LANEPITANT
N-[(2R)-1-[acetyl-[(2-methoxyphenyl)methyl]amino]-3-(1H-indol-3-yl)
propan-2-yl]-2-(4-piperidin-1-ylpiperidin-1-yl)acetamide
propan-2-yl]-2-(4-piperidin-1-ylpiperidin-1-yl)acetamide
- N-[(2R)-1-[Acetyl-[(2-methoxyphenyl)methyl]amino]-3-(1H-indol-3-yl)propan-2-yl]-2-(4-piperidin-1-ylpiperidin-1-yl)acetamid
- (R)- 1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(piperidin-l-yl)piperidin-1-yl)acetyl)amino]propane
- ELI LILLY
170566-84-4 cas no
Molecular Formula: C33H45N5O3 Molecular Weight: 559.7421
167678-33-3 (diHCl, tri H2O)
170508-05-1 (diHCl)
PHASE 2
DESCRIBED IN
Practical and Enantiospecific Synthesis of LY303870
J. Org. Chem., 1995, 60 (21), pp 7033–7036
DOI: 10.1021/jo00126a069
Lanepitant is a chemical compound , as a potential drug for the treatment of pain , including migraine was developed headache.Having been in clinical trials no migraine efficacy was observed, its further clinical development for this indication was from thepharmaceutical company Eli Lilly and Company set. [2] [3] Pharmacologically Lanepitant is a neurokinin - antagonist .
Lanepitant inhibits antagonist via the neurokinin NK 1 receptor mediated effects of substance P . Experimental has Lanepitant anti-inflammatory and pain perception affecting properties. [4] In animal experiments , in which the pathophysiology of migraine has been simulated, the substance inhibits the inflammatory response in the meninges . [5] Animal experiments also submitted a possible efficacy in neuropathic pain [6] and the complex regional pain syndrome [7] [8] near. In clinical studies , however, neither a migraine efficacy has [2] [3] nor an analgesic effect in diabetic neuropathy [9] and osteoarthritis [10] are occupied.
Lanepitan is a chiral chemical compound with a stereogenic center . It is the R - enantiomer , while the biologically active stereoisomer ( eutomer ) Compared with the L -enantiomer, his distomer , has Lanepitant at least 1000-fold higher affinity for the neurokinin NK 1 receptor on. [11]
Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's.
Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now termed neurokinin A (also known as substance K, neuromedin L, and neurokinin α), and neurokinin B (also known as neuromedin K and neurokinin β). See. J.E. Maggio, Peptides. 6 (Supplement 3):237-243 (1985) for a review of these discoveries.
Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
Substance P is believed inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.
Tachykinins play a major role in mediating the sensation and transmission of pain or nociception, especially migraine headaches, see. e.g., S.L. Shepheard, et al.. British Journal of Pharmacology. 108:11-20 (1993); S.M. Moussaoui, et al., European Journal of Pharmacology . 238:421-424 (1993); and W.S. Lee, et al.. British Journal of Pharmacology. 112:920-924 (1994). In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions. The earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
Recent publications have described novel classes of non- peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists. Examples of such newer non-peptidyl tachykinin receptor antagonists are found in United States Patent 5,491,140, issued February 13, 1996; United States Patent 5,328,927, issued July 12, 1994; United States Patent 5,360,820, issued November 1, 1994; United States Patent 5,344,830, issued September 6, 1994; United States Patent 5,331,089, issued July 19, 1994; European Patent Publication 591,040 Al, published April 6, 1994; Patent Cooperation Treaty publication WO 94/01402, published January 20, 1994; Patent Cooperation Treaty publication WO 94/04494, published March 3, 1994; Patent Cooperation Treaty publication WO 93/011609, published January 21, 1993; Canadian Patent Application 2154116, published January 23, 1996; European Patent Publication 693,489, published January 24, 1996; and Canadian Patent Application 2151116, published December 11, 1995.
United States Patent 5,530,009, issued June 25, 1996, describes a 1,2-diacylaminopropane for use in treating conditions associated with an excess of tachykinins. This patent also teaches processes for preparing this compound.
In essence, this invention provides a class of potent non- peptidyl tachykinin receptor antagonists similar to those of United States Patent 5,530,009. By virtue of their non-peptidyl nature, the compounds of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based tachykinin receptor antagonists.
