Hockeydemon
Hazard to Others
Posts: 218
Registered: 25-2-2013
Member Is Offline
Mood: No Mood
|
|
Synthesis of the nonbenzodiazepine Pagoclone
A few months ago someone on this forum posted about a drug synthesized by David Nutt that had similar effects to alcohol because it is a partial
agonist of the GABAa receptor. Here is the wikipedia on it
Anyways I thought that was interesting, but I could only find limited information on the drug. I happened to find a Chinese website that had a synthesis of it.
From what I can tell it does not seem like an extremely hard synthesis to perform - though I'm prepared for you to tell me I'm wrong and it is hard.
The only chemical I can't get much information on which is the starting point of the synthesis is 7-hydroxy-1,8-naphthyridin-2-amine.
The condensation of 7-hydroxy-1,8-naphthyridin-2-amine (I) with phthalic anhydride (II) in refluxing acetic acid gives
N-(7-hydroxy-1,8-naphthyridin-2-yl)phthalimide (III) which is treated with refluxing POCl3 to yield the 7-chloro derivative (IV)
Reduction of compound (IV) with KBH4 in dioxane affords 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one (V), which is condensed with
5-methyl-2-hexanone (VI) by means of NaH in DMF to give (?-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)isoindolin-1-one (VII) (racemic
pagoclone).
The treatment of (VII) with NaOH in dioxane/water yields the racemic benzoic acid (VIII). Optical resolution of racemic (VIII) by means of
(+)-ephedrine or cinchonine affords the (+)-isomer (IX), which is finally cyclized to the chiral (+)-indolinone derivative pagoclone by means of SOCl2
and imidazole in dichloromethane.
Silvestre, J.S.; Castar, J.; Leeson, P.A.; Sorbera, L.A.
Silvestre, J.S.; Castar, J.; Leeson, P.A.; Sorbera, L.A.; Pagoclone. Drugs Fut 2001, 26, 7, 651
Drugs Fut2001,26,(7):651
Synthesis of Pagoclone (EN:162990)
Anyone of you smarter people able to use this information to write up someone could use?
|
|
|
forgottenpassword
Hazard to Others
Posts: 374
Registered: 12-12-2013
Member Is Offline
Mood: No Mood
|
|
A 7 step synthesis with optical resolution to give something with the same effects as alcohol?
|
|
|
Dr.Bob
International Hazard
Posts: 2660
Registered: 26-1-2011
Location: USA - NC
Member Is Offline
Mood: No Mood
|
|
Aldrich sells 7-hydroxy-1,8-naphthyridin-2-amine (I) for the mere price of $740 / gram, I think forgotten is right, that makes for an expensive drink.
That chemistry certainly looks doable in a well set up lab, but not something I would try at home. And it would cost $1000's to make it in any
real amount.
|
|
|
AvBaeyer
National Hazard
Posts: 644
Registered: 25-2-2014
Location: CA
Member Is Offline
Mood: No Mood
|
|
The scheme looks like a medicinal chemistry first pass synthesis in order to get enough material for some early testing and a patent application if
warranted. I agree with Dr Bob. If you do not have access to HPLC, NMR and several assistants, don't try this at home. Spend your money on some good
Scotch.
|
|
|
Hockeydemon
Hazard to Others
Posts: 218
Registered: 25-2-2013
Member Is Offline
Mood: No Mood
|
|
Here is more detailed information on it - I had someone with access to the publication give me a copy.
| Quote: |
2-Amino-7-hydroxy-1,8-naphthyridine Sulfuric Acid Salt (6).
2,6-Diaminopyridine (150 kg, 1375 mol) was added in six portions to concd sulfuric acid (1030 kg) at 40-50 °C. The solution was allowed to exotherm,
and the next portion was not added until the temperature was within range. After the solution became homogeneous, the reaction was cooled to 25 °C
and D,L-malic acid (185 kg, 1380 mol) was added in one portion. The reaction was heated to 110-120 °C over 1 h. CAUTION: Carbon monoxide is evolved
during this time. After 1 h, the reaction was cooled to 25 °C and transferred into a cold aqueous sodium chloride solution (10 °C, 150 kg in 1125 L
of water), maintaining the temperature below 50 °C. The slurry was stirred for 2 h at 20 °C and then filtered. The filter cake was washed with
hexanes (270 L) to drive out residual water. The solid was dried under vacuum at 60 °C to afford 303 kg (85% yield) of a pale yellow powder.
