guideline on “Chemistry of Active Substances”

December 22, 2016 11:36 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

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The new EMA “Guideline on the chemistry of active substances” represents the current state of the art in regulatory practice and fits into the context of the ICH Guidelines Q8-11. Find out what information regarding active substances European authorities expect in an authorization application.

http://www.gmp-compliance.org/enews_05704_EMA-issues-new-Guideline-on-%22Chemistry-of-Active-Substances%22_15982,15721,S-WKS_n.html

A medicinal product authorization application requires comprehensive information on origin and quality of an active substance. What information is required was defined in two Guidelines so far: the Guideline “Chemistry of Active Substances” (3AQ5a) from 1987 and the “Guideline on the Chemistry of New Active Substances” from 2004. Because both Guidelines’ content do not take into account the ICH Guidelines Q8-11 issued in the meantime and do thus not meet the current state of the art in sciences and in regulatory practice, the EMA Quality Working Party (QWP) developed an updated document entitled “Guideline on the chemistry of active substances” (EMA/454576/2016), which was issued…

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MODANAFIL

December 11, 2016 4:58 am / 1 Comment on MODANAFIL

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MODANAFIL

Modafinil; 68693-11-8; Provigil; Modiodal; 2-[(diphenylmethyl)sulfinyl]acetamide; Modafinilum [Latin]
Molecular Formula:	C₁₅H₁₅NO₂S
Molecular Weight:	273.35 g/mol

Patent EP0966962 and Patent US2002043207.

Modafinil (INN,^[6] USAN, BAN, JAN) is a wakefulness-promoting agent (or eugeroic) used for treatment of disorders such as narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea.^[7] It has also seen widespread off-label use as a purported cognition-enhancing agent. In English-speaking countries it is sold under the brand names Alertec, Modavigil, and Provigil. In the United States modafinil is classified as a schedule IV controlled substance and restricted in availability and usage, due to concerns about possible addiction potential. In most other countries it is a prescription drug but not otherwise legally restricted.

Although the mechanism of action of modafinil was initially unknown, it now appears that the drug acts as a selective, relatively weak, atypical dopamine reuptake inhibitor. However, it appears that other additional mechanisms may also be at play.

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History

Modafinil was originally developed in France by neurophysiologist and emeritus experimental medicine professor Michel Jouvet and Lafon Laboratories. Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, including adrafinil, which was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil, lacking the polar -OH group on its terminal amide,^[77] and has similar activity to the parent drug but is much more widely used. It has been prescribed in France since 1994 under the name Modiodal, and in the US since 1998 as Provigil.

In 1998, modafinil was approved by the U.S. Food and Drug Administration^[78] for the treatment of narcolepsy and in 2003 for shift work sleep disorder and obstructive sleep apnea/hypopnea^[79] even though caffeine and amphetamine were shown to be more wakefulness promoting on the Stanford Sleepiness Test Score than modafinil.^[80]

It was approved for use in the UK in December 2002. Modafinil is marketed in the US by Cephalon Inc., who originally leased the rights from Lafon, but eventually purchased the company in 2001.

Cephalon began to market the R-enantiomer armodafinil of modafinil in the U.S. in 2007. After protracted patent litigation and negotiations (see below), generic versions of modafinil became available in the U.S. in 2012.

That’s how it went…

2-benzhydryl-sulfanylacetamide.

Diphenylbromomethane (4,95g = 0.02 moles) and thiourea (1,52g=0.02moles) were refluxed in 20mls water for 30mins. As the synth from Rh’s says, a clear solution must have been formed in 5 mins, but in the end we still had a lot of oil at the bottom (the reasion to blame was old, semidecomposed diphenylbromomethane – when we opened the can, it emitted HBr). We were too lazy to separate the oil , so 2.5g (0.04moles) KOH in 15mls water was added straight and the reflux continued for 30 more mins. A disgusting stench filled the lab.

Thus obtained solution of potassium salt of diphenylmercaptane was cooled to 50-60 C and 1.9g (0.02moles) of chloroacetamide was added thereto. The mixtr was left to its own devices for 2hours – the precipitated oil crystallized. The xtals were filtered, washed thrice w/water, thrice w/ether (removing all benzhydrol). After drying there was obtained 1.9g (37%) of finely divided crystals with mp of 111 C.

With fresh diphenylbromomethane this will give not less than 80% – otherwise I’ll bee a reddish (this is an idiom which I am again unable to translate).

Modafinil

Into the solution of 3.6g benzhydrylsulfanylacetamide (0.014moles) in 15mls of GAA there was added 3mls (~0.03moles) 30% hydrogene peroxide. The mixture was left at RT (15 Ñ in our case, better not to heat above) for 20 hrs. Then into the solution there was added 30mls aqua, scratching the walls with a glass rod. After 1 hr the precipitate was filtered, washed w/water twice, then w/ether and dried. Yield – 2,3g (61%), mp – 158-159 C. After some time the mother liquor yielded some more product but we were too lazy to work it up.

PATENT
Patent US2002183552

This is a part of the experimental section:

Preparation of isothiouronium Salt (IV).

Diphenylmethanol (130 g, 0.7 mole) and thiourea (65 g, 0.85 mole) are added in 0.5 L reactor charging with water (325 ml). The mixture is heated to 95°C. (an emulsion is obtained) and 48% HBr (260 gr. 3.22 mole, 4.6 equivalents) is then added gradually during 0.5 hour. The mixture is heated under reflux {106-107°C) for 0.5 hour and cooled to 80-85°C. At this temperature, the mixture is seeded with several crystals of the product and the mixture is stirred at that temperature for 0.5 hour and then cooled to 25°C. The colorless crystals are collected by filtration, washed with water (200 ml) yielding about 240 gr. of wet crude isothiouronium salt.

Preparation of diphenylmethylthioacetamide.

A 2 L reactor was charged with diphenylmethylisothiouronium bromide crude wet obtained (240 gr.) and water {700 mL) under nitrogen. The suspension was heated to 60°C and 46% aqueous NaOH solution (98 ml, 1.68 mole, 2.4 eq.) was added. The reaction mixture was heated to 85°C and stirred until all the solid was dissolved. Then, it was cooled to 60°C and chloroacetamide (80 g, O.84 mole, 1.2 eq.) was added in five portions hour at 60-70°C during one hour. The suspension is stirred at 70°C for 4-5 hours. The mixture was filtered while warm and the cake was washed with hot water (250 ml). Diphenylmethylthioacetamide crude wet is obtained [220 gr., HPLC assay: 78%, HPLC purity: 95%, yield: 95% (from diphenylmethanol.)]

20 gr. of the product was recrystallized twice from ethyl acetate, dried in vacuo to give 15 gr. of pure title compound.

Preparation of Modafinil.

A 1.0 L reactor was charged with diphenylmethylthioacetamide crude wet (220 gr.) obtained above and glacial acetic acid (610 mL). The mixture was heated to 40°C and stirred until full dissolution is achieved. 5.8% H2O2 solution (500g, 1.2 eq) was added dropwise during 0.5 hours at 40-45°C. The reaction mixture was stirred at 40-45°C for 4 hours. Then sodium metabisulfite (18.3g) in 610 mL water was added in order to quench the unreacted H2O2 and the suspension was stirred for 0.5 hours. Then the reaction mixture was cooled to 15°C and filtered. The cake was washed with water (610 mL) and dried on air to obtain crude wet Modafinil (205 g). Reslurry in refluxing ethyl acetate, followed by recrystallization from methanol:water (4:1) solution afforded pure Modafinil [125 g, HPLC assay: 99.9%, HPLC purity: 99.9%, yield: 67% (from diphenylmethanol)]. tongue

CLIP

Anti-Narcoleptic Agent Modaﬁnil and Its Sulfone: A Novel
Facile Synthesis and Potential Anti-Epileptic Activity
Nithiananda Chatterjie, James P. Stables, Hsin Wang, and George J. Alexander
Neurochemical Research, Vol. 29, No. 8, August 2004 (© 2004), pp. 1481–1486

Abstract:

We report a facile procedure to synthesize racemic modaﬁnil (diphenylmethylsulﬁnylacetamide), which is now being used in pharmacotherapy, and its achiral oxidized derivative (diphenylmethylsulfonyl acetamide). Modaﬁnil is of interest more than for its potential anti-narcoleptic activity. It has also been reported to have neuroprotective properties and may potentially be effective in the enhancement of vigilance and cognitive performance. Finally, it may also protect from subclinical seizures that have been implicated as causative factors in autistic spectrum disorders and other neurodegenerative conditions. This agent can now be synthesized simply and in larger amounts than previously, making it more readily available for testing in various research modalities. The described procedure also lends itself to production of several other amides of potential interest. We are currently in the process of synthesizing and testing several new derivatives in this series. The anticonvulsant properties of modaﬁnil and its sulfone derivative have not previously been extensively described in the literature. It may be of interest to note that the oxidized derivative of modaﬁnil is also nontoxic and almost as effective as an anticonvulsant as the parent.

Experimental

Diphenylmethylthioacetic Acid (3)
Benzhydryl bromide (14.78 gm, 0.059 mole) was dissolved in 75 ml of acetone in a 250-ml round-bottomed ﬂask. To this solution was added dropwise sodium mercaptoacetate (6.59 g, 0.058 mole) in about 60 ml of H2O; the mixture was stirred under N2 for 2 h at room temperature and was thereafter warmed at about 60–70°C for 1 h. The reaction mixture was evaporated to dryness and taken up in CH2Cl2 and saturated aqueous NaHCO3. The organic extract was rejected, and the aqueous phase was treated with acid to pH 2 and chilled. Suction ﬁltration gave the 6.9 g of the acid (3, 46%), mp 125°C. Rf 0.2. Recrystallization from MeOH/H2O gave mp 126–128°C.