- ↑ This substance has not yet been classified on their dangerousness either in terms or a reliable and quotable source for this purpose has not been found.
- ↑ a b Goldstein DJ, Open WW, Klein EC, et al. : Lanepitant, antagonist of NK-1 in migraine prevention . In: Cephalalgia . 21, No. 2, March 2001, pp. 102-106. PMID 11,422,091 .
- ↑ a b Goldstein DJ, Wang O, Saper JR, Stoltz R, Silberstein SD, Mathew NT: ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study . In: Cephalalgia . 17, No. 7, November 1997, pp. 785-790. PMID 9.39901 million .
- ↑ Iyengar S, Hipskind PA, Gehlert DR, et al. : LY303870, a centrally active neurokinin-1 antagonist with a long duration of action . In: J. Pharmacol. Exp Ther. . 280, No. 2, February 1997, pp. 774-785. PMID 9023291 .
- ↑ LA Phebus, KW Johnson, PW Stengel, Lobb KL, Nixon JA, Hipskind PA: The non-peptide NK-1 receptor antagonist LY303870 Inhibits neurogenic dural inflammation in guinea pigs . In: Life Sci. . 60, No. 18, 1997, pp. 1553-1561. PMID 9126877 .
- ↑ Campbell EA, Gentry CT, Patel S, Panesar MS, Walpole CS, Urban L: Selective neurokinin-1 receptor antagonists are anti-hyperalgesic in a model of neuropathic pain in the guinea-pig . In: Neuroscience . 87, No. 3, December 1998, pp. 527-532. PMID 9758219 .
- ↑ Guo TZ, Offley SC, Boyd EA, Jacobs CR, Kingery WS: Substance P signaling Contributes to the vascular and nociceptive abnormalities observed-in a tibial fracture rat model of complex regional pain syndrome type I in:. Pain . 108, No. 1-2, March 2004, pp. 95-107. doi : 10.1016/j.pain.2003.12.010 . PMID 15,109,512 .
- ↑ Kingery WS, Davies MF, Clark JD: A substance P receptor (NK1) antagonist can reverse vascular and nociceptive abnormalities in a rat model of complex regional pain syndrome type IIin:. Pain . 104, No. 1-2, July 2003, pp. 75-84. PMID 12,855,316 .
- ↑ Goldstein DJ, Wang O, grid BD, Iyengar S: Dose-response study of the analgesic effect of lanepitant in patients with painful diabetic neuropathy . In: Clin Neuropharmacol . 24, No. 1, 2001, pp. 16-22. PMID 11,290,877 .
- ↑ Goldstein DJ, Wang O, Todd LE, grid BD, DeBrota DJ, Iyengar S: Study of the analgesic effect of lanepitant in patients with osteoarthritis pain . In: Clin. Pharmacol. Ther. . 67, No. 4, April 2000, pp. 419-426. doi : 10.1067/mcp.2000.105243 . PMID 10,801,252 .
- ↑ grid BD, Bruns RF, Howbert JJ, et al. : Pharmacological characterization of LY303870: a novel, potent and selective nonpeptide substance P (neurokinin-1) receptor antagonist . In: J.Pharmacol. Exp Ther. . 275, No. 2, November 1995, pp. 737-744. PMID 7473161 .
