Anagrelide
From The Cure For The Needy
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Anagrelide (Agrylin, Xagrid)
Effective Against
CML - Chronic myeloid leukemia and Essential thrombocytosis
Anagrelide works by inhibiting the maturation of platelets from megakaryocytes. The exact mechanism of action is unclear, although it is known to be a phosphodiesterase inhibitor. It is a potent (IC50 = 36nM) inhibitor of phosphodiesterase-II.
Cost
Cost of molecule from Tocris Bioscience: 99 USD (10mg) or 444 USD (50 mg) for anagrelide hydrochloride
Reported Route of Synthesis
The nitration of 1,2,3-trichlorobenzene (I) with concentrated HNO3 gives 2,3,4-trichloronitrobenzene (II), which by reaction with cuprous cyanide in hot pyridine is converted to 2,3-dichloro-6-nitrobenzonitrile (III). The reduction of (III) with borane in THF yields 2,3-dichloro-6-nitrobenzylamine (IV), which by reaction with ethyl bromoacetate (V) by means of triethylamine in refluxing dioxane affords ethyl N-(2,3-dichloro-6-nitrobenzyl)glycinate (VI). The reduction of (VI) with SnCl2 in concentrated HCl gives ethyl N-(6-amino-2,3-dichlorobenzyl)glycinate (VII), which is cyclized with cyanogen bromide (VIII) in toluene affording ethyl 5,6-dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3-acetate (IX). Finally, this compound is submitted to a new cyclization by means of triethylamine in refluxing ethanol.
Jenks, TA; Beverung, WNJr.; Partyka, RA (Bristol-Myers Squibb Co.); Preparation of 6,7-dichloro-1 ,5-dihydroimidazo [2,1-b] quinazolin-2 (3H)-one. CA 1137474
Cost of Starting Materials and Selected Reagents:
Starting Material 1,2,3-trichlorobenzene from Sigma-Aldrich: 15.5 USD (1 g)
Nitric acid from Sigma-Aldrich: 96.2 USD (25 g)
Cuprous cyanide: pricing not available from Sigma-Aldrich
Pyridine from Sigma-Aldrich: 66.5 USD (100 mL)
Diborane from Sigma-Aldrich: 1055 USD (24 L)
Ethyl bromoacetate from Sigma-Aldrich: 24.5 USD (5 g)
Tin(II) chloride from Sigma-Aldrich: 102.5 USD (10 g)
Hydrochloric acid from Sigma-Aldrich: 46.5 USD (100 mL)
Cyanogen bromide from Sigma-Aldrich: 114.5 USD (25 g)
Triethylamine from Sigma-Aldrich: 12 USD (100 mL)
The reaction of 3-chloroaniline (X) with choral hydrate (XI) and hydroxylamine gives isonitroso-3-chloroacetanilide (XII), which is cyclized by means of H2SO4 to 4-chloroisatin (XIII). Chlorination of (XIII) with SO2Cl2 affords 4,5-dichloroisatin (XIV), which is oxidized with H2O2 yielding 5,6-dichloroanthranilic acid (XV). The reduction of (XV) with borane in THF gives 6-amino-2,3-dichlorobenzyl alcohol (XVI), which by reaction with SOCl2 in benzene is converted to 6-amino-2,3-dichlorobenzyl chloride (XVII). This compound is condensed with ethyl glycinate (XVIII) by means of triethylamine in refluxing methylene chloride to give ethyl N-(6-amino-2,3-dichlorobenzyl)glycinate (VII), which is cyclized with cyanogen bromide (VIII) in toluene affording ethyl 5,6-dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3-acetate (IX). Finally, this compound is submitted to a new cyclization by means of triethylamine in refluxing ethanol.
Jenks, TA; Beverung, WNJr.; Partyka, RA (Bristol-Myers Squibb Co.); Preparation of 6,7-dichloro-1 ,5-dihydroimidazo [2,1-b] quinazolin-2 (3H)-one. CA 1137474
Cost of Starting Materials and Selected Reagents:
Starting Material 3-chloroaniline from Sigma-Aldrich: 12.6 USD (1 g)
Chloral hydrate from Sigma-Aldrich: 39.6 USD (100 g)
Hydroxylamine solution from Sigma-Aldrich: 28 USD (10 mL)
Sulfuric acid from Sigma-Aldrich: 67.2 USD (100 mL)
Sulfuryl chloride from Sigma-Aldrich: 103.5 USD (1 L)
Hydrogen Peroxide from Sigma-Aldrich: 165.5 USD (3.7 L)
Borane tetrahydrofuran complex solution from Sigma-Aldrich: 39.7 USD (100 mL)
Thionyl chloride from Sigma-Aldrich: 64.4 USD (500mL)
Glycine ethyl ester hydrochloride from Sigma-Aldrich: 47.9 USD (5 g)
Triethylamine from Sigma-Aldrich: 12 USD (100 mL)
Cyanogen bromide from Sigma-Aldrich: 114.5 USD (25 g)
The condensation of 2-nitro-6-chlorobenzyl chloride (I) with ethyl glycinate (II) by means of triethylamine in refluxing ethanol gives ethyl N-(2-nitro-6-chlorobenzyl)glycinate (III), which is reduced with H2 over Pd/C in ethanol yielding ethyl N-(2-amino-6-chlorobenzyl)glycinate (IV). The cyclization of (IV) with cyanogen bromide (A) in refluxing ethanol affords 6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one (V), which is finally chlorinated with Cl2 and FeCl3 in hot nitromethane.