Diphenylmethylthioacetamide (4)
Diphenylmethylthioacetic acid (19.5 g, 0.076 mole)
in 114 ml of dry benzene was taken in a 250-ml roundbottomed
ﬂask attached to a reﬂux condenser, under N2 gas. To this was added thionyl chloride (19.5 ml, 0.097 mole) with a dropping funnel. The mixture was stirred at room temperature with a magnetic stirrer and reﬂuxed for 1 h. Thereafter, the mixture was evaporated under low pressure to give a yellow oil that was taken up in about 100 ml of CH2Cl2 and ﬁltered to yield a clear orange solution. This was chilled in ice water and added slowly to an ice-cold solution of concentrated NH4OH in H2O (40:40 ml). The ensuing mixture was stirred for 1 h and shaken well in a separatory funnel. The organic layer was dried (Na2SO4) and evaporated to dryness to give 14.39 g (54%) of the amide (4), mp 108–109°C (lit2 110°C). Rf 0.8. Recrystallization from CH3OH/H2O gave mp 109–110°C.

Diphenylmethylsulﬁnylacetamide (modaﬁnil, 1)
Diphenylthioacetamide (3.46 g, 0.013 mole) was taken in glacial acetic acid (14 ml) with stirring; to this was added 1.34 ml of 30% H2O2 with chilling in ice water. The mixture was left in the refrigerator for 4 h and thereafter worked up by treating it with 70 ml of ice-cold water. The precipitated material was ﬁltered under suction and washed with ice-cold water to give 1.5 g of white crystals (43%), mp 159–160°C. Rf 0.6. Recrystallization from hot MeOH gave mp 161–162°C

Diphenylmethylsufonylacetamide (2)
Diphenylmethylthioacetamide (2.5 g, 0.009 mole) (reg. No. 118779-53-6) was dissolved in about 12 ml of glacial acetic acid and 3 ml of 30% H2O2 and set aside overnight (16 h or more). The next day, the mixture was diluted with 100 ml of H2O and set aside to cool in the refrigerator. Upon ﬁltration and drying, 2.1 g (80%) of 2 was obtained as a white powder. Rf 0.89. The melting point of sample after recrystallization from absolute EtOH was 195–197°C.

One aspect of our preparation of modaﬁnil needs further mention. When diphenylmethylthioacetamide (4) is being oxidized by H2O2, care must be taken to keep the reaction mixture cool, and workup should be done in a timely manner. Allowing the reaction to go to 24 h or longer at room temperature results in the formation of the sulfone (2). The paper by Mu et al. (3) does not discuss this possibility. In our hands, the procedure stated therein led to the higher melting sulfone and not the modaﬁnil. Our NMR data for the newly prepared modaﬁnil preparation are in consonance with the data of the patented commercial product. It should be noted that the methylene protons in modaﬁnil are geminally
coupled and appear as a pair of doublets. This is due to the fact that the adjacent sulfoxide moiety is chiral, and therefore the methylene protons adjacent to it wind up being diastereotopic with different chemical shifts and coupling. In the sulfone 2, the methylene protons appear as a singlet due to the fact that the adjacent sulfone moiety is achiral, thus making the two protons equivalent. Modaﬁnil 1 is, however, an equal mixture of enantiomers, as in the reported patent and publication (2,3).

RESULTS
The chemical pathway leading to modaﬁnil may be
represented in Scheme 1.

see pdf for further information and references,

CLIP

Synthesis and determination of the absolute configuration of the enantiomers of modafinil
Thomas Prisinzano^a, John Podobinski^a, Kevin Tidgewell^a, Min Luo^a and Dale Swenson^b
Tetrahedron: Asymmetry 15(6), 1053-1058 (2004) (../rhodium/pdf /modafinil.enantiomers.pdf)
DOI:10.1016/j.tetasy.2004.01.039

^a Division of Medicinal & Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242-1112, USA
^b Department of Chemistry, The University of Iowa, Iowa City, Iowa 52242, USA

Abstract
The asymmetric synthesis of both enantiomers of modafinil, a unique CNS stimulant with a reduced abuse liability, is described. This approach effectively prepares modafinil on a multigram scale in several steps from benzhydrol. The described synthetic route has also been used to produce the more water soluble analogue, adrafinil. X-ray crystallographic analysis on (-)-(diphenylmethanesulfinyl)acetic acid has determined the absolute configuration to be R.

Graphical Abstract

Stereochemistry Abstract

(S)-(+)-(Diphenylmethanesulfinyl)acetic acid
C₁₅H₁₄O₃S

[alpha]D²² + 40.2 (c=1.11, MeOH)
Source of chirality: resolution via diastereomeric salt formation with (R)-(+)-alpha-methylbenzylamine
Absolute configuration: S CLIP

Click to access modafinil.pdf

Narcolepsy is a debilitating neurological disorder which is characterized by chronic sleepiness and is marked to be disorganization of sleep and wake patterns. Every six out of ten thousand people in Western Europe and North America are affected by this disorder. Modafinil (Provigil®) is approved by the Food and Drug Administration for the treatment of narcolepsy. It is commonly used in opposition to Ritalin®, however Ritalin® has an associated dependency issue. Modafinil, a central nervous system stimulant, has reported to have little abuse potential. Modafinil has the ability to act like wake-promoting sympathomimetic agents which includes amphetamine. At relevant pharmacological concentrations modafinil lacks binding ability to receptors for sleep/wake regulation, which includes the ones used for norepinephrine and serotonin. The precise mechanism of action of modafinil is unknown and is presently being researched. Modafinil contains a chiral sulfoxide moiety but is prescribed as a racemate. In collaboration with faculty from the Psychology department at Western Michigan University we were to synthesize modafinil for behavioral studies with animals. Therefore a large scale of pure modafinil was synthesized.

The tetrahedral sulfur atom acts as a chiral center (being surrounded by two dissimilar carbon atoms, an oxygen atom and an electron lone pair (Figure 1). Unlike most analogous trisubstituted amines that undergo umbrella-like inversion at the nitrogen atom, sulfoxides are configurationally stable.

The initial target of this synthesis was to prepare the 2-(diphenylmethylthio)acetamide (1) (Scheme I). The reaction of benzyhydral chloride and thiourea are reacted with potassium iodide, water, heat, 30% sodium hydroxide, 2-chloroacetamide and triethylamine. The procedure required the 2-(diphenylmethylthio) acetamide (1) to be recrystallized to remove any impurities with methanol:water solution 60:40 . After recrystallization (Figure 2) the ¹H NMR spectrum of the synthesized 2-(diphenylmethylthio)acetamide (1) provides evidence that the recrystallization did not purify the compound. In addition recrystallization significantly reduced the percent yield from 78.3-79.2% to 56%. If the compound were pure it would only show peaks at the following locations (ppm): 3.05 (s, 2H), 5.18 (s, 1H), 6.53 (s, 1H), 7.21-7.44(m, 10H).

In preparing (±) modafinil (2) the procedure used acetic acid and hydrogen peroxide to form peracetic acid to react with 2-(diphenylmethylthio)acetamide (1) to form (±) modafinil (2) . The summation of experimentations of Scheme II eventually lead us to use of commercially available peracetic acid to obtain a more pure molecule of (±) modafinil (2). Over oxidation of the sulfone product can be seen if occurs at the peak (ppm):3.7-3.8 in a¹H NMR spectrum of (±) modafinil (2) . str1

To produce pure 2-(diphenylmethylthio)acetamide (1) elimination of the recrystallization step and 2-(diphenylmethylthio)acetamide (1) was then purified via column chromatography using dichloromethane:ether 80:20 as an eluent with the stationary phase (silica gel). After testing several of the fractions from the column using thin layer chromatography the fractions where able to be identified that contained 2- (diphenylmethylthio)acetamide (1). Once 2-(diphenylmethylthio)acetamide (1) was isolated it was oxidized with peracetic acid. The oxidation process was extended to three hours due to lack of desired product (±) modafinil (Figure 1).

With the procedure we used and modified through experimentation a new procedure was developed that increased the percent yield from 56% to 78.3-79.2%. We encountered a few problems that lead to the removal of the recrystallization step and the use of column chromatography was performed to purify 2-(diphenylmethylthio)acetamide (1) . Over- oxidation could have occurred but would have showed up at 3.7-3.8 (ppm), this did not occur in our experiment. The peak at 1.5 (ppm) is a water peak that was not fully removed during the rotovep procedure. After a precise and confident procedure was perfected then we were able to upscale the reaction and sythesize12gs of pure (±) modafinil.

FROM EROWID………

Benzhydrylsulphinylacetamide (Modafinil)²

Benzhydrylthioacetyl chloride

19.5g (0.076 mol) of benzhydrylthioacetic acid in 114 ml of benzene are placed in a three-necked flask provided with a condenser and a dropping funnel. The mixture is heated and 19 ml of thionyl chloride are added drop by drop. Once the addition is complete, the reflux is continued for about 1 hour, cooling and filtering are carried out and the benzene and the excess thionyl chloride and then evaporated. In this way, a clear orange oil is obtained.

Benzhydrylthioacetamide

35 ml of ammonia in 40 ml of water are introduced into a three-necked flask provided with a condenser and a dropping funnel and the benzhydrylthioacetyl chloride dissolved in about 100 ml of methylene chloride is added drop by drop. Once the addition is complete, the organic phase is washed with a dilute solution of soda and dried over Na₂SO₄, the solvent is evaporated and the residue is taken up in diisopropyl ether; in this way, the benzhydrylthioacetamide is crystallized. 16.8 g of product (yield 86%) are obtained. M.p. 110°C.

Modafinil (CRL 40,476)

14.39 g (0.056 mol) of benzhydrylthioacetamide are placed in a balloon flask and 60 ml of acetic acid and 5.6 ml of H₂O₂ (about 110 volumes, 33%) are added. The mixture is left in contact for one night at 40°C. and about 200 ml of water are then added; the CRL 40476 crystallizes. By recrystallization from methanol, 11.2 g of benzhydrylsulphinylacetamide are obtained. Yield: 73%. M.p. 164-66°C.