1-26-2000
Methods of treating or preventing interstitial cystitis
12-15-1999
Methods of treating or preventing sleep apnea
8-5-1999
METHODS OF TREATING OR PREVENTING INTERSTITIAL CYSTITIS METHODS OF TREATING OR PREVENTING INTERSTITIAL CYSTITIS
10-9-1998
METHODS OF TREATING BONE LOSS
9-19-1997
METHODS OF TREATING OR PREVENTING INTERSTITIAL CYSTITIS
9-5-1997
METHODS OF TREATING OR PREVENTING SLEEP APNEA
7-25-1997
METHODS OF TREATING OR PREVENTING PAIN OR NOCICEPTION
9-27-1996
METHODS OF TREATING OR PREVENTING PAIN OR NOCICEPTION
| WO2002085458A2 * | Feb 2, 2002 | Oct 31, 2002 | Hoffmann La Roche | Use of nk-1 receptor antagonists against benign prostatic hyperplasia |
| WO2013004766A1 | Jul 4, 2012 | Jan 10, 2013 | Ferrari Giulio | Nk-1 receptor antagonists for treating corneal neovascularisation |
| US5328927 * | Feb 24, 1993 | Jul 12, 1994 | Merck Sharpe & Dohme, Ltd. | Hetercyclic compounds, processes for their preparation and pharmaceutical compositions containing them |
| US5360820 * | Sep 18, 1992 | Nov 1, 1994 | Glaxo Group Limited | Medical use for tachykinin antagonists |
| US5491140 * | Jun 30, 1994 | Feb 13, 1996 | Eli Lilly And Company | Naphthyl tachykinin receptor antagonists to treat physiological conditions |
| US5530009 * | Jun 5, 1996 | Jun 25, 1996 | Eli Lilly And Company | Bis-piperidinyl non-peptidyl neurokinin receptor antagonists |
| US5554627 * | Oct 27, 1993 | Sep 10, 1996 | Merck, Sharp & Dohme Ltd. | Tachykinin antagonists |
| US5594022 * | Nov 29, 1994 | Jan 14, 1997 | Warner-Lambert Company | Tachykinin antagonists |
| US5652369 * | Apr 6, 1995 | Jul 29, 1997 | Hoffmann-La Roche Inc. | Amino acid derivatives |
| US5328927 * | 24 Feb 1993 | 12 Jul 1994 | Merck Sharpe & Dohme, Ltd. | Hetercyclic compounds, processes for their preparation and pharmaceutical compositions containing them |
| US5344830 * | 10 Dec 1992 | 6 Sep 1994 | Merck & Co., Inc. | N,N-diacylpiperazine tachykinin antagonists |
Preparation 1
Preparation of (R)-3-(lH-indol-3-yl)-N-(2-methoxybenzyl)-2-(N- triphenylmethylamino)propan amide.
In a 50 gallon, glass-hned reactor, L-tryptophan (4.50 kg, 22.0 mol) was added to acetonitrile (30 L, 6.7 vol) at 20 °C. This reactor was vented to a scrubber containing water, intended to scrub ammonia generated during the silylation reaction and HCl generated during the tritylation and esterification reactions. Bis(trimethylsilyl)amine (HMDS, 5.81 L, 27.5 mol, 1.25 eq) was transferred by gravity to the L- tryptophan slurry from a plastic carboy. The carboy was rinsed with acetonitrile (0.5 L). The slurry was heated to 55 °C and stirred until reaction completion. The reaction endpoint was defined as the point at which the slurry has completely gone into solution. The reaction was clear yellow at completion and took about 2 hours.
Trityl chloride (6.45 kg, 23.1 mol, 1.05 eq) was slurried in acetonitrile (30 L, 6.7 vol) and transferred into the reactor at 47 °C, using trapped vacuum at 325 mm Hg. N-methylmorphohne (5.38 L, 48.9 mol, 2.20 eq) was also transferred into the reactor at this time. The reaction slurry was heated and maintained at 55 °C until reaction completion, determined by high performance hquid chromatography analysis. Reaction time was about 2.5 hours.
The reactor was isolated from the scrubber, and cooled to 35- 40 °C. Methyl alcohol (2.29 L, 56.5 mol, 2.55 eq.) was charged to the reactor and the mixture cooled to 25 °C. 2-Chloro-4,6-dimethoxy- 1,3,5- triazine (CDMT, 4.14 kg, 23.61 mol, 1.07 eq) was added to the reactor with acetonitrile (28 L, 6.2 vol) at 25 °C. The reactor was again vented to the scrubber. The reaction slurry was stirred at room temperature until completion. The reaction endpoint is determined by high performance hquid chromatography analysis. Reaction time is approximately 2 hours. The reactor was isolated from the scrubber following the reaction. 2-Methoxybenzylamine (3.11 L, 23.8 mol, 1.08 eq) was charged to the reactor from a plastic carboy by gravity. The slurry thickens with the addition of 2-methoxybenzylamine. The reaction slurry was heated to 35°C and stirred until reaction completion, determined by high performance hquid chromatography analysis. Reaction time was 2.5 hours.
