134234-12-1 (free base)
Traxoprodil mesylate, CP-101606-27,
(S, S) -1 – (4-Hydroxyphenyl) -2 – [4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol methanesulfonate trihydrate
this exhibits activity as NMDA (N-methyl-D-aspartic acid) receptor antagonists and are useful in the treatment of epilepsy, anxiety, cerebral ischemia, muscular spasms, multiinfarct dementia, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, urinary incontinence and degenerative CNS (central nervous system) disorders such as stroke, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.
The free base, the anhydrous mesylate and methods of preparing them are referred to, generically, in United States Patent 5,185,343, which issued on February 9, 1993. They and their use in treating certain of the above disorders are referred to, specifically, in United States Patent 5,272,160, which issued on December 21 , 1993. Their use in treating the above disorders is referred to in lntemational Patent Application PCT/IB 95/00380, which designates the United States and was filed on May 18, 1995. Their use in combination with a compound capable of enhancing and thus restoring the balance of excitatory feedback from the ventral lateral nucleus of the thalamus into the cortex to treat Parkinson’s disease is referred to in International Patent Application PCT/IB 95/00398, which designates the United States and was filed on May 26, 1995. The foregoing U.S. patents and patent applications are incoφorated herein by reference in their entireties.
NMDA is an excitatory amino acid. The excitatory amino acids are an important group of neurotransmitters that mediate excitatory neurotransmission in the central nervous system. Glutamic acid and aspartic acid are two endogenous ligands that activate excitatory amino acid (EAA) receptors. There are two types of EAA receptors, ionotropic and metabotropic, which differ in their mode of signal transduction. There are at least three distinct ionotropic EAA receptors characterized by the selective agonist that activates each type: the NMDA, the AMPA (2-amino-3-(5-methyl-3- hdyroxyisoxazol-4-yl)propanoic acid) and the kainic acid receptors. The ionotropic EAA receptors are linked to ion channels that are permeable to sodium and, in the case of NMDA receptors, calcium. Metabotropic receptors, linked to phosphoinositide hydrolysis by a membrane associated G-protein, are activated by quisqualic acid, ibotenic acid, and (1S, 3R)-1-aminocyclopentane 1 ,3-dicarboxyiic acid.
The NMDA receptor is a macromolecular complex consisting of a number of distinct binding sites that gate on ion channels permeable to sodium and calcium ions. Hansen and Krogsgaard-Larson, Med. Res. Rev.. .10, 55-94 (1990). There are binding sites for glutamic acid, glycine, and polyamines, and a site inside the ion channel where compounds such as phencyclidine (PCP) exert their antagonist effects.
Competitive NMDA antagonists are compounds that block the NMDA receptor by interacting with the glutamate binding site. The ability of a particular compound to competitively bind to the NMDA glutamate receptor may be determined using a radioligand binding assay, as described by Murphy e l., British J. Pharmacol.. 95, 932- 938 (1988). The antagonists may be distinguished from the agonists using a rat cortical wedge assay, as described by Harrison and Simmonds, British J. Pharmacol.. 84, 381- 391 (1984). Examples of competitive NMDA antagonists include D-2 amino 5- phosphonopentanoic acid (D-AP5), and D-2-amino-7-phosphonoheptanoic acid, Schoepp et a]. , J. Neur. Transm.. 85, 131-143 (1991).
4-Hydroxypropiophenone (I) was protected as the triisopropylsilyl ether (II) and subsequently brominated with elemental bromine in CCl4. The resultant bromo ketone (III) was subsequently coupled with 4-hydroxy-4-phenylpiperidine (IV) to afford the racemic amino ketone (V). This was stereoselectively reduced with NaBH4 in EtOH yielding the threo-amino alcohol (VI). Then, desilylation of (VI) with tetrabutylammonium fluoride furnished the racemic phenol compound. Resolution into the enantiomers has been reported by formation of the . corresponding D-tartaric acid salts Finally, the title product was obtained by dissolving D-(-)-tartaric salt (VII) in water in the presence of methanesulfonic acid
EXAMPLE 1 Enantiomeric (1S,2S)- and (1R,2R)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanols
(+)-Tartaric acid (300 mg, 2 mmol) was dissolved in 30 mL warm methanol. Racemic 1S*,2S*-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol (655 mg, 2 mmol) was added all at once. With stirring and gentle warming a colorless homogeneous solution was obtained. Upon standing at ambient temperature 24 hours, 319 mg (66%) of a fluffy white precipitate was obtained. This product was recrystallized from methanol to give 263 mg of the (+)-tartrate salt of levorotatory title product as a white solid; mp 206.5-207.5.degree. C.; [alpha].sub.D =-36.2.degree.. This salt (115 mg) was added to 50 mL of saturated NaHCO.sub.3. Ethyl acetate (5 mL) was added and the mixture was vigorously stirred 30 minutes. The aqueous phase was repeatedly extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over calcium sulfate, and concentrated. The tan residue was recrystallized from ethyl acetate-hexane to give 32 mg (39%) of white, levorotatory title product; mp 203-204 C.sub.20 H.sub.25 NO.sub.3 : C, 73.37; H, 7.70; N. 4.28. Found: C, 72.61; H, 7.45; N. 4.21.