Novel Synthesis of Modafinil and its sulfone analog³

Our interest in synthesis of modified neuroactive compounds has led us to consider Modafinil (1), a stimulant and anti-narcoleptic agent that is finding increasing use in a number of neurological areas. The compound was originally prepared by a rather tedious route described in a procedure patented by L. Lafon². More recently, its preparation has been reported by Mu et al.⁴ We believe that this compound has many interesting properties and possible alternative uses in addition to its recognized anti-narcoleptic actions.

Fig 1.
The chemical pathway leading to modafinil

Not having been able to obtain it from the patent holder, we proceeded to explore alternate synthetic pathways and settled on a convenient synthesis, which permitted us to produce this compound along with a primary derivative, the sulfone (2) in sufficient quantities for whole-animal studies. The current, more facile method starts with benzhydryl bromide and sodium thiolacetate in aqueous acetone, which reacts directly to form diphenylmethylthioacetic acid (3), possibly by an ionic mechanism. This resultant compound can be converted to its acid chloride that, in turn, may be used to acylate ammonia. The ensuing primary amide (4) may be gently oxidized by H₂O₂ to form the corresponding sulfoxide (Modafinil, 1) and, under more vigorous conditions, the modafinil sulfone (2), whose anticonvulsant and biological properties have not been described extensively in the literature. Additionally, this procedure is also uniquely suitable for large-scale preparation of Modafinil and its congeners.

One aspect of our preparation of modafinil needs further mention. When diphenylmethylthioacetamide (4) is being oxidized by H₂O₂, care must be taken to keep the reaction mixture cool, and workup should be done in a timely manner. Allowing the reaction to go to 24 h or longer at room temperature results in the formation of the sulfone (2). The paper by Mu et al.⁴ does not discuss this possibility. In our hands, the procedure stated therein led to the higher melting sulfone and not the modafinil. Our NMR data for the newly prepared modafinil preparation are in consonance with the data of the patented commercial product. It should be noted that the methylene protons in modafinil are geminally coupled and appear as a pair of doublets. This is due to the fact that the adjacent sulfoxide moiety is chiral, and therefore the methylene protons adjacent to it wind up being diastereotopic with different chemical shifts and coupling. In the sulfone 2, the methylene protons appear as a singlet due to the fact that the adjacent sulfone moiety is achiral, thus making the two protons equivalent. Modafinil 1 is, however, an equal mixture of enantiomers, as in the reported patent and publication^2,4.

Experimental

The new compounds were prepared according to modified procedures published in the patent literature. Starting materials and solvents were obtained commercially from Fluka and/or Aldrich Chemical Corp. Thin layer chromatography (TLC) was performed on silica gel plates. Solvent system was EtOAc:MeOH:NH₄OH, 100:10:3 by volume. Melting points are uncorrected.

Diphenylmethylthioacetic Acid (3)

Benzhydryl bromide (14.78 gm, 0.059 mole) was dissolved in 75 ml of acetone in a 250-ml round-bottomed flask. To this solution was added dropwise sodium mercaptoacetate (6.59 g, 0.058 mole) in about 60 ml of H₂O; the mixture was stirred under N₂ for 2 h at room temperature and was thereafter warmed at about 60–70°C for 1 h. The reaction mixture was evaporated to dryness and taken up in CH₂Cl₂ and saturated aqueous NaHCO₃. The organic extract was rejected, and the aqueous phase was treated with acid to pH 2 and chilled. Suction filtration gave the 6.9 g of the acid (3, 46%), mp 125°C. R_f 0.2. Recrystallization from MeOH/H₂O gave mp 126–128°C.

Diphenylmethylthioacetamide (4)

Diphenylmethylthioacetic acid 3 (19.5 g, 0.076 mole) in 114 ml of dry benzene was taken in a 250-ml roundbottomed flask attached to a reflux condenser, under N₂ gas. To this was added thionyl chloride (19.5 ml, 0.097 mole) with a dropping funnel. The mixture was stirred at room temperature with a magnetic stirrer and refluxed for 1 h. Thereafter, the mixture was evaporated under low pressure to give a yellow oil that was taken up in about 100 ml of CH₂Cl₂ and filtered to yield a clear orange solution. This was chilled in ice water and added slowly to an ice-cold solution of concentrated NH₄OH in H₂O (40:40 ml). The ensuing mixture was stirred for 1 h and shaken well in a separatory funnel. The organic layer was dried (Na₂SO₄) and evaporated to dryness to give 14.39 g (54%) of the amide (4), mp 108–109°C (lit⁴ 110°C). R_f 0.8. Recrystallization from CH₃OH/H₂O gave mp 109–110°C.

Diphenylmethylsulfinylacetamide (Modafinil, 1)

Diphenylmethylthioacetamide 4 (3.46 g, 0.013 mole) was taken in glacial acetic acid (14 ml) with stirring; to this was added 1.34 ml of 30% H₂O₂ with chilling in ice water. The mixture was left in the refrigerator for 4 h and thereafter worked up by treating it with 70 ml of ice-cold water. The precipitated material was filtered under suction and washed with ice-cold water to give 1.5 g of white crystals (43%), mp 159–160°C. R_f 0.6. Recrystallization from hot MeOH gave mp 161–162°C

Diphenylmethylsulfonylacetamide (2)

Diphenylmethylthioacetamide (2.5 g, 0.009 mole) (CAS No. 118779-53-6) was dissolved in about 12 ml of glacial acetic acid and 3 ml of 30% H₂O₂ and set aside overnight (16 h or more). The next day, the mixture was diluted with 100 ml of H₂O and set aside to cool in the refrigerator. Upon filtration and drying, 2.1 g (80%) of 2 was obtained as a white powder. R_f 0.89. The melting point of sample after recrystallization from absolute EtOH was 195–197°C.

High-yield Synthesis of Modafinil from Benzhydrol⁵

A recent patent⁵ describes a very easy two-step route to the Modafinil precursor diphenylmethanethioacetamide from benzhydrol (diphenylmethanol) in 90% yield and with 95% purity. A 200g batch is made in a 2000 mL vessel using water as reaction medium and ethyl acetate for recrystallization of the product.

Diphenylmethylbromide is prepared in situ from benzhydrol and react it with thiourea in a one-pot reaction to form the corresponding isothiouronium salt. The crude salt is then reacted with chloroacetamide (by generating the thiolate cation in situ), and after filtration and washing, diphenylmethylthioacetamide is isolated in excellent yield and good purity. After oxidation of the thioacetamide with hydrogen peroxide, followed by recrystallization, the overall yield of Modafinil is 67% from the benzhydrol.

(Chimimanie’s Voice:) The synthesis works just as great without the nitrogen inert atmosphere (most patents do not use it at all), step two is only a hydrolysis of the thiouronium salt to the thiolate. You just have to put the salt, NaOH and heat till you got a homogenous solution, with no more solid material floating around. The following chloroacetamide S_N2 reaction is a breeze too. Sometime a blue solution can bee obtained, it is nothing to worry about. In the final step, you just have to filter off the solid which did not dissolve when the crude thioacetamide is put in the GAA/H₂O₂, bee4 crashing the soluble one with water.
Do not forget to slurry the modafinil in EtOAc and then recrystallize it from aqueous MeOH, as the crystalline shape of modafinil is important for the kinetic and quality of effects, at least according to the patents EP0966962 and US2002043207.

Experimental

Preparation of isothiouronium Salt (IV)

Diphenylmethanol (130 g, 0.7 mole) and thiourea (65 g, 0.85 mole) are added in 0.5 L reactor charging with water (325 ml). The mixture is heated to 95°C. (an emulsion is obtained) and 48% HBr (260 gr. 3.22 mole, 4.6 equivalents) is then added gradually during 0.5 hour. The mixture is heated under reflux (106-107°C) for 0.5 hour and cooled to 80-85°C. At this temperature, the mixture is seeded with several crystals of the product and the mixture is stirred at that temperature for 0.5 hour and then cooled to 25°C. The colorless crystals are collected by filtration, washed with water (200 ml) yielding about 240 gr. of wet crude isothiouronium salt.

(Antoncho’s Voice:) Assholium successfully made Modafinil by this method, but there turned out to be a mistake in the original patent text – In the preparation of IV, the quantity of HBr stated here is excessive and leads to complete hydrolysis of the initially formed isothiouronium salt. The acid should bee added until the reaction mixture turns completely clear (about half as much as the patent says) – a sort of titration. Further addition will result in precipitation of heavy stinky oil, benzhydrylmethanethiol.

Preparation of diphenylmethylthioacetamide

A 2 L reactor was charged with diphenylmethylisothiouronium bromide crude wet obtained (240 gr.) and water (700 mL) under nitrogen. The suspension was heated to 60°C and 46% aqueous NaOH solution (98 ml, 1.68 mole, 2.4 eq.) was added. The reaction mixture was heated to 85°C and stirred until all the solid was dissolved. Then, it was cooled to 60°C and chloroacetamide (80 g, 0.84 mole, 1.2 eq.) was added in five portions hour at 60-70°C during one hour. The suspension is stirred at 70°C for 4-5 hours. The mixture was filtered while warm and the cake was washed with hot water (250 ml). Diphenylmethylthioacetamide crude wet is obtained [220 gr., HPLC assay: 78%, HPLC purity: 95%, yield: 95% from diphenylmethanol]. 20g of the product was recrystallized twice from ethyl acetate, dried in vacuo to give 15g of pure title compound.