Water (45 kg, 10 vol) was pre-weighed into a separate 50 gallon, glass-lined tank. The water was pressure-transferred into the reaction mixture slurry over about 45 minutes. The resulting yellow- colored slurry was cooled to 0-5 °C over two hours and stirred overnight. The title intermediate was isolated by vertical basket centrifuge isolation using three micron polyethylene multiple filament isolation bag. During the centrifugation, the load speed was generally between 900-1050 rpm, the wash speed was 900-1500 rpm, and the spin speed was 1500-2300 rpm. The title intermediate was then dried by rotary vacuum drying. Yield: 86.4% with isomer purity of 99.6%.
Preparation 2 Reduction of Carbonyl
Preparation of (R)-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)amino]-2-(N- triphenylmethylamino)propane
RED-AL®. [a 3.4 M, solution of sodium bis(2- methoxyethoxy) aluminum hydride in toluene] (535 ml, 1.819 mol), dissolved in anhydrous tetrahydrofuran (400 ml) was slowly added using an addition funnel to a refluxing solution of the acylation product, (R)-3- (lH-indol-3-yl)-N-(2-methoxybenzyl)-2-(N- triphenylmethylamino)propanamide (228.6 g, 0.404 mols) produced supra. in anhydrous tetrahydrofuran (1.0 L) under a nitrogen atmosphere. The reaction mixture became a purple solution. The reaction was quenched after at least 20 hours by the slow addition of excess saturated Rochelle's salt solution (potassium sodium tartrate tetrahydrate). The organic layer was isolated, washed with brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to an oil on a rotary evaporator. No further purification was done and the product was used directly in the next step.
Preparation 3 Acylation of Secondary Amine
Preparation of (R)-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)-acetylamino]- 2-(N-triphenylmethylamino)propane
To a stirring solution of (R)-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 mol) in anhydrous tetrahydrofuran (1.2 L) under a nitrogen atmosphere at 0°C was added triethylamine (66.5 ml, 0.477 mol) and acetic anhydride (45.0 ml, 0.477 mol). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2X) and brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to a sohd on a rotary evaporator. The resulting sohd was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes. The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of (R)-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane was crystallized and isolated over three crops giving 208.97 grams (87% yield) of analytically pure material. Analysis for C40H39N3O2:
Theory: C, 80.91; H, 6.62; N, 7.08. Found: C, 81.00; H, 6.69; N, 6.94. Preparation 4
Deprotection
Preparation of (R)-2-amino-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)acetylamino]prop ane dihy drochloride
A stirring solution of (R)-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane in two volumes of methylene chloride was cooled to between -40°C and -50°C. Anhydrous hydrogen chloride gas was added at such a rate that the temperature of the reaction mixture did not exceed 0°C. The reaction mixture was stirred for 30 minutes to one hour at 0-10°C.
To this reaction mixture was added two volumes of methyl t- butyl ether and the resulting mixture was allowed to stir for 30 minutes to one hour at 0-10°C. The resulting crystalline sohd was removed by filtration and then washed with methyl £ -butyl ether. The reaction product was dried under vacuum at 50°C. (Yield >98%) Analysis for C21H25N3O2 • 2 HCl:
Theory: C, 59.44; H, 6.41; N, 9.90.
Found: C, 60.40; H, 6.60; N, 9.99.
Preparation 5
Preparation of (R)-2-[(2-bromo)acetyl]amino-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)acetylamino]propane
To a stirring solution of (R)-2-amino-3-(lH-indol-3-yl)-l-[N- (2-methoxybenzyl)acetylamino]propane (7.51 g, 21.369 mmol) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere at 0°C were added diisopropylethylamine (4.1 ml, 23.537 mmol) and bromoacetyl bromide (2.05 ml, 23.530 mmol). After 2 hours, ethyl acetate was added and the reaction mixture washed with water twice, 1.0 N hydrochloric acid (2X), saturated sodium bicarbonate solution (2X), and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to a tan foam on a rotary evaporator. In this manner the 2- [(2-bromo)acetyl]amino-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)acetylamino]propane was obtained in quantitative yield. No further purification was necessary.