The filtrate from the (+)-tartrate salt preparation above was treated with 100 mL saturated aqueous NaHCO.sub.3 and extracted well with ethyl acetate. The combined organic extracts were washed with brine, dried over calcium sulfate and concentrated to give 380 mg of recovered starting material (partially resolved). This material was treated with (-)-tartaric acid (174 mg) in 30 mL of methanol as above. After standing for 24 hours, filtration gave 320 mg (66%) of product which was further recrystallized from methanol to produce 239 mg of the (-)-tartrate salt of dextrorotatory title product; mp 206.5-207.5.degree. C. [alpha].sub.D =+33.9.degree.. The latter was converted to dextrorotatory title product in the manner above in 49% yield; mp 204-205 Found: C, 72.94; H. 7.64; N, 4.24.
EXAMPLE 2 (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-yl)-1-propanol Methanesulfonate Trihydrate
A 50 gallon glass lined reactor was charged with 17.1 gallons of acetone, 8.65 kilograms (kg) (57.7 mol) of 4′-hydroxypropiophenone, 9.95 kg (72.0 mol) of potassium carbonate and 6.8 liters (l) (57.7 mol) of benzylbromide. The mixture was heated to reflux (56 hours. Analysis of thin layer chromatography (TLC) revealed that the reaction was essentially complete. The suspension was atmospherically concentrated to a volume of 10 gallons and 17.1 gallons of water were charged. The suspension was granulated at 25 product was filtered on a 30″ Lapp and washed with 4.6 gallons of water followed by a mixture of 6.9 gallons of hexane and 2.3 gallons of isopropanol. After vacuum drying at 45 (96.4%) of the above-depicted product.
A second run was carried out with 9.8 kg (65.25 mol) of 4′-hydroxypropiophenone using the procedure described above. After drying 15.1 kg (96.3%) of the above-depicted product was obtained.
Under a nitrogen atmosphere, a 100 gallon glass lined reactor was charged with 75 gallons of methylene chloride and 28.2 kg (117.5 mol) of the product from step 1. The solution was stirred five minutes and then 18.8 kg of bromine was charged. The reaction was stirred for 0.5 hours at 22 complete. To the solution was charged 37 gallons of water and the mixture was stirred for 15 minutes. The methylene chloride was separated and washed with 18.5 gallons of saturated aqueous sodium bicarbonate. The methylene chloride was separated, atmospherically concentrated to a volume of 40 gallons and 60 gallons of isopropanol was charged. The concentration was continued until a pot temperature of 80 40 gallons were obtained. The suspension was cooled to 20 granulated for 18 hours. The product was filtered on a 30″ Lapp and washed with 10 gallons of isopropanol. After vacuum drying at 45 yielded 29.1 kg (77.6%) of the above-depicted product.
Under a nitrogen atmosphere, a 20 gallon glass lined reactor was charged with 4.90 kg (15.3 mol) of the product from step 2, 7.0 gallons of ethyl acetate, 2.70 kg (15.3 mol) of 4-hydroxy-4-phenylpiperidine and 1.54 kg of triethylamine (15.3 mol). The solution was heated to reflux (77 C.) for 18 hours. The resulting suspension was cooled to 20 Analysis by TLC revealed that the reaction was essentially complete. The byproduct (triethylamine hydrobromide salt) was filtered on a 30″ Lapp and washed with 4 gallons of ethyl acetate. The filtrate was concentrated under vacuum to a volume of 17 liters. The concentrate was charged to 48 liters of hexane and the resulting suspension granulated for 2 hours at 20 gallons of hexane. After vacuum drying at 50 kg (77%) of the above-depicted product.
A second run was carried out with 3.6 kg (11.3 mol) of the product from step 2 using the procedure described above. After drying 4.1 kg (87%) of the above-depicted product was obtained.
Under a nitrogen atmosphere, a 100 gallon glass lined reactor was charged with 87.0 gallons of 2B ethanol and 1.7 kg (45.2 mol) of sodium borohydride. The resulting solution was stirred at 25 kg (22.6 mol) of the product from step 3 was charged. The suspension was stirred for 18 hours at 25-30 reaction was essentially complete to the desired threo diastereoisomer. To the suspension was charged 7.8 liters of water. The suspension was concentrated under vacuum to a volume of 40 gallons. After granulating for 1 hour, the product was filtered on a 30″ Lapp and washed with 2 gallons of 2B ethanol. The wet product, 9.4 gallons of 2B-ethanol and 8.7 gallons of water were charged to a 100 gallon glass lined reactor. The suspension was stirred at reflux (78 cooled to 25 water followed by 4 gallons of 2B ethanol. After air drying at 50 C., this yielded 8.2 kg (86.5%) of the above-depicted product. This material was recrystallized in the following manner.