Preparation of Modafinil

A 1.0 L reactor was charged with diphenylmethylthioacetamide crude wet (220 gr.) obtained above and glacial acetic acid (610 mL). The mixture was heated to 40°C and stirred until full dissolution is achieved. 5.8% H₂O₂ solution (500g, 1.2 eq) was added dropwise during 0.5 hours at 40-45°C. The reaction mixture was stirred at 40-45°C for 4 hours. Then sodium metabisulfite (18.3g) in 610 mL water was added in order to quench the unreacted H₂O₂ and the suspension was stirred for 0.5 hours. Then the reaction mixture was cooled to 15°C and filtered. The cake was washed with water (610 mL) and dried on air to obtain crude wet Modafinil (205 g). Reslurry in refluxing ethyl acetate, followed by recrystallization from methanol:water (4:1) solution afforded pure Modafinil [125 g, HPLC assay: 99.9%, HPLC purity: 99.9%, yield: 67% (from diphenylmethanol)].

References

US Pat 4,066,686
L. Lafon, US Pat 4,177,290 (1979); L. Lafon, Eur. Pat. 283,362 (1988)
Nithiananda Chatterjie, James P. Stables, Hsin Wang, and George J. Alexander, Anti-Narcoleptic Agent Modafinil and Its Sulfone: A Novel Facile Synthesis and Potential Anti-Epileptic Activity, Neurochemical Research, 29(8), 1481–1486 (2004)
Mu, B., Lei, G., He, X., and Du, X., Synthesis of central stimulant modafinil. Zhongguo Yaowu Huaxue Zazhi, 9(2), 132–134 (1999)
US Pat. 6,649,796 (2002)

Modafinil
Clinical data
(R)-(−)-modafinil (armodafinil; top) (S)-(+)-modafinil (bottom)
Trade names	Provigil, others (see below)
AHFS/Drugs.com	Monograph
MedlinePlus	a602016
License data	US FDA: Modafinil
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Dependence liability	Psychological: Very low^[1] Physical: Negligible^[1]
Addiction liability	Very low to low^[2]
Routes of administration	Oral (tablets)
ATC code	N06BA07 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: Schedule F UK: POM (Prescription only) US: Schedule IV
Pharmacokinetic data
Bioavailability	Not determined due to the aqueous insolubility
Protein binding	62%
Metabolism	Hepatic (primarily via amide hydrolysis;^[3] CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 involved ^[4]
Biological half-life	15 hours (R-enantiomer), 4 hours (S-enantiomer)^[5]
Excretion	Urine (80%)
Identifiers
IUPAC name [show]
Synonyms	CRL-40476; Diphenylmethylsulfinylacetamide
CAS Number	68693-11-8
PubChem (CID)	4236
IUPHAR/BPS	7555
DrugBank	DB00745
ChemSpider	4088
UNII	R3UK8X3U3D
KEGG	D01832
ChEBI	CHEBI:31859
ChEMBL	CHEMBL1373
ECHA InfoCard	100.168.719
Chemical and physical data
Formula	C₁₅H₁₅NO₂S
Molar mass	273.35 g/mol
3D model (Jmol)	Interactive image

Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC02623K, Communication

Shivam Maurya, Dhiraj Yadav, Kemant Pratap, Atul Kumar
We developed a post-sulfoxidation protocol for the synthesis of Modafinil that exhibits improved sustainability credentials, utilizing the recyclable heterogeneous catalyst Nafion-H.

Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil

Shivam Maurya,^a^b Dhiraj Yadav,^a Kemant Pratap^a^b and Atul Kumar*^a^b

*Corresponding authors

^aMedicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, P.O. Box 173, Lucknow 226031, India
E-mail: dratulsax@gmail.com, atul_kumar@cdri.res.in

^bAcademy of Scientific and Innovative Research, New Delhi 110001, India

Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC02623K

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC02623K?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Atul Kumar

Professor, Academy of Scientific and Innovative Research (AcSIR)/ Senior Principal Scientist at CSIR-CDRI

Central Drug Research Institute

Medicinal and Process Chemistry Division (CDRI)

Lucknow, Uttar Pradesh, India

Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide, MOD) is a key psychostimulant drug used for the treatment of narcolepsy and other sleep disorders that has a very low addiction liability. Recently, MOD has been clinically investigated for the treatment of cocaine addiction and used by astronauts in long-term space missions. We have developed a synthetic strategy for “smart drug” Modafinil. An efficient atom and step economic (EASE) synthesis has been carried out by the direct reaction of benzhydrol and 2-mercaptoacetamide using the recyclable heterogeneous catalyst Nafion-H along with post-sulfoxidation. This protocol exhibits improved sustainability credentials. We have also developed a superior pre-sulfoxidation approach for the synthesis of Modafinil.

Modafinil Physical State – White solid; M.p. 158-159ºC,

IR (KBr): 3383, 3314, 3256, 1690, 1 1616, 1494, 1376, 1027, 702 cm-1;

H NMR (CDCl3) δ(ppm): 3.14(d, J=14.3 Hz, 1H); 3.48(d, J=14.3 Hz, 1H); 5.24(s, 1H); 5.88(br s, 1H); 7.09(br s, 1H); 7.29-7.43(m, 7H); 7.43-7.51(m, 3H);

13C NMR (CDCl3) δ(ppm): 52.00, 71.61, 128.80, 128.98, 129.10, 129.58, 129.62, 134.30, 134.74, + 166.46; Molecular formula C15H15NO2S;

ESI-MS (m/z): 274.1 (M+H) .

Dr. Atul Kumar

Senior Principal Scientist

///////Efficient atom, step economic (EASE) synthesis, Modafinil

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Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil

December 11, 2016 3:39 am / Leave a comment

Green Chemistry International

Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC02623K, Communication

Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil

Shivam Maurya,^a^b Dhiraj Yadav,^a Kemant Pratap^a^b and Atul Kumar*^a^b

*Corresponding authors

^bAcademy of Scientific and Innovative Research, New Delhi 110001, India

Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC02623K

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC02623K?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Atul Kumar

Professor, Academy of Scientific and Innovative Research (AcSIR)/ Senior Principal Scientist at CSIR-CDRI

Central Drug…

View original post 206 more words

Selection and justification of starting materials: new Questions and Answers to ICH Q11 published

December 8, 2016 12:20 pm / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

The ICH Q11 Guideline describing approaches to developing and understanding the manufacturing process of drug substances was finalised in May 2012. Since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experience has shown that there is some need for clarification. Thus the Q11 Implementation Working Group recently issued a Questions and Answers Document.

http://www.gmp-compliance.org/enews_05688_Selection-and-justification-of-starting-materials-new-Questions-and-Answers-to-ICH-Q11-published_15619,15868,S-WKS_n.html

The ICH Q11 Guideline describes approaches to developing and understanding the manufacturing process of drug substances. It was finalised in May 2012 and since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experiences during implementation of these principles within this 4 years period have shown that there is need for clarification in particular with regard to the selection and justification of starting materials.

On 30 November 2016 the ICH published a Questions and Answers…

View original post 2,105 more words

Lumefantrine

December 5, 2016 1:23 am / Leave a comment

Image result for lumefantrine synthesis

lumefantrine

Molecular FormulaC₃₀H₃₂Cl₃NO
Average mass528.940 Da

Benflumetol
dl-Benflumelol

UNIIF38R0JR742

CAS number82186-77-4

(±)-2-(Dibutylamino)-1-((9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl)ethanol

(±)-2,7-Dichloro-9-((Z)-p-chlorobenzylidene)-α-((dibutylamino)methyl)fluorene-4-methanol

(9Z)-2,7-Dichloro-9-[(4-chlorophenyl)methylene]-α-[(dibutylamino)methyl]-9H-fluorene-4-methanol

120583-70-2 [RN]

120583-71-3 [RN]

2-(dibutylamino)-1-[(9Z)-2,7-dichloro-9-[(4-chlorophenyl)methylidene]-9H-fluoren-4-yl]ethan-1-ol

(±)-2,7-Dichloro-9-((Z)-p-chlorobenzylidene)-α-((dibutylamino)methyl)fluorene-4-methanol

2-Dibutylamino-1-[2,7-dichloro-9-(4-chloro-benzylidene)-9H-fluoren-4-yl]-ethanol

2-Dibutylamino-1-{2,7-dichloro-9-[1-(4-chloro-phenyl)-meth-(Z)-ylidene]-9H-fluoren-4-yl}-ethanol

Benflumetol

dl-Benflumelol

UNII F38R0JR742
CAS number 82186-77-4
Weight Average: 528.94
Monoisotopic: 527.154947772
Chemical Formula C30H32Cl3NO

Lumefantrine (or benflumetol) is an antimalarial drug. It is only used in combination with artemether. The term “co-artemether” is sometimes used to describe this combination.^[1] Lumefantrine has a much longer half-life compared to artemether and so is therefore thought to clear any residual parasites that remain after combination treatment.^[2]

Lumefantrine, along with pyronaridine and naphtoquine, were synthesized in course of the Project 523 antimalaria drug research initiated in 1967; these compounds are all used in combination antimalaria therapies.^[3]^[4]^[5]

Image result for lumefantrine synthesis

Lumefantrine is an antimalarial drug chemically known as 2-(dibutylamino)-1-[(9Z)-2, 7-dichloro-9-(4- chlorobenzylidene)-9H-floren-4-yl] ethanol, which is used in the prevention and treatment of Malaria in worm blooded animals. Lumefantrine is using the combination of β-Artemether in the treatment of Malaria

SYN

Synthetic Reference

Beutler, Ulrich; Fuenfschilling, Peter C.; Steinkemper, Andreas. An Improved Manufacturing Process for the Antimalaria Drug Coartem. Part II. Organic Process Research & Development. Volume 11. Issue 3. Pages 341-345. 2007.

SYN 2

Synthetic Reference

Rao, Dharmaraj Ramachandra; Kankan, Rajendra Narayanrao; Phull, Manjinder Singh. Process for preparation of lumefantrine as antimalarial agent with improved method. Assignee Cipla Co., Ltd., India. CN 1865227. (2006).