Preparation 6
Preparation of a polystyrene bound isocyanate resin
To a stirred suspension of 50 grams (61 mmol) aminomethylated polystyrene resin (1.22 mmol/g) in 800 ml toluene was added 193 ml (366 mmol) 1.9 M phosgene in toluene. After stirring the reaction mixture for 10 minutes, 67 ml (482 mmol) triethylamine was added and the reaction mixture was stirred for 18 hours at room temperature. The mixture was filtered and the recovered sohd washed with 10 times with dichloromethane. A hght pink resin mixed with a white sohd was obtained. This sohd mixture was resuspended in 700 ml dichloromethane, stirred for 10 minutes and then filtered and washed well with dichloromethane. The resulting sohd was again suspended, stirred and washed with dichloromethane to provide the desired resin. IR(KBr): 2252 cm"1 (characteristic peak for -N=C=0)
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Synthesis of (R)-2-[N-(2-((4-cyclohexyl)piperazin-l-yl)acetyl)amino]-3-(lH- indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]propane
(a) Preparation of 2-(4-(piperidin-l-yl)piperidin-l-yl)acetic acid, potassium salt
4-(Piperidin-l-yl)piperidine (1.20 kg, 7.13 mol) was added to methylene chloride (12.0 L) under a nitrogen atmosphere. Tetrabutylammonium bromide (0.150 kg, 0.47 mol) and sodium hydroxide (1.7 L of a 5 N solution, 8.5 mol) were then added. The reaction mixture was cooled to 10-15°C and methyl bromoacetate (1.17 kg, 7.65 mol) was added and the resulting mixture was stirred for a minimum of 16 hours.
Deionized water (1.2 L) was then added to the mixture and the layers separated. The aqueous layer was back-extracted with methylene chloride (2.4 L). The organic fractions were combined and washed with deionized water (3 x 1.2 L), a saturated sodium bicarbonate solution (1.1 L) and a saturated sodium chloride solution (1.1 L). The organic fraction was then dried over anhydrous magnesium sulfate and concentrated to an oil on a rotary evaporator to -yield 1.613 kg (93.5%) of methyl 2-(4-(piperidin-l-yl)piperidin-l-yl)acetate.
A solution of methyl 2-[4-(piperidin-l-yl)piperidin-l- yl]acetate (2.395 kg, 9.96 mol) in methanol (2.4 L) was added to a solution of potassium hydroxide (0.662 kg, 10.0 mol @ 85% purity) in methanol (10.5 L) under a nitrogen atmosphere. The reaction mixture was heated to 45-50°C for a minimum of 16 hours.
A solvent exchange from methanol to acetone (15.0 L) was performed on the solution on a rotary evaporator. This solution was slowly cooled to room temperature over 16 hours. The resulting solids were filtered, rinsed with acetone (5.0 L) and then dried to yield 2.471 kg (93.8%) of 2-(4-(piperidin-l-yl)piperidin-l-yl)acetic acid, potassium salt. MS 265 (M+1)
(b) Preparation of (R)-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin-l-yl)piperidin-l- yl)acetyl)amino]propane
The title compound was. prepared by first admixing (R)-2- amino-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]propane dihydrochloride (50.0 g, 0.118 mol) with 100 ml of methylene chloride under a nitrogen atmosphere.
In a second flask, under a nitrogen atmosphere, 2-(4- (piperidin-l-yl)piperidin-l-yl)acetic acid potassium salt (62.3 g, 0.236 mol) was added to 600 ml of methylene chloride. This mixture was cooled to about -10°C and stirring was continued. To this mixture isobutylchloroformate (23 ml, 0.177 mol) was added dropwise such that the temperature of the 2-(4-(piperidin-l-yl)piperidin-l-yl)acetic acid potassium salt mixture never rose appreciably.
This reaction mixture was stirred at about -10°C for about 1.5 hours at which time the (R)-2-amino-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)acetylamino]propane dihydrochloride/methylene chloride mixture prepared supra was slowly added to the 2-(4-(piperidin- l-yl)piperidin-l-yl)acetic acid potassium salt isobutylchloroformate/methylene chloride solution. The resulting mixture was then stirred for about 1 hour at a temperature between - 15°C and -8°C.
The reaction mixture was removed from the ice bath and allowed to warm to 15-20°C and the reaction was quenched by the addition of 200 ml of water. The pH ofthe solution was adjusted to 2.3-2.7 by the additon of IN sulfuric acid. The layers were separated and the aqueous layer was washed with 100 ml of methylene chloride.