MS (DCI) M + 1 at 162, 100%; 1H NMR (200 MHz, DMSO-d6): δ 4.32 (br s, 5H, -OH, -NH2, H2SO4), 6.41 (d, J = 9.0 Hz, 1H), 6.56 (d, J = 9.0 Hz, 1H),
7.85(d,J = 6.6Hz,1H),7.91(d,J = 6.6Hz,1H);mp >350 °C.
2-Hydroxy-7-N-phthalimidyl-1,8-naphthyridine (7).
A reactor was charged with naphthyridine salt (6) (165 kg, 636 mol), phthalic anhydride (246 kg, 1660 mol), and glacial acetic acid (850 kg) and
cooled to 20 °C. Triethylamine was added (257 kg, 2540 mol) while maintaining the temperature below 30 °C. The reaction was heated to 115 °C and
held for 5 h. After cooling to below 30 °C, methanol (900 L) was added, and the slurry was stirred for 30 min. The solids were filtered and rinsed
with methanol (440 L). The product was dried under vacuum at 60 °C to afford 176 kg (95%) of a tan powder.
1H NMR: 12.45 (s, 1H), 8.43 (d, J = 8.1 Hz, 1H), 8.09 (m, 5H), 7.49 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 9.5 Hz, 1H); CI (MS) M + 1 at 292, 100%.
(±)-2-(7-Chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1- isoindolinone (4).
A reactor was charged with hydroxyphthalimide (7) (120 kg, 412 mol), sodium chloride [1] (1.2 kg), acetonitrile (755 kg), and dimethylformamide (1.5
kg). The mixture was heated to reflux (ca. 83 °C), and a solution of phosphorus oxychloride (69.1 kg, 450 mol) in acetonitrile (5 kg) was added.
After 4 h at reflux, the mixture was cooled to 5 °C, and acetonitrile (240 kg) and potassium hydroxide (201 kg of a 45% aqueous solution) were added.
After the mixture was stirred for 15 min, the pH was adjusted to 8 with additional potassium hydroxide if necessary. A solution of potassium
borohydride (83.3 kg, 1544 mol) in water (900 L) was added to the reaction at 0-15 °C. After the mixture was stirred for 1 h at 20-30 °C, the
reaction was quenched by addition of glacial acetic acid (630 kg) and water (5 L). After the mixture was stirred for 15 min, the solids were collected
by filtration and washed with water (2 × 300 L) and methanol (2 × 300 L). The solids were dried under vacuum at 75 °C to afford 109 kg (85%) of a
tan solid.
MS (DCI) M + 1 at 312, 100%; 1H NMR (400 MHz, DMSO- d6): 8.58 (d, J = 10.5 Hz, 1H), 8.52 (d, J = 10.5 Hz), 8.45 (d, J ) 8.7 Hz, 1H), 7.83 (ddd, J =
7.7, 1.0, 1.0 Hz, 1H), 7.77 (ddd, J = 7.7, 7.7, 1.4 Hz, 1H), 7.72 (ddd, J = 7.7, 1.4, 1.4 Hz, 1H), 7.63 (dd, J = 7.7, 1.4 Hz), 7.60 (d, J = 8.7 Hz,
1H), 7.05 (s, 1H), 6.95 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) 166, 154, 153, 153, 144, 141, 139, 134, 130, 130, 124, 123, 122, 119, 116.
(±)-2-(7-Chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2- oxo-hexyl)-1-isoindolinone (3).
While being stirred, the following were charged to a reactor in this order: water (1185 L), sodium carbonate (120 kg, 1700 mol), phosphonium salt (10)
(370 kg, 813 mol), and xylenes (1350 kg). After the mixture was stirred for 30 min, the reaction became clear, and the lower aqueous layer was
removed. The or- ganics were then washed [2] with a sodium carbonate solution (60 kg in 1185 L of water). To the organics was added the hydroxy
compound (4) (158 kg, 507 mol). The reaction mixture was heated to 136 °C for 24 h (initially under distillation conditions to remove residual water,
then under reflux). The reaction mixture was cooled to 80 °C and then vacuum distilled to remove the majority of the xylenes. To the resulting slurry
was charged 2-propanol (2284 L). The slurry was heated to reflux and then cooled to 20 °C. The solids were collected by filtration, washed with
2-propanol (600 L) and methanol (300 L), and dried under vacuum at 60 °C to afford 170 kg (82%) of the title compound as an off-white solid. APCI/MS:
M + H+ at 408, 100%; 1H NMR (200 MHz, DMSO-d6): 8.87 (d, J = 8.8 Hz, 1H), 8.61 (m, 2H), 7.93 (d, J = 7.0 Hz, 1H), 7.74 (m, 4H), 6.05 (m, 1H), 3.62 (m,
1H), 3.28 (dd, J = 7.0, 17.2 Hz, 1H), 2.42 (m, 2H), 1.35 (m, 3H), 0.79 (d, J = 6.2 Hz, 6H); mp 173-174 °C.