SYN 3

Synthetic Reference

Sethi, Madhuresh Kumar; Gonuguntla, Anantavena Rani; Arikatla, Siva Lakshmi Devi; Mulukutla, Suryanarayana; Yerramalla, Rajakrishna; Bontalakoti, Jaganmohanarao; Vemula, Lakshminarayana; Thirunavukarasu, Jayaprakash. Synthesis and characterization of novel related substances of Lumefantrine, an anti-malarial drug. Pharma Chemica. Volume 8. Issue 3. Pages 91-100. 2016.

SYN4

Synthetic Reference

Mathur, Prafull; Mathur, Suvigya; Vishwanath, Kannan; Mishra, Anand Kumar. Preparation of lumefantrine. Assignee Aanjaneya Lifecare Limited, India. IN 2013MU00611. (2015).

SYN 5

Synthetic Reference

Wu, Guang-liang; Dai, Ying-jie; Kang, Cong-min; Zi, Yan. A new synthetic technology of anti-malarial drug lumefantrine. Zhongguo Xinyao Zazhi. Volume 21. Issue 24. Pages 2944-2947. 2012.

SYN 6

Synthetic Reference

Krishna, Bettadapura Gundappa; Verma, Sudhakar; Krishna, Sujatha; Naik, Gajanan; Arulmoli, Thangavel. A process for preparation of lumefantrine. Assignee SeQuent Scientific Limited, India. IN 2012CH00470. (2012).

SYN 7

Synthetic Reference

Bansi, Lal; Genbhau, Gund Vitthal; Prabhakar, Bapat Chintamani; Popat, Bochiya Pravin; Banshi, Punde Dnyanadeo; Venkata, Reddy Prabhakar Gorla. Improved one pot process for the synthesis of lumefantrine. Assignee Calyx Chemicals and Pharmaceuticals Ltd., India. IN 2009MU01437. (2010).

SYN 8

Synthetic Reference

Shailesh, Singh; Dhaval, Vashi; Vinod, Gaikwad; Sanjay, Chowkekar; Sanjay, Bute. Process for the preparation of lumefantrine. Assignee Ajanta Pharma Ltd., India. IN 2008MU01677. (2010).

SYN 9

Synthetic Reference

Rawalnath, Sakhardande Rajiv; Kanji, Khatri Navin; Nilkanth, Firake Pandharinath; Vasant, Panchal Rajesh; Nagesh, Babrekar Chandan; Madhukar, Mohite Dhanaji. Preparation of lumefantrine. Assignee Saxena, Alok, India. IN 2006MU00260. (2007).

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PATENT

https://patents.google.com/patent/CN107501316A/en

Embodiment 1：The synthesis of (the chloro- 2- of 2- (the chloro- 9H- fluorenes -4- bases of 2,7- bis-) ethyoxyl) trimethyl silane

2,7- dichloro fluorenes -4- oxirane (100g, 0.368mol), zinc oxide are sequentially added in 1000ml there-necked flasks (2.94g, 0.036mol) and 500ml dichloromethane, TMSCl (43g, 0.4mol) are added drop-wise in above-mentioned reaction solution, room temperature reaction 2h.Filtering, a small amount of dichloromethane washing of filter cake, filtrate washing, organic phase anhydrous sodium sulfate drying, filtering, filtrate are rotated to analysis After going out solid, stop revolving, stand and separate out a large amount of yellow solids, filtering, drain to obtain (the chloro- 2- of 2- (2,7- bis- chloro- 9H- fluorenes- 4- yls) ethyoxyl) trimethyl silane yellow solid 102g, yield 73%.δ(¹HNMR,CDCl₃)：7.78-7.80(m,1H), 7.56(s,1H),7.48(s,1H),7.41(s,1H),7.32-7.35(m,1H),5.64-5.67(m,1H),4.03-4.11(m, 2H),3.84(m,2H),0.63(s,9H),ppm。

Embodiment 2：N- butyl-N- (1- (the chloro- 9H- fluorenes -4- bases of 2,7- bis-) -2- (trimethylsiloxy group) ethyl) butyl – The synthesis of 1- amine：

(the chloro- 2- of 2- (the chloro- 9H- fluorenes -4- bases of 2,7- bis-) ethyoxyl) trimethyl silicane is sequentially added in 1000ml there-necked flasks Alkane (100g, 0.26mol), di-n-butylamine (67g, 0.52mol), potassium carbonate (71.65g, 0.52mol) and 800ml acetonitriles.Put It is changed to nitrogen system, back flow reaction 16h.After being down to room temperature, filtering, a small amount of acetonitrile of filter cake washs, and filtrate is evaporated to obtain fourth containing N- The crude yellow oil of base-N- (1- (the chloro- 9H- fluorenes -4- bases of 2,7- bis-) -2- (trimethylsiloxy group) ethyl) butyl -1- amine. Crude product is directly used in be synthesized in next step, without purifying.MS:479(MH⁺)

Embodiment 3：The synthesis of 2- dibutyl aminos -2- [the chloro- 9H- fluorenes -4- bases of 2,7- bis-] ethanol

By-the N- of butyl containing N- obtained in the previous step (1- (the chloro- 9H- fluorenes -4- bases of 2,7- bis-) -2- (trimethylsiloxy group) second Base) crude yellow oil of butyl -1- amine is dissolved in 500ml tetrahydrofurans, concentrated hydrochloric acid (1ml), nitrogen protection, heating is added dropwise To 50 DEG C of reactions, TLC tracing detections to raw material have reacted completely, cool, and separate out solid, filtering, the washing of filter cake tetrahydrofuran, take out Dry, filtrate is abandoned, and filter cake is transferred in beaker, adds 200ml dichloromethane, and saturated aqueous sodium carbonate is adjusted pH=8, separated Machine phase, water layer are extracted once with 200ml dichloromethane again, merge organic phase, are washed, and are dried, are concentrated to give yellow oil 68g, two step yields 64%.δ(¹HNMR,CDCl₃)：7.80(s,1H),7.56(s,1H),7.38(m,2H),7.25(s,1H), 4.7(brs,1H),4.03-4.11(m,2H),3.99(m,1H),3.56(m,2H),2.42-2.85(m,4H),1.44-1.48 (m,4H),1.23-1.28(m,4H),0.86-0.91(m,6H).ppm。

Embodiment 4：(RS, Z) -2- dibutyl aminos -2- [bis- chloro- 9- of 2,7- (4- chlorobenzenes methylene) -9H- fluorenes -4- bases] second The synthesis of alcohol

2- dibutyl aminos -2- [the chloro- 9H- fluorenes -4- bases of 2,7- bis-] ethanol (68g, 0.167mol) is dissolved in 200ml ethanol In, 4-chloro-benzaldehyde (28.2g, 0.2mol) and sodium hydroxide (2.68g, 0.067mol) are added, nitrogen protection, is heated to reflux anti- Answer 1h.Room temperature is down to, watery hydrochloric acid, which is added dropwise, makes product be filtered into salting out, and the washing of filter cake ethanol, drains to obtain yellow solid, shifts Into beaker, 200ml dichloromethane is added, adds saturated aqueous sodium carbonate to dissociate, be layered, aqueous phase uses 200ml dichloromethane again Extraction once, merges organic phase, washing, and anhydrous sodium sulfate drying 6h is filtered, and filtrate is concentrated to give (RS, Z) -2- dibutyl aminos -2- [2,7- bis- chloro- 9- (4- chlorobenzenes methylene) -9H- fluorenes -4- bases] ethanol be yellow foam shape solid 74g, yield 83%, 0-5 DEG C Preserve.δ(¹HNMR,CDCl₃)：7.75(brs,1H),7.66(s,1H),7.55(s,1H),7.44-7.48(m,5H),7.28- 7.29(m,1H),7.30-7.31(m,1H),4.7(brs,2H),3.88-3.89(m,2H),2.71-2.72(m,2H),2.60- 2.63(m,2H),1.44-1.48(m,4H),1.23-1.31(m,4H),0.86-0.90(m,6H).ppm。

PATENT

https://www.researchgate.net/publication/221933417_Process_for_high_purity_lumefantrine

