7-methoxy-4,5-dihydro- -chloride

Frydman et aZ. reported the sjmthesis of ethyl 5-methoxy-6-azagramine-2-carboxylate, isolated in 75% yield as the dihydro-chloride. 

N,N-Diacyl-thiohydroxylamine werden durch Natrium-bis-[2-methoxy-athyl]-dihydrido-aluminat in Benzol mit guten Ausbeuten zu Aldehyden reduziert. Mit Hilfe von 3-Oxo-2,3-dihydro-(benzo-[d]-l,2-thiazol)-l,l-dioxid gelingt es auf diese Weise Car-bonsaure-chloride auf einfache Weise in Aldehyde zu iiberfiihren z. B.2 ... 

Methoxycarbonylmethyl-2(l//)-quinoxalinone (220) with p-chlorobenzene-diazonium chloride gave a product, initially formulated as 3-[a-(p-chloro-phenylazo)-a-methoxycarbonylmethylene]-3,4-dihydro-2(l//)-quinoxalinone (221) but later as the tautomeric 3-[a-(p-chlorophenyUiydrazono)-a-methoxy-carbonylmethyl]-2(l//)-quinoxalinone (222) (HCl, H2O, AcOH, <5°C, 10 min, then 95°C, 30 min 90%). ° Such tautomerisms have been studied in some detail.(See also Section 6.6.)... 

Mit 1-Amino-propan erhalt man analog das 13-Methyl-9-propylamirw-2,3,IQ-trimethoxy-5,6-dihydro-(dibenzo aig]chinolizinium)-chlorid mit Pyrrolidin und einigen anderen Ami-nen verlauft die Reaktion anders. N-Methyl-papaverinium-jodid laBt sich mil 2-Amino-ethanol, wie oben beschrieben, unter Austausch nur einer Methoxy-Gruppe in l-(3,4-Dimethoxy-benzyl)-6-(2-hydroxy-ethylamino)-7-methoxy-2-methyl-isochmolinium-jodid (90%) uberfiihren1. 

The reactions of 5,6-dihydro-2-methoxy-2H-pyran (101) with 1,3-dibromo-5,5-dimethylhydantoin in ether-methanol,137 and with ethanesulfenyl chloride,138 have been described by Baldwin and Brown. The former reaction gave a 2 1 mixture of the isomers 3/3-bromotetrahydro-2a ,4a-dimethoxypyran (102) and 3a-bromotetrahy-dro-2a,4/3-dimethoxypyran (103), respectively the structures and favored conformations of the isomers are shown. The reaction of ethanesulfenyl chloride with 5,6-dihydro-2-methoxy-2H-pyran (101)... 

Oxidation of ethyl 7-allyl-10-methoxy-4-oxo-6,7-dihydro-4//-pyrimido-[2,l-a]isoquinoline-3-carboxylate (99) by ozone in methylene chloride at -70°C, then treatment of the mixture with dimethyl sulfide at ambient temperature for 1 h gave either 7-(2-oxoethyl)- or 7-(2,2-dimethoxyethyl) derivatives (105 and 106), depending upon whether methanol was used during the workup (78USP4127720). 

Benzo[6]furan is cleaved on reduction with excess sodium in liquid ammonia, followed by quenching with ammonium chloride or methanol, to produce 2-ethylphenol (69%). 2-Methyl- and 2-phenyl-benzo[6]furan similarly yield 2-propylphenol (54%) and 2-(2-phenylethyl)phenol (45%) (59JA2795). Similarly, 5-methoxybenzo[6]furan, on reduction with 2 mol of lithium and a limited amount of t- butanol, gives the cleavage product, but by operating with 2 mol each of lithium and f-butanol, 5 -methoxy-2-methylbenzo[6 jfuran supplies the 2,3-dihydro compound. With excess of the alcohol, however, 5-methoxy-2,3,4,7-tetrahydrobenzo[6]furan is secured so that the reduction is stepwise (67JOC2794). 

An excellent method for the preparation of gem-difluoro compounds from aldehydes and ketones consists of conversion of the carbonyl compound to the corresponding 1,3-dithiolane followed by treatment with two equivalents of l,3-dibromo-5,5-dimethylhydantoin (DBH) and pyridinium poly(hydrogen fluoride) (HF-pyridine) in methylene chloride. Attempted extension of this procedure to 7-methoxy-2,2-dimethyl-4-chromanone, however, gave only the dihydro- 1,4-dithiin derivative 1 in 78% yield. This transformation, which proceeded in excellent yield with a variety of 4-chromanones, was found to require only the DBH (i.e. fluoride ion played no role). 

The reaction of 3-benzyloxy-, 5-methoxy-, and 5-nitro-2-aminopyridines and 3-acetyl-4,5-dihydro-2(3//)-furanone in warm toluene in the presence of phosphoryl chloride afforded 3-(2-chloroethyl)-2-methyl-4//-pyrido[l, 2-a]pyrimidin-4-ones 102 (84EUP110435 90EUP368388 92USP5158952). 