[(5-Methyl-2-oxo)-hexyl]-triphenylphosphonium Bromide (8).
To a solution of methanol (850 L) and 5-methyl-2-hexanone (152 kg, 1330 mol) at 0 °C was added bromine (185 kg, 1156 mol) such that the temperature
remained below 15 °C. The solution was stirred at 10 °C for about 2 h. An exotherm (ca. 10 °C) occurs when the reaction is about 80% complete;
after this subsides, the reaction is complete. The reaction was quenched with water (148 L). After the mixture was stirred for 30 min, tert-butyl
methyl ether (1100 kg) was added, followed by a sodium chloride solution (133 kg in 740 L of water). After the mixture was stirred for 15 min [3], the
aqueous layer was discarded. The organics were further washed with a sodium bicarbonate solution (36 kg in 744 L of water) and a sodium chloride
solution (as above). The solvent was vacuum distilled, replaced with tert-butyl methyl ether (550 kg), and redistilled. To the cooled bromoketone
product in tert-butyl methyl ether (281 kg, 10 °C) was added a solution of triphenylphosphine (303 kg, 1156 mol) in tert- butyl methyl ether (281
kg). After 12 h at 20 °C, the solids were filtered and washed with tert-butyl methyl ether (115 kg). The material was dried under vacuum for at least
12 h at 40 °C to afford 300 kg (57%) of white crystals.
1H NMR: 7.87 (m, 15H), 5.66 (dd, J = 2.9, 12.8 Hz, 2H), 2.71 (m, 2H), 1.35 (m, 3H), 0.80 (d, J = 6.2 Hz, 6H); CI (MS) M at 455, 100%.
(±)-2-[1-(7-Chloro-1,8-naphthyridin-2-ylamino)-6-meth- yl-3-oxo-heptyl]-benzoic Acid (13).
A reactor was charged with racemic pagoclone (3) (111 kg, 272 mol), 1,2- dimethoxyethane (404 kg), and tetrahydrofuran (633 L), followed by addition
of a potassium hydroxide solution (85 kg in 1100 L of water). The solution was stirred at 34 °C for at least 30 h. The reaction was cooled to 20 °C,
and the lower aqueous layer was discarded. Water (610 L) was added, and the pH was adjusted to 9 with aqueous hydrochloric acid (4N). The
tetrahydrofuran was removed by vacuum distillation. Water (350 L) was added, and the pH was adjusted to 11.5 with aqueous potassium hydroxide (1.4N).
The precipitate (residual racemic pagoclone) was removed by filtration. After adding dichloromethane (1027 kg), the aqueous layer was acidified to
less than pH 1.4. The organic layer was washed with water (450 L) and concentrated under vacuum. The residue was precipitated from methanol (300 L)
and water (320 L), filtered, and dried at 50 °C under vacuum to afford 99.7 kg (86%) of a white powder.
DCI/MS: M + H+ at 426, 100%; 1H NMR (200 MHz, DMSO-d6): δ 13.5 (br s, 1H), 8.25 (d, J ) 8 Hz, 1H),8.04(d,J)9Hz,1H),7.85(d,J)9Hz,1H),7.80 (d,J =
9Hz,1H),7.60(dd,J = 8,8Hz,1H),7.45(dd,J = 8,8 Hz, 1H),7.30(dd,J = 8,8 Hz, 1H),7.15(d,J = 9 Hz), 6.90 (d, J = 9 Hz, 1H), 2.9 (m, 2H), 2.5 (m, 2H), 1.3
(m, 3H), 0.8 (d, 6H); mp 173-174 °C.
(+)-2-(7-Chloro-1,8-naphthyridin-2-yl)-3S-(5-methyl- 2-oxohexyl)-1-isoindolinone (1).