The organic fractions were combined and washed with water (100 ml). The water wash was back extracted with methylene chloride (50 ml) and combined with the aqueous fraction from above. Methylene chloride (500 ml) was added to the combined aqueous layers and the mixture was stirred at room temperature for 15 minutes as basification with 2N sodium hydroxide to a final pH of 9.8 to 10.2 was achieved. The organic and aqueous fractions were separated. The aqueous fraction was washed with methylene chloride and the methylene chloride was added to the organic fraction. The organic fraction was then washed with a mixture of saturated sodium bicarbonate solution (100 ml) and water (50 ml). The bicarbonate wash was separated from the organic fraction and back extracted with methylene chloride (50 ml).
The back extraction was combined with the methylene chloride fraction and the combined fractions were dried over magnesium sulfate. The magnesium sulfate was removed by filtration and the volatiles were removed by vacuum distillation to yield the title product as a foam. (72.5 g, >98% yield). MS 559(M+1)
NMR (DMSO-dβ 3:2 mixture of amide rotamers) δ 1.25-1.70 (m, 10H),
1.77-2.00 (m, 2H), 1.95 (s, 3/5-3H), 2.04 (s, 2/5-3H), 2.10-2.97 (m, 9H), 3.10- 3.65 (m, 3H), 3.72 (s, 2/5-3H), 3.74 (s, 3/5- 3H), 4.26-4.58 (m, 3H), 6.76-7.12 (m, 6H), 7.13-7.35 (m, 2H), 7.42-7.66 (m, 2H), 10.80 (br s, IH). Analysis for C33H45N5O3:
Theory: C, 70.81; H, 8.10; N, 12.51.
Found: C, 70.57; H, 8.05; N, 12.39.
Preparation of 2-(4-(piperidin-l-yl)piperidin-l-yl)acetic acid, potassium salt
4-(Piperidin-l-yl)piperidine (1.20 kg, 7.13 mol) was added to methylene chloride (12.0 L) under a nitrogen atmosphere.
Tetrabutylammonium bromide (0.150 kg, 0.47 mol) and sodium hydroxide (1.7 L of a 5 N solution, 8.5 mol) were then added. The reaction mixture was cooled to 10-15°C and methyl bromoacetate (1.17 kg, 7.65 mol) was added and the resulting mixture was stirred for a minimum of 16 hours.
Deionized water (1.2 L) was then added to the mixture and the layers separated. The aqueous layer was back-extracted with methylene chloride (2.4 L). The organic fractions were combined and washed with deionized water (3 x 1.2 L), a saturated sodium bicarbonate solution (1.1 L) and a saturated sodium chloride solution (1.1 L). The organic fraction was then dried over anhydrous magnesium sulfate and concentrated to an oil on a rotary evaporator to yield 1.613 kg (93.5%) of methyl 2-(4-(piperidin-l-yl)piperidin-l-yl)acetate.
A solution of methyl 2-[4-(piperidin-l-yl)piperidin-l- yl]acetate (2.395 kg, 9.96 mol) in methanol (2.4 L) was added to a solution of potassium hydroxide (0.662 kg, 10.0 mol @ 85% purity) in methanol (10.5 L) under a nitrogen atmosphere. The reaction mixture was heated to 45-50°C for a minimum of 16 hours.
A solvent exchange from methanol to acetone (15.0 L) was performed on the solution on a rotary evaporator. This solution was slowly cooled to room temperature over 16 hours. The resulting solids were filtered, rinsed with acetone (5.0 L) and then dried to yield 2.471 kg (93.8%) of 2-(4-(piperidin-l-yl)piperidin-l-yl)acetic acid, potassium salt. MS 265 (M+l)
dihydrochloride trihydrate
Preparation of (R)-3-( lH-indol-3-yl)- l-[N-(2-methoxybenzyl)acetylamino]- 2-[N-(2-(4-(piperidin-l-yl)piperidin-l-yl)acetyl)amino]propane dihydrochloride trihydrate
3 H20 Under a nitrogen atmosphere 2-(4-(piperidin-l-yl)piperidin- l-yl)acetic acid, potassium salt (0.75 kg, 2.84 mol) was added to methylene chloride (7.5 L). The resulting mixture was cooled to -15 to - 8°C and isobutyl chloroformate (0.29 kg, 2.12 mol) was added at such a rate so as to maintain the temperature of the reaction mixture below - 8°C. After the addition the resulting reaction mixture was stirred for 90 minutes between -15 and -8°C.