Process for high purity lumefantrine Dr KrishnaSarma Pathy,Ramesh.D,P atchutaramaiah,Ch Sivasubramanyam Abstract. The present invention relates to Process for the preparation of lumefantrine Lumefantrine is a dichlorobenzylidine derivative effective for the treatment of various types of malaria. Chemically lumefantrine is 2-Dibutylamino-1-[ 2, 7-dichloro-9-(4- chlorobenzylidene)-9H-fluoren-4-yl]-Ethanol (racemate) The antimalarial agent is active against multi-drug resistant strains of Plasmodium falciparum. In combination with artemether, the drug is also used for the treatment of uncomplicated falciparum malaria. It has primary action as blood schizontocidal and secondary action as inhibition of nucleic acid and protein synthesis within the malarial parasite thus having a longer duration of anti malarial action. Thus, today lumefantrine is a drug of choice in antimalarial treatment against P. faliciparum. Therefore, development of an appropriate analytical procedure for the quantitative analysis of lumefantrine is of considerable importance to pharmaceutical industry. The spectroscopic techniques were used to confirm the identity of lumefantrine. The IR spectra, showed strong absorption band at 3404.67 cm-1(OH), 2953.28 cm-1(aliphatic and aromatic CH), 1757.31 cm-1(-C=C-), 933 cm-1(alkanes) and 696.37-373.22 cm-1 (Cl). Thus, IR spectra confirmed the presence of these functional groups in the structure of lumefantrine. The mass spectrum showed a sharp molecular ion peak at 528.0 m/z in Q1 MS (m/z, parent ion) parameter at negative polarity confirming the molecular weight of lumefantrine. The NMR spectra observed triplet at 0.943-0.989 (methyl protons of alkyl chain); a multiplet at 1.372-1.498 (methylene protons of alkyl chains); a multiplet at 2.449-2.909 (methylene protons of alkyl chain); broad singlet at 4.573 (OH proton); and multiplet at 7.314-7.733 (aromatic proton), thus confirming identity of lumefantrine. Summary of the process Stage1 Cl Cl 2,7-dichloro-9H-fluorene ClCl O Cl 2-chloro-1-(2,7-dichloro-9H-fluoren-3-yl)ethanone AlCl3 Chloroacetyl chloride In a 1 liter 3-necked flask, equipped with stirrer, thermometer and reflux condenser450.0 ml MDC cool to 0C.Start addition of 59.4 gm chloro acetyl chloride at 0-5C and stir for 15 min.Start addition of aluminium chloride at 0-5C. Stir for 30.0 min at same temp.Start addition of 2,7-dichloro fluorene soln. preprepared in 300.0 ml MDC d 150.0 ml saturated brine for washing and stir for 15-20 min. at 50-55 C.Allow to settle the layers at 50- 55C for 30.0 min.Separate the ORGANIC LAYER. at 50-55C.Again repeat Abovestep. for one time.Collect ORGANIC LAYER. and distill out dibutyl amine under vac. At 60- 90C.Disconnect vac. And cool reaction mass to 60C add 400.0 ml methanol and reflux to 30.0 min. After maintaining the reaction mass cool reaction mass to 50C.Seed the reaction mass by adding 500 mg stage 2 material at . 50C.Cool reaction mass to 30- 35C.Stir reaction mass further at same temp. fot 2 hrs.Filter reaction mass at 30- 35C.Suck dry and wash with 50.0 ml methanol at 30-35C.Suck dry and unload. Dry at 50-55C. Wt. of wet cake : 139.0 gm Wt. of dry material : 123.0 gm . . . a b c . . . a b c M.P: 72-76C Stage3: ClCl N OH + Cl COH ClCl N OH Cl 2,7-dichloro-alpha-[(dibutyl amino) p-chloro benzaldehyde methyl]-9H-fluoren-4-yl]oxirane Mol. Wt. 406 Lumefantrine Mol. Wt. 140.5Mol. Wt. 528.5 Under Nitrogen In a 2 liter 3-necked flask, equipped with stirrer, thermometer and reflux.Charge 840.0 ml ethanol at 30-35C.Chrge 120.0gm stage2 material at 30-35C.Charge 27.96 gm sodium methoxide in 30 min. at 30C exothermobserved temp. rise to 45C.Charge 41.52 gm p- Chloro benzaldehyde .Maintain reaction mass temp. 30-35C for 24 hrs. Check TLC a : Stage 2 b : Co spot c : reaction mass Mobile phase Hexane : Ethyl acetate 9 : 1 If TLC complies 1) 2) 3) Filter reaction mass at 30-35C. Suck dry and wash with 100.0 ml methanol. Suck dry and unload wet cake. Dry material at 50-55 C . . . a bc Wt. of wet cake : 184.0 gm Wt. Of dry material : 141.0 gm M.P : 122-126C Purification : In a 1 liter 3-necked flask, equipped with stirrer, thermometer and reflux .Charge 700.0 ml ethyl acetate at 30-35C.Chrge crude 141.0 gm material at 30-35C.Heat reaction mass to refluxand main for 30.0 min. to dissolve the material.Filter reaction mass at 75-80C.Collect filtrate cool to reaction mass to 0- 5C.Maintain reaction mass at same temp. for 30.0 min.Filter the reaction mass at 0- 5C.Suck dry and wash with 100.0 ml ethyl acetate at 0-5C.Suck dry and unload. Dry material at 50-55 C Wt. of wet cake : 100.0 gm Wt. Of dry material : 70-80 gm
(19) (PDF) Process for high purity lumefantrine. Available from: https://www.researchgate.net/publication/221933417_Process_for_high_purity_lumefantrine [accessed Feb 06 2022].

M.P: 128-132C RESULTS:= Lumefantrine 99.15% (by HPLC) 128 – 130 Purity Melting Pointo C Liquid chromatography HPLC-UV investigation of the impurity profiles was performed on a HPLC-PDA apparatus consisting of a Waters Alliance 2695 separation module and a Waters 2998 photodiode array detector with Empower 2 software for data acquisition . For PDA detection, the UV spectrum was recorded at 190-400 nm. Quantification was performed at 266 nm. The positive ion ESI and the collision-induced dissociation (CID) mass spectra were obtained from the LC-UV/MS apparatus consisting of a Spectra System SN4000 interface, a Spectra System SCM1000 degasser, a Spectra System P1000XR pump, a Spectra System AS3000 autosampler, and a Finnigan LCQ Classic ion trap mass spectrometer in positive ion mode mass to charge range m/z 100 to m/z 2000 at unit resolution and with a peak width of 0.25 daltons/z, equipped with a Waters 2487 dual wavelength UV detector and Xcalibur 2.0 software (Thermo) for data acquisition. ESI was conducted using a needle voltage of 4.5 kV. Nitrogen was used as sheath and auxiliary gas with the heated capillary set at 250C. UV-detection was used for quantification (at 266 nm), while ESI-ion trap MS detection was used for identification. LC determination of impurities in lumefantrine samples was performed using a Purospher STAR RP-18 endcapped (150 4.6 mm, 5 m particle size) column (Merck, Darmstadt, Germany) with guard column at 30C under isocratic conditions with a mobile phase consisting of ammonium acetate (pH 4.9; 0.1 M) and acetonitrile (10:90, v/v). The flow rate was set at 2.0 mL/min (minimal run time: 30 min.). The injection volume was 10 l. Under these conditions, lumefantrine elutes at approximately 22 min. System suitability tests (SSTs) were established as the plate number on lumefantrine (N 8.2 103) and the oxidative stress degradation product (N 2.4 103), the signal-to-noise ratio of 0.5% l.c. lumefantrine solution (S/N 30), the peak area ratio of the 0.5% l.c. versus 100% l.c. (between 0.4 and 0.6) and the relative position of the in-situ prepared N-oxide by H2O2 treatment (RRTbetween 0.12 and 0.22). The LC method was validated for the determination of lumefantrine and its related impurities. The selectivity of the developed chromatographic method was established by the separation of lumefantrine and its impurities. A correlation coefficient (r2) of 0.9998 for lumefantrine (0.0006 to 0.01 mg/ml) and 1.0 for impurity A and DBK (0.001 to 0.1 mg/ml) demonstrated that the HPLC method is linear in the lower range. LOD/LOQ values for lumefantrine, DBK and impurity A were calculated (S/N = 3 resp. 10): 0.004 mg/mland 0.026 mg/ml for lumefantrine (0.004% respectively 0.026% l.c.), 0.011 mg/ml and 0.040 mg/ml for DBK (0.012% respectively 0.042% l.c.) and 0.110 mg/ml and 0.393 mg/ml for impurity A (0.115% respectively 0.409% l.c.). The analytical stability of lumefantrine, impurity A and DBK was confirmed over a storage period of 24 hours at 5C, i.e. the sample compartment temperature. Accuracy and precision were evaluated by repeated analysis (n = 6), with 102.6% l.c. recovery and 2.1%, respectively 2.86%, for repeatability, respectively intermediate precision. Structural information for the observed and/or reported lumefantrine related impurities # Compound [formula, mono-isotopic mass]Structure Origin # Compound [formula, mono-isotopic mass]Structure Origin Alkaline stress Oxidative stress Oxidative stress Metabolite 1Desbenzylketo N-oxide [C23H27NO3Cl2, MW 435.14] 2 Lumefantrine (mono-)desbutyl derivative [C26H24NOCl3, MW 473.09] 3Lumefantrine N-oxide [C30H32NO2Cl3, MW 543.15] Oxidative stress Degradation 4 2,7-dichloro-4-[2-(di-n-butylamino)-1-hydroxyethyl]- 9H-fluoren-9-one; Desbenzylketo derivative (DBK) [C23H27NO2Cl2, MW 419.14] Oxidative stress Acidic stress Degradation 5 2-(di-n-butylamino)-1-[2,7-dichloro-9H-fluoren-4- yl]ethanol; Desbenzyl derivative [C23H29NOCl2,405.16] Synthesis 6 Synthesis impurity found in lumefantrine API; Lumefantrine oxide [C30H32NO2Cl3, MW 543.14] Synthesis 7 Synthesis impurity found in lumefantrine API; Lumefantrine oxide [C30H32NO2Cl3, MW 543.14] Synthesis 8 (RS,Z)-2-(Dibutylamino)-2-(2,7-dichloro-9-(4- chloro-benzylidene)-9H-fluoren-4-yl)ethanol (isomeric compound); Impurity A (Ph. Int./USP Salmous) [C30H32NOCl3, MW 527.15] Synthesis 9 Synthesis
(19) (PDF) Process for high purity lumefantrine. Available from: https://www.researchgate.net/publication/221933417_Process_for_high_purity_lumefantrine [accessed Feb 06 2022].