A 100 gallon glass lined reactor was charged with 7.9 kg (18.9 mol) of the product from step 3, 20 gallons of 2B ethanol and 4 gallons of acetone. The suspension was heated to 70 solution was concentrated atmospherically to a volume of 15 gallons. The suspension was cooled to 25 product was filtered on a 30″ Lapp. The wet product and 11.7 gallons of 2B ethanol was charged to a 100 gallon glass lined reactor. The suspension was heated to reflux (78 cooled to 25 of 2B ethanol. After air drying at 50 (70.6%) of the above-depicted product.
Under a nitrogen atmosphere, a 50 gallon glass lined reactor was charged with 825 g of 10% palladium on carbon (50% water wet), 5.5 kg (13.2 mol) of the product from step 4 and 15.5 gallons of tetrahydrofuran (THF). The mixture was hydrogenated between 40-50 time, analysis by TLC revealed that the reduction was essentially complete. The reaction was filtered through a 14″ sparkler precoated with Celite and washed with 8 gallons of THF. The filtrate was transferred to a clean 100 gallon glass lined reactor, vacuum concentrated to a volume of 7 gallons and 21 gallons of ethyl acetate were charged. The suspension was atmospherically concentrated to a volume of 10 gallons and a pot temperature of 72 filtered on a 30″ Lapp and washed with 2 gallons of ethyl acetate. After air drying at 55 above-depicted product (i.e., the free base).
A 100 gallon glass lined reactor was charged with 20 gallons of methanol and 3.7 kg (11.4 mol) of the product from step 5 (i.e., the free base). The suspension was heated to 60 D-(-)-tartaric acid were charged. The resulting solution was heated to reflux (65 suspension was cooled to 35 with 1 gallon of methanol. The wet solids were charged to a 100 gallon glass lined reactor with 10 gallons of methanol. The suspension was stirred for 18 hours at 25 Lapp and washed with 2 gallons of methanol. After air drying at 50 C. this yielded 2.7 kg (101%) of the above-depicted product (i.e., the tartaric acid salt of the free base (R-(+)-enantiomer)). This material was purified in the following manner:
A 100 gallon glass lined reactor was charged with 10.6 gallons of methanol and 2.67 kg (5.6 mol) of the above tartaric acid salt. The suspension was heated to reflux (80 to 30 methanol. After air drying at 50 of the above-depicted product (i.e., the tartaric acid salt of the free base).
•Tar tar i c Rc i d
A 55 liter nalgene tub was charged with 30 liters of water and 1056 g (12.6 mol) of sodium bicarbonate at 20 charged 2.0 kg (4.2 mol) of the product from step 6 (i.e., the tartaric acid salt of the free base). The suspension was stirred for 4 hours during which a great deal foaming occurred. After the foaming ceased, the suspension was filtered on a 32 cm funnel and washed with 1 gallon of water. After air drying at 50 the above-depicted product (i.e., the free base).
A 22 liter flask was charged with 1277 g (3.9 mol) of product from step 7 and 14 liters of water. The suspension was warmed to 30 g (3.9 mol) of methane sulfonic acid were charged. The resulting solution was warmed to 60 washed with 2 liters of water. The speck-free filtrate was concentrated under vacuum to a volume of 6 liters. The suspension was cooled to 0-5 18″ filter funnel and washed with 635 ml of speck-free water. After air drying at 25 above-depicted product (i.e., the mesylate salt trihydrate).
Proton and Carbon Nuclear Magnetic Resonance (NMR) Spectra of the Mesylate Salt Trihydrate
The proton and carbon NMR spectra of the mesylate salt trihydrate are described below. Chemical shift assignments in CD3OD (relative to tetramethylsilane (TMS) were made on the basis of ‘HJH Correlated Spectroscopy (COSY), ‘H-‘O Distortionless Enhancement by Polarization Transfer (DEPT), and ‘HJ’C Heteronuclear Chemical Shift Correlation (HETCOR) two-dimensional NMR experiments. The tentative proton and carbon peak assignments are given below and are consistent with the structure of the mesylate salt trihydrate. III
assignment, 13 C (δ, ppm), Protons, 1 H (δ, ppm) 4' 159.2 0 -- 1"' 148.2 0 -- 1' 132.6 0 -- 2' 129.8 2 7.30 (m) 3"' 129.5 m 2 7.38 (t) 4"' 128.4 1 7.30 (m) 2"' 125.6 2 7.56 (d) 3' 116.5 2 6.84 (d) 1 73.5 1 4.66 (d) 4" 69.8 0 -- 2 68.3 1 3.58 (m) 6"(1) 48.8 2 3.32 (d),3.72(t) 2"(1) 43.2 2 3.58 (m) 4 39.5 3 2.70 (s) 5"(2) 36.6 2 2.64 (t),1.98(d) 3"(2) 36.5 2 2.42 (t),1.98(d) 3 9.7 3 1.12(d)
(1) The 6″ and 2″ positions are not chemically equivalent; the assignments may be interchangeable. (2) The 5″ and 3″ positions are not chemically equivalent the assignments may be interchangeable. The proton splitting pattem at 1.96-2.06 ppm appears as two doublets when acquired on a high-field instrument (500 MHz), but only as a triplet when acquired with a lower field (300 MHz) instrument. This is believed to be due to a salt effect arising from the mesylate.