The enol acetate 77 of 3,4-dihydro-7-methoxy-5-methyl-l-(2l/)-naphthalenone was converted to the acid 78 by ozonolysis and hydrolysis and this by a Wittig reaction with a-methoxyethyltriphenyl-phosphonium chloride gave 79. Compound 79 was converted into 80 by a series of reactions, five in number, which in turn was converted into 81 by reaction with potassium in -butanol. The methyl ester of compound 81, one isomer of which was recognized as that having the correct stereo structure, was converted to 82 by heating with acetic anhydride and 10-camphorsulfonic acid. Subsequent steps involved ozonization, reaction with V,iV -carbonyldiimidazole, lactam formation, reaction with pyridinium bromide perbromide, reaction with sodium hydride, and a further series in which (+ )-oxodendrobine (83) was ultimately obtained. Reduction of the latter to ( )-dendrobine... 

The submitters report that /3-methylglutaraldehyde may be isolated at this point from an analogous hydrolysis. The hydrolysis is carried out with 196 g. of 3,4-dihydro-2-methoxy-4-methyl-2H-pyran in 650 ml. of water and 15 ml. of concentrated hydrochloric acid for 3 hours. After neutralization with sodium bicarbonate, the solution is saturated with sodium chloride and extracted continuously with ether for 20 hours. The ether is removed by distillation, and the product is dried thoroughly by azeotropic distillation using a benzene-hexane mixture. Distillation affords /3-methylglutaraldehyde, b.p. 85-86°/15 mm., 1.4307-1.4351. Yields up to 90% have been secured. The aldehyde polymerizes on standing but is stable as a 50% solution in water or ether. The monomer may be recovered by careful destructive distillation of the polymer. 

Trifluoroacetic acid, 85 ml, was added to 30.5 g (0.0958 mole) of the 5-methoxy-2-(tert-butoxycarbonylamino)-2,3-dihydro-lH-phenalene. The resulting solution was stirred for 20 min. Ice was then added, and the resulting mixture was made pH basic with 20% w/w sodium hydroxide in water solution and stirred for 1 h at room temperature. The mixture was extracted well with chloroform, the chloroform extract was separated and washed with water, with saturated sodium chloride solution dried with magnesium sulfate, and evaporated to give 18.8 g (92% yield) of the 2-amino-5-methoxy-2,3-dihydro-lH-phenalene as a brown oil. 

This 2-amino-5-methoxy-2,3-dihydro-lH-phenalene was converted to its hydrochloride salt in methanol with 1.5 N hydrogen chloride in diethyl ether solution to give 18.11 g of the 2-amino-5-methoxy-2,3-dihydro-lH-phenalene hydrochloride as colorless needle crystals, melting point 252°C (dec.). 

The 2-(di-n-propylamino)-5-methoxy-2,3-dihydro-lH-phenalene was dissolved in diethyl ether, treated with ethereal hydrogen chloride which resulted in the formation of the crude gummy solid hydrogen chloride salt. 2.67 g (66% yield) of the 2-(di-n-propylamino)-5-methoxy-2,3-dihydro-lH-phenalene hydrochloride, melting point 196°-197°C (crystallized from a methanol/diethyl ether). 

A solution of the above product (19.2 g, 0.093 mol) in DMF (125 mL) was added to a suspension of sodium hydride (3.08 g, 80% oil dispersion, 0.103 mol) in DMF at 006. When the addition was completed the ice bath was removed and the reaction 20 mixture stirred at ambient temperature for 1 h. The reaction mixture was cooled to 0°C and 2-bromoethyl methylether (13.6 mL, 0.14 mol) was added. The reaction mixture was stirred at ambient temperature for 18 h after which time it was evaporated to dryness. The residue was suspended in brine (100 mL) and extracted with methylene chloride (4x80 mL). The combined extracts were dried (MgS04), filtered and evaporated to a solid which was recrystallized from ethyl acetate to give the desired subject (17.4 g). Chromatography of the mother liquor (silica, 3% ethanol/methylene chloride) furnished more subject which was combined with the first batch to give a total of 19.3 g (78%) of 3,4-dihydro-4-hydroxy-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-l,2-thiazine 1,1-dioxide. 

Dihydro-2-(2-methoxy)ethyl-4-propylamino-2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-l,1-dioxide hydrochloride was obtained by the reaction of 3,4-dihydro-4-hydroxy-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-1,1-dioxide in THF containing triethylamine with tosyl chloride at -16°C and the next stirring for 18 hrs at room temperature. After which time the mixture was cooled to 0°C and propylamine was added, the desired product (0.57 g, 46%) was obtained m.p. 178°-181°C. 

Mycophenolic acid may be obtained by the fermentation broth of Pennicillium brevicompactum. The synthesis of Mycophenolate mofetil (Patent U.S. 4,753,935). The mixture of Mycophenolic acid (32.0 g), thionyl chloride (25.0 ml) and DMF (0.3 ml) in dichloromethane (250 ml) was stirred at room temperature for 3 hours, after which the volatile components were removed under vacuum to afford mycophenolic acid chloride as an oil. The mycophenolic acid chloride oil was dissolved in dichloromethane (50.0 ml) and added to the chilled solution of morpholinoethanol (30.5 ml) in dichloromethane (250 ml). After stirring for 90 min at 4°C, the reaction mixture was washed with water and then with aqueous sodium bicarbonate. The organic solution was dried with sodium sulfate and evaporated to yield Mycophenolate mofetil morpholinoethyl E-6-(l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate (melting point 93-94°C). 

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