mpurity found in lumefantrine API; Lumefantrine oxide [C30H32NO2Cl3, MW 543.14] Synthesis 10 (1S,3R,5R)-1,3-bis((EZ)-2,7-Dichloro-9-(4- chlorobenzyl-idene)-9H-fluoren-4-yl)-2,6- dioxabicyclo[3.1.0]hexane; Impurity BA(USP Salmous) [C44H24Cl6O2, 797.39] 2-((EZ)-2,6-Dichloro-9- (4-chlorobenzylidene)-9H- fluoren-4-yl)-3′-((EZ)-2,7-dichloro-9-(4- chlorobenzylidene)-9H-fluoren-4-yl)-2,2′-bioxirane; Impurity BB (USP Salmous) [C44H24Cl6O2, 797.39] Percentage maximum actual levels of lumefantrine related impuritiesobserved(1) Synthesis 11 Synthesis # CompoundAPIFPP Unstressed Stressed Release Accelerated Stressed 1.39 0.560.11 21.32 1 Desbenzylketo N-oxide 2 Monodesbutyl derivative 3 Lumefantrine N-oxide 4 Desbenzylketo derivative 5 Desbenzyl derivative 6Lumefantrine oxide (RRT ~ 0.49) 7Lumefantrine oxide (RRT ~ 0.52) 8 Impurity A 9Lumefantrine oxide (RRT ~ 0.59) (1) RT: reporting threshold = 0.10% 0.60 0.12 0.34 0.86 4.26 HPLC characteristics of lumefantrine related impurities # CompoundRT(1)RRT(2) Most abundant m/z observed 436.14 474.00 544.08 420.13 406.09 544.12 544.12 528.10 544.12 528.10 1 Desbenzylketo N-oxide 2 Monodesbutyl derivative 3.25 3 Lumefantrine N-oxide 4 Desbenzylketo derivative 7.41 5 Desbenzyl derivative 6 Lumefantrine oxide 7 Lumefantrine oxide 8 Impurity A 9 Lumefantrine oxide L Lumefantrine (1) Retention time (min.) (2) Relative retention time reference 1.790.08 0.15 0.17 0.33 0.34 0.49 0.52 0.58 0.59 1.00 3.96 7.69 10.96 11.45 12.70 12.97 22.28 1. De Spiegeleer B, Vergote V, Pezeshki A, Peremans K, Burvenich C. Impurity profiling quality control testing of synthetic peptides using liquid chromatography-photodiode array-fluorescence and liquid chromatography-electrospray ionization-mass spectrometry: The obestatin case. Anal Biochem. 2008;376:229234. doi: 10.1016/j.ab.2008.02.014.[ 2. Nicolas EC, Scholz TH. Active drug substance impurity profiling – Part I. LC/UV diode array spectral matching. J Pharm Biomed Anal. 1998;16:813824. doi: 10.1016/S0731-7085(97)00131- 3Roy J. Pharmaceutical impurities – A mini review. AAPS PharmSciTech. 2002;3:article 6. doi: 10.1208/pt030206. ICH guidelines – International Conference on Harmonization, Q3A(R2) Impurities in new drug substances CPMP/ICH/2737/99. (October 2006) http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC50000 2675.pdf [Accessed on 5 November 2010 at 11:06] 3. Authorized Lumefantrine USP Salmous Standard (Februari 2009) http://www.usp.org/pdf/EN/nonUSStandards/lumefantrine.pdf [Accessed on 24 October 2010 at 17:14] 4. Lumefantrine: Document QAS/06.186/FINAL (WHO Ph. Int. – July 2008) http://www.who.int/medicines/publications/pharmacopoeia/Lumef_monoFINALQAS06_186_July 08.pdf [Accessed on 24 October 2010 at 17:37] 5. Lee H. Pharmaceutical applications of liquid chromatography coupled with mass spectrometry (LC/MS) J Liq Chromatogr Relat Technol. 2005;28:11611202. doi: 10.1081/JLC-200053022.] 6. Cesar ID, Nogueira FHA, Pianetti GA. Simultaneous determination of artemether and lumefantrine in fixed dose combination tablets by HPLC with UV detection. J Pharm Biomed Anal. 2008;48:951954. doi: 10.1016/j.jpba.2008.05.022 7. Cesar ID, Nogueira FHA, Pianetti GA. Comparison of HPLC, UV spectrophotometry and potentiometric titration methods for the determination of lumefantrine in pharmaceutical products. J Pharm Biomed Anal. 2008;48:223226. doi: 10.1016/j.jpba.2008.05.006. 8. Patil KR, Rane VP, Sangshetti JN, Shinde DB. A Stability-Indicating LC Method for Lumefantrine. Chromatographia. 2009;69:375379. doi: 10.1365/s10337-008-0894-x. [Cross Ref] 9. Munjal V, Paliwal N, Chaursia BK, Varshney B, Ahmed T, Paliwal J. LC-tandem mass spectrometry method for quantification of lumefantrine in human plasma and its application to bioequivalence study. Chromatographia. 2010;71:505510. doi: 10.1365/s10337-009-1446-8. [Cross Ref] 10. ICH guidelines – International Conference on Harmonization, Q1A(R2) Stability testing of new drug substances and products CPMP/ICH/2736/99. (August 2003) http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
(19) (PDF) Process for high purity lumefantrine. Available from: https://www.researchgate.net/publication/221933417_Process_for_high_purity_lumefantrine [accessed Feb 06 2022].

PATENT

2503-MUM-2008-DESCRIPTION(COMPLETE)-(24-4-2009).pdf	2018-08-09

PAPER

Tropical Journal of Pharmaceutical Research October 2013; 12 (5): 791-798 ISSN: 1596-5996 (print); 1596-9827 (electronic) © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights reserved. Available online at http://www.tjpr.org

CLIP

NMR

https://www.researchgate.net/publication/338694609_Structural_Characterization_and_Thermal_Properties_of_the_Anti-malarial_Drug_Lumefantrine/figures?lo=1

1H NMR

COSY

NOESY

HSQC

DEPT

13C NMR

DSC

CLIP

Click to access DPC-2016-8-3-91-100.pdf

REFERENCES

[1] Ulrich Beutler, C Peter.; Fuenfschilling.; and Andreas, Steinkemper.; Novartis Pharma AG; Chemical and Analytical Development: CH-4002 Basel, Switzerland, Organic Process Research & Development 2007, 11, 341- 345.

[2] Boehm, M. Fuenfschilling.; Krieger, P. C.; Kuesters, E. M.; Struber, F.; Org. Process Res. DeV. 2007, 11, 336- 340.

[3] (a) Rao, D. R.; Kankan, R. N.; Phull, M. S.; Patent Application CN 1009-3724 20060424, 2005. (b) Deng, R.; Zhong, J.; Zhao, D.; Wang, J.; Yaoxue, X. 2000, 35 (1), 22. (c) Allmendinger, Th.; Wernsdorfer, W. H. PCT WO 99/67197.

[4] Perrumattam, J.; Shao, Ch.; Confer, W. L. Synthesis 1994, 1181.

[5] Fuenfschilling, P. C.; Hoehn P.; Mutz J.-P. Organic Process Res. Dev. 2007, 11, 13.

[6] Di Nunno, L.; Scilimati, A. Tetrahedron 1988, 44, 3639.

[7] Pharmacopeial Forum, Vol. 36(2) [Mar.-Apr. 2010]

Preparation of 2-(dibutylamino)-1-[(9Z)-2, 7-dichloro-9-(4-chlorobenzylidene)-9H-floren-4-yl] ethanol (Lumefantrine) 1.

To a stirred solution of NaOH (1.97 g 0.0492 mol) in methanol (100 ml) there was added 1-(2, 7- dichloro-9 H-fluren-4-yl)-2-(dibutyl amino) ethanol (10 g, 0.0246 mol) and para chloro benzaldehyde (5.24 g 0.0372). The suspension obtained was stirred at reflux temperature till the absence of starting material by TLC. After confirming the product formation reaction mixture was cooled to room temperature and further stirred at same temperature for overnight. The precipitated solids were filtered and washed with methanol and dried under vacuum at 50°C to get desired compound. (Purity by HPLC: 99%).

IR (cm-1): 3408, 3092, 2953, 2928, 2870, 2840, 1634, 1589, 1487, 1465, 1443, 1400, 1365, 1308, 1268, 1241, 1207, 1173, 1156, 1085, 1071, 1014, 980, 933, 874, 839, 815, 806, 770;

1H NMR (CDCl3, δ ppm): 7.75 (d, 1H, CH, J 1.5 Hz), 7.68 (d, 1H, CH, J 1.5 Hz), 7.60-7.63 (m, 1H, CH), 7.32-7.35 (dd, 1H, CH, J 1.7,8.3 Hz), 7.45-7.50 (m, 1H, CH), 5.35-5.39 (dd, 1H, CH, J 3.0,9.9 Hz), 2.41-2.74 (m, 1H, CH2Ha), 2.86-2.92 (m, 1H, CH2Hb), 2.41-2.74 (m, 4H, CH2), 1.25-1.56 (m, 8H, CH2), 0.97 (t, 1H, CH, J 7.2 Hz), 7.60-7.63 (m, 1H, CH), 7.45-7.50 (m, 4H, CH), 4.54 (broad, 1H, OH),

13C NMR (CDCl3, δ ppm): 138.2, 141.5, 120.6, 133.2, 126.3, 135.0, 135.0, 136.4, 123.9, 128.3, 132.8, 123.0, 139.8, 65.5, 60.0, 53.5, 29.1, 20.6, 14.0, 127.6, 134.7, 130.5, 129.1, 133.2;

MS: m/z: 528 [M+H]+ ; Analysis calcd. for C30H32Cl3NO: C, 68.12; H, 6.10; N, 2.65% Found: C, 68.38; H, 6.14; N, 2.63 %.

CLIP

One-dimensional 1H NMR spectrum of B) a lumefantrine standard,

A CLIP

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532012000100010&lng=en&nrm=iso

Image result for lumefantrine synthesis

CLIP

A simple and precise method for quantitative analysis of lumefantrine …

https://www.ncbi.nlm.nih.gov › NCBI › Literature › PubMed Central (PMC)

by P Hamrapurkar – ‎2010 – ‎Cited by 2 – ‎Related articles

[2–4] Thus, today lumefantrine is a drug of choice in antimalarial treatment against P. …. The NMRspectra observed triplet at 0.943-0.989 (methyl protons of alkyl …

The spectroscopic techniques were used to confirm the identity of lumefantrine. The IR spectra, showed strong absorption band at 3404.67 cm^-1 (OH), 2953.28 cm^-1 (aliphatic and aromatic CH), 1757.31 cm^-1 (-C=C-), 933 cm^-1 (alkanes) and 696.37-373.22 cm^-1 (Cl). Thus, IR spectra confirmed the presence of these functional groups in the structure of lumefantrine.