A reactor was charged with 100 kg of carboxylic acid (13) (234 mol), ethanol (385 kg), water (23 L), and (1S,2R)-ephedrine hemihydrate (42.8 kg, 246
mol). The reaction was heated at 40 °C until homoge- neous, filtered, and cooled to 20 °C until onset of crystal- lization and then to 0 °C for 2
h. The precipitate was filtered and washed with a solution of ethanol (221 kg) and water (11 L). This solid was added to a solution of concd
hydrochloric acid (12.8 kg), water (133 L), and dichlo- romethane (535 kg). After 15 min, the aqueous layer was removed, and the organics were washed
with water (135 L). The dichloromethane was distilled at atmospheric pressure to a volume of 250 L, and then a solution of N,N- carbonyldiimidazole
(30.3 kg) in dichloromethane (234 kg) was added. After 15 min, water (256 L) was added. The aqueous layer was removed, and the organics were washed
with additional water (256 L). The organics were concentrated by distillation and replaced with ethanol (530 kg). The slurry was cooled to 5 °C for 3
h and filtered. The solids were dried under vacuum at 60 °C to afford 35 kg (63% of theory, 32% yield) of a white crystalline material. 1H NMR (200
MHz, DMSO-d6): δ 8.87 (d, J = 8.8 Hz, 1H), 8.61 (m, 2H), 7.93 (d, J = 7.0 Hz, 1H), 7.74 (m, 4H), 6.05 (m, 1H), 3.62 (m, 1H), 3.28 (dd, J = 7.0,
17.2 Hz, 1H), 2.42 (m, 2H), 1.35 (m, 3H), 0.79 (d, J = 6.2 Hz, 6H); 13C NMR (100 MHz, DMSO- d6): δ 80.74 (C2), 115.98 (C19), 119.068 (C17),
121.91 (C15), 123.39 (C9), 124.10 (C6), 129.90 (C8), 130.23 (C4), 133.90 (C7), 139.40 (C18), 140.53 (C16), 144.45 (C3), 152.69 (C12), 153.06 (C10),
153.77 (C14), 166.43 (C5); CI (MS)M+1at 408, 100%;[R]20D )+135°(c)1, dichloromethane); mp 169 °C.
Multicolumn Chromatography Conditions.
A 26 kg lot of racemic material (3) was purified using a mobile phase of 90% toluene and 10% 2-propanol and a feed of 17 gm/L in the mobile phase. The
chiral stationary phase was 720 gm of (S,S)-Whelk-O 1 available from Regis Technologies which was packed into 6 × 5 cmID columns. The feed flow rate
was 59 mL/min, and the raffinate produced a stream of product with >99.5% optical purity. The product was isolated by concentration and
crystallization from ethanol. The extract stream was racemized with 0.1% (v/v) of 0.5N potassium hydroxide at 50 °C for 2 h. Following racemization,
the solution was washed with one volume 0.1N hydrochloric acid and 1 vol of water.
Notes.
[1] The product was very fine and difficult to isolate by centrifuge unless sodium chloride was added to the reaction mixture.
[2] The purpose of this additional wash is to remove residual bromide. If this is not done, up to 0.5% of the resulting product will have bromo rather
than chloro-naphthyridine.
[3] The reaction was initially monitored for completion by GC and was complicated by some methyl ketal formation during the reaction. This stir allows
adequate time for the ketals to be converted to ketone.
|
I don't see how the 5-methylhexan-2-one can be obtained easily unless one can order from a big chem company like aldrich.
|
|
|
AvBaeyer
National Hazard
Posts: 644
Registered: 25-2-2014
Location: CA
Member Is Offline
Mood: No Mood
|
|
"I don't see how the 5-methylhexan-2-one can be obtained easily unless one can order from a big chem company like aldrich"
Alkylation of ethyl acetoacetate with isobutyl bromide/iodide followed by hydrolysis and decarboxylation will give you the target ketone. You will
need to run the reaction under anhydrous conditions with a base compatible with the chosen solvent, eg. ethanol/ethoxide. This is pretty basic
chemistry and should be immediately recognized in a retrosynthetic analysis. Ethyl acetoacetate is easily available on ebay and the isobutyl halide
can be prepared from the available isobutanol.
|
|
|
forsh
Harmless
Posts: 18
Registered: 12-11-2013
Member Is Offline
Mood: No Mood
|
|
"I don't see how the 5-methylhexan-2-one can be obtained easily unless one can order from a big chem company like aldrich."
That ketone is easy, i'd be more worried about diaminopyridine - its dirt cheap but not available OTC at all. A shame because this looks like a fun
synthesis.
|
|
|
|
![[*]](images/xpblue/default_icon.gif){kind=icon}