Castaner, J.; Hillier, K. Anagrelide Hydrochloride. Drugs Fut 1980, 5(3): 117
Beverung, WNJr.; Partyka, A. (Bristol-Myers Squibb Co.); Optionally substituted 1,2,3,5-tetrahydroimidezo (2,1-b)-quinazolin-2-ones and 6 (H) -1,2,3,4-tetrahydropyimido ( 2,1-b) quinazolin-2-ones. US 3932407
Cost of Starting Materials and Selected Reagents:
Starting Material 2-nitro-6-chlorobenzyl chloride pricing not available from Sigma-Aldrich
Glycine ethyl ester hydrochloride from Sigma-Aldrich: 47.9 USD (5 g)
Triethylamine from Sigma-Aldrich: 12 USD (100 mL)
Ethanol from Sigma-Aldrich: 37.6 USD (100 mL)
Cyanogen bromide from Sigma-Aldrich: 114.5 USD (25 g)
Iron(III) chloride from Sigma-Aldrich: 71.4 USD (1 g)
Chlorine from Sigma-Aldrich: 255.5 USD (454 G)
The nitration of 2,3-dichlorobenzaldehyde (I) with HNO3/H2SO4 gives 2,3-dichloro-6-nitrobenzaldehyde (II), which is reduced with NaBH4 in methanol, yielding 2,3-dichloro-6-nitrobenzyl alcohol (III). The reaction of (III) with SOCl2 and TEA affords the benzyl chloride (IV), which is condensed with glycine ethyl ester (V) by means of TEA to provide the adduct (VI). The reduction of the nitro group of (VI) with SnCl2 in aq. HCl or H2 over PtO2/C in ethanol gives the expected amino derivative (VII), which is cyclized with CN-Br in toluene to yield the iminoquinazoline (VIII). Finally, this compound is further cyclized by means of TEA in water to afford the target imidazoquinazolinone.
Lang, PC; Spencer, RP; Yeh, W.-L.; Roth, MJ (Shire Richwood Inc.); Method for the manufacture of anagrelide WO 2002008228, EP 1700840, EP 1700841, EP 1700842, EP 1700843, EP 1700859
Cost of Starting Materials and Selected Reagents:
Starting Material 2,3-Dichlorobenzaldehyde from Sigma-Aldrich: 36.5 USD (25 g)
Nitric acid from Sigma-Aldrich: 96.2 USD (25 g)
Sulfuric acid from Sigma-Aldrich: 67.2 USD (100 mL)
Sodium borohydride from Sigma-Aldrich: 79.2 USD (100 g)
Thionyl chloride from Sigma-Aldrich: 64.4 USD (500 mL)
Glycine ethyl ester hydrochloride from Sigma-Aldrich: 47.9 USD (5 g)
Triethylamine from Sigma-Aldrich: 12 USD (100 mL)
Cyanogen bromide from Sigma-Aldrich: 114.5 USD (25 g)
Tin(II) chloride from Sigma-Aldrich: 102.5 USD (10 g)
Platinum(IV) oxide from Sigma-Aldrich: 122 USD (1 g)
The nitration of 2,3-dichlorobenzaldehyde (I) with HNO3/H2SO4 gives 2,3-dichloro-6-nitrobenzaldehyde (II), which is treated with hydroxylamine and pyridine to yield the corresponding oxime (III). The dehydration of (III) with hot Ac2O affords 2,3-dichloro-6-nitrobenzonitrile (IV), which is reduced at the nitro group by means of H2 over activated Fe yielding 6-amino-2,3-dichlorobenzonitrile (V). The reduction of the cyano group of (V) by means of LiAlH4 in ether affords the benzylamine derivative (VI), which is condensed with ethyl 2-bromoacetate (VII) by means of TEA in hot acetonitrile to provide N-(2,3-dichloro-6-aminophenyl)glycine ethyl ester (VIII). The cyclization of (VIII) with cyanogen bromide in methanol gives the quinazoline derivative (IX), which is finally submitted to a new cyclization process by means of NaHCO3 in ethanol to provide the target Anagrelide.
Method for the production of anagrelide hydrochloride. AOP Orphan Pharmaceuticals AG. WO 2005080398
2,3-Dichloro-6-nitrobenzaldehyde (I) is reduced with NaBH4 in MeOH-CH2Cl2 producing the benzylic alcohol (II), which is converted to the corresponding mesylate (III) by treatment with methanesulfonyl chloride and Et3N. Subsequent condensation of mesylate (III) with glycine ethyl ester (IV) by means of DMAP and K2CO3 produces the N-benzyl glycine derivative (V). Nitro group reduction in (V) with SnCl2 in aqueous HCl yields diamine (VI), which is cyclized to the imino quinazoline (VII) by treatment with cyanogen bromide in hot toluene. Finally, cyclization of the imino ester (VII) in the presence of Et3N in boiling isopropanol furnishes the title tricyclic compound (1).
Process for the preparation of ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride. Cipla Ltd. WO 2008096145