The mass spectrum showed a sharp molecular ion peak at 528.0 m/z in Q1 MS (m/z, parent ion) parameter at negative polarity confirming the molecular weight of lumefantrine.

The NMR spectra observed triplet at 0.943-0.989 (methyl protons of alkyl chain); a multiplet at 1.372-1.498 (methylene protons of alkyl chains); a multiplet at 2.449-2.909 (methylene protons of alkyl chain); broad singlet at 4.573 (OH proton); and multiplet at 7.314-7.733 (aromatic proton), thus confirming identity of lumefantrine.

IH NMR PREDICT

13C NMR PREDICT

Image result for lumefantrine synthesis

References

Jump up^ Toovey S, Jamieson A, Nettleton G (2003). “Successful co-artemether (artemether-lumefantrine) clearance of falciparum malaria in a patient with severe cholera in Mozambique”. Travel medicine and infectious disease. 1 (3): 177–9. doi:10.1016/j.tmaid.2003.09.002. PMID 17291911.
Jump up^ White, Nicholas J.; van Vugt, Michele; Ezzet, Farkad (1999). “Clinical Pharmacokinetics and Pharmacodynamics of Artemether-Lumefantrine”. Clinical Pharmacokinetics. 37 (2): 105–125. doi:10.2165/00003088-199937020-00002. ISSN 0312-5963.
Jump up^ Cui, Liwang; Su, Xin-zhuan (2009). “Discovery, mechanisms of action and combination therapy of artemisinin”. Expert Review of Anti-infective Therapy. 7 (8): 999–1013. doi:10.1586/eri.09.68. PMC 2778258. PMID 19803708.
Jump up^ http://aac.asm.org/content/56/5/2465.full
Jump up^ Laman, M; Moore, BR; Benjamin, JM; Yadi, G; Bona, C; Warrel, J; Kattenberg, JH; Koleala, T; Manning, L; Kasian, B; Robinson, LJ; Sambale, N; Lorry, L; Karl, S; Davis, WA; Rosanas-Urgell, A; Mueller, I; Siba, PM; Betuela, I; Davis, TM (2014). “Artemisinin-naphthoquine versus artemether-lumefantrine for uncomplicated malaria in Papua New Guinean children: an open-label randomized trial”. PLoS Med. 11: e1001773. doi:10.1371/journal.pmed.1001773. PMC 4280121. PMID 25549086.

Lumefantrine
Clinical data

AHFS/Drugs.com	International Drug Names
MedlinePlus	a609024
Routes of administration	Oral
ATC code	P01BF01 (WHO) (combination with artemether)
Legal status
Legal status	US: C
Identifiers
IUPAC name [show]
CAS Number	82186-77-4
PubChem (CID)	6437380
DrugBank	DB06708
ChemSpider	4941944
UNII	F38R0JR742
KEGG	D03821
ChEBI	CHEBI:156095
ChEMBL	CHEMBL38827
Chemical and physical data
Formula	C₃₀H₃₂Cl₃NO
Molar mass	528.939 g/mol
3D model (Jmol)	Interactive image

Title: Lumefantrine

CAS Registry Number: 82186-77-4

CAS Name: (9Z)-2,7-Dichloro-9-[(4-chlorophenyl)methylene]-a-[(dibutylamino)methyl]-9H-fluorene-4-methanol

Additional Names: 2-dibutylamino-1-[2,7-dichloro-9-(4-chlorobenzylidene)-9,11-fluoren-4-yl]ethanol; dl-benflumelol; benflumetol; BFL

Manufacturers’ Codes: CPG-56695

Molecular Formula: C30H32Cl3NO

Molecular Weight: 528.94

Percent Composition: C 68.12%, H 6.10%, Cl 20.11%, N 2.65%, O 3.02%

Literature References: Racemic aryl alcohol originally synthesized in the 1970’s by the Academy of Military Medical Sciences in Beijing, China. Inhibits hemozoin formation. Prepn: R. Deng et al., CN 1042535 (1990 to Acad. Military Med. Sci., Microbiol. & Epidemic Dis. Instit.); C.A. 114, 6046 (1991). LC determn in plasma: A. Annerberg et al., J. Chromatogr. B 822, 330 (2005). In vitro activity against Plasmodium falciparum: B. Pradines et al., Antimicrob. Agents Chemother. 43, 418 (1999).

Properties: Odorless, yellow powder. Poorly sol in water, oil, and most organic solvents. Sol in unsaturated fatty acids.

Derivative Type: Co-artemether

CAS Registry Number: 141204-94-6

Manufacturers’ Codes: CPG-56697

Trademarks: Coartem (Novartis); Riamet (Novartis)

Literature References: Fixed 6:1 mixture with artemether, q.v. Clinical pharmacokinetics and bioavailability: F. Ezzet et al., Br. J. Clin. Pharmacol. 46, 553 (1998). Clinical trial in children against P. falciparum malaria: C. Hatz et al., Trop. Med. Int. Health 3, 498 (1998); in adults: S. Looareesuwan et al., Am. J. Trop. Med. Hyg. 60, 238 (1999). Review of comparative clinical trials in malaria: A. A. Omari et al., Trop. Med. Int. Health 9, 192-199 (2004).

Therap-Cat: Antimalarial.

Keywords: Antimalarial.

///////////lumefantrine, lumefantrene, Antimalarial, CPG-56695, CPG 56695,

CCCCN(CCCC)CC(O)C1=C2C(=CC(Cl)=C1)\C(=C/C1=CC=C(Cl)C=C1)C1=C2C=CC(Cl)=C1

Designing Polymers for Amorphous Solid Dispersions — AAPS Blog

December 1, 2016 1:07 am / Leave a comment

By: Laura I. Mosquera-Giraldo and Lynne S. Taylor Imagine spending billions of dollars in the discovery of a new drug, and then realizing that it is impractical to administer it orally because it cannot reach the systemic circulation and achieve a therapeutic effect. This is the case for many emerging drugs that are insoluble in water, […]

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Ranolazine Intermediate, An Efficient Synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β-Adrenoblockers

December 1, 2016 1:04 am / Leave a comment

Abstract Image

An efficient process for the preparation of 1-(2-methoxyphenoxy)-2,3-epoxypropane, a key intermediate for the synthesis of ranolazine is described.

http://pubs.acs.org/doi/suppl/10.1021/op300056k

Preparation of 1-(2-Methoxyphenoxy)-2,3-epoxypropane 4.

To a stirring solution of 2-methoxy phenol 2 (10 kg, 80.55 mol) and water (40 L) at about 30 °C was added sodium hydroxide (1.61 kg, 40.25 mol) and water (10 L). After stirring for 30−45 min, epichlorohydrin 3 (22.35 kg, 241.62 mol) was added and stirred for 10−12 h at 25−35 °C. Layers were separated, and water (40 L) was added to the organic layer (bottom layer) containing product. Sodium hydroxide solution (3.22 kg, 80.5 mol) and water (10 L) were added at 27 °C and stirred for 5−6 h at 27 °C.

The bottom product layer was separated and washed with sodium hydroxide solution (3.0 kg 75 mol) and water (30 L). Excess epichlorohydrin (3) was recovered by distillation of the product layer at below 90 °C under vacuum (650−700 mmHg) to give 13.65 kg (94%) of title compound with 98.3% purity by HPLC, 0.2% of 2- methoxy phenol 2, 0.1% of epichlorohydrin 3, 0.1% of chlorohydrin 11, 0.3% of dimer 12 and 0.3% of dihydroxy 13.

1 H NMR (400 MHz, CDCl3, δ) 6.8−7.0 (m, 4H), 4.3 (dd, J = 5.6 Hz, 5.4 Hz, 1H), 3.8 (dd, J = 5.6 Hz, 5.3 Hz, 1H), 3.7 (s, 3H), 3.2−3.4 (m, 1H), 2.8 (dd, J = 5.6 Hz, 5.4 Hz, 1H), 2.7 (dd, J = 5.6 Hz, 5.3 Hz, 1H);

IR (KBr, cm−1 ) 2935 (C−H, aliphatic), 1594 and 1509 (CC, aromatic), 1258 and 1231 (C−O−C, aralkyl ether), 1125 and 1025 (C−O−C, epoxide);

MS (m/z) 181 (M+ + H).

Compound Details

Properties
MWt	180.2
MF	C10H12O3

CAS 2210-74-4

Glycidyl 2-methoxyphenyl ether
	Guaiacol glycidyl ether

1H NMR PREDICT

13C NMR PREDICT

COSY PREDICT

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CREDIT……….http://www.molbase.com/en/synthesis_2210-74-4-moldata-95563.html

RakeshwarBandichhor

DR REDDYS LABORATORIES

An Efficient Synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β-Adrenoblockers

Lokeswara Rao Madivada†, Raghupathi Reddy Anumala†, Goverdhan Gilla†, Mukkanti Kagga‡, and RakeshwarBandichhor *†

^† Innovation Plaza, IPD, R&D, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45,46, and 54, Bachupally, Qutubullapur – 500073, Andhra Pradesh, India

^‡ Institute of Science and Technology, Center for Environmental Science, JNT University, Kukatpally, Hyderabad – 500 072, Andhra Pradesh, India

Org. Process Res. Dev., 2012, 16 (10), pp 1660–1664

DOI: 10.1021/op300056k

Publication Date (Web): September 14, 2012

*Telephone: +91 4044346000. Fax: +91 4044346285. E-mail: rakeshwarb@drreddys.com.

////////////////1-(2-Methoxyphenoxy)-2,3-epoxypropane, β-Adrenoblockers, ranolazine

COc2ccccc2OCC1CO1

OTHER COMPD

Glycidyl 2-methylphenyl ether technical grade, 90%

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