The reaction mixture was then cooled to -35°C and solid (R)- 2-amino-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)amino]propane dihydrochloride (0.60 kg, 1.14 mol) was added at such a rate that the reaction temperature was maintained at less than -20°C. After the addition, the reaction mixture was stirred for about one hour with the temperature being maintained between -37°C and -20°C. The reaction was quenched by the addition of deionized water (7.5 L). The reaction mixture was basified to pH 12.8-13.2 by the addition of 5 N sodium hydroxide. The aqueous fraction was removed and retained. Additional deionized water (3.75 L) was added to the organic fraction as was sufficient 5 N sodium hydroxide to re-adjust the pH to 12.8-13.2.
The two aqueous fractions were combined, back-extracted with methylene chloride (1.5 L) and then discarded. The organic fractions were combined and washed with deionized water (4 x 3.5 L). These extracts were combined, back-extracted with methylene chloride (1.5 L), and then discarded. The two organic layers were combined and washed with a saturated sodium chloride solution (3.7 L). The organic fraction was dried over anhydrous magnesium sulfate, filtered, and solvent exchanged from methylene chloride to acetone (3.75 L) on a rotary evaporator. An aqueous solution of hydrochloric acid (0.48 L of 6 N solution, 2.88 mol) and seed crystals (2 g) were added and mixture was stirred for 30-90 minutes. Acetone (13.2 L) was then added and the slurry stirred for one hour. The resulting solid was then filtered, washed with acetone (2 x 1.4 L), and dried to yield 633 g (90%) of (R)-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]-2-[N- (2-(4-(piperidin- 1-yl )piperidin- 1-yl )acetyl)amino]propane dihydrochloride trihydrate.
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http://pubs.acs.org/doi/pdf/10.1021/jo00126a069http://pubs.acs.org/doi/pdf/10.1021/jo00126a069
Practical and Enantiospecific Synthesis of LY303870
J. Org. Chem., 1995, 60 (21), pp 7033–7036
DOI: 10.1021/jo00126a069
(R)-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]-2-[N- (2-(4-(piperidin- 1-yl )piperidin- 1-yl )acetyl)amino]propane dihydrochloride trihydrate
(R)-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]-2-[N- (2-(4-(piperidin- 1-yl )piperidin- 1-yl )acetyl)amino]propane dihydrochloride trihydrate
mp 192-196 degC(lossofWATER), 240deg C
1H(300MHz,CDCl3)
1H(300MHz,CDCl3)
1.25-1.70(m, 10H);1.77-2.00(m,3H);1.95,(s,1.8H [rotamerl),2.04,(s,1.2H [rotamerl);2.10-2.97,(m, 9H);
3.10-3.65,(m,3H),
3.72,(s,1.2H[rotamerl);
3.74,(s,1.8Hhotamer]);
4.26-4.58,(m,3H);
6.76-7.12,(m,6H);
7.13-7.35(m,2H),
7.42-7.66(m,2H);
10.80 (broads,1H);
13CNMR(75MHz,DMSO)
169.9,
169.4,
169.3, 156.8, 156.7, 136.1
128.5,127.7,127.5,127.3,127.2,126.9,125.4,124.6,123.2,123.1,
120.08,
120.7,
120.2,
120.0, 118.4, 118.2, 118.1,
111.2,
110.6,
110.5,
110.4, 110.3,
79.1,
61.7, 61.4,
61.3,
55.1,
53.4, 53.3,
53.2,
51.2,49.7,47.9,47.7,47.6,47.5,47.2,43.1,27.8,27.6,27.5,27.4,
27.3,27.1,26.0,25.8,24.5,21.4,21.2;
massspec559au;
IR
1658cm-l;
[alpha D =+15.7deg(c=1,MeOH).
Anal.Calcdfor
C33H53Cl2N506:
C,
57.72,
H,
7.78;
N,
10.20.
Found:
C,
58.00;
H,
7.54;
N,
10.16
DR ANTHONY MELVIN CRASTO Ph.D
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
did you feel happy, a head to toe paralysed man's soul in action for you round the clock
need help, email or call me
MOBILE-+91 9323115463
web link
I was paralysed in dec2007
