CA1146952A - Process for making alpha-loweralkylfurocoumarins and novel intermediates produced therein - Google PatentsProcess for making alpha-loweralkylfurocoumarins and novel intermediates produced therein
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- CA1146952A CA1146952A CA 346784 CA346784A CA1146952A CA 1146952 A CA1146952 A CA 1146952A CA 346784 CA346784 CA 346784 CA 346784 A CA346784 A CA 346784A CA 1146952 A CA1146952 A CA 1146952A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
.alpha.-Loweralkylfurocoumarins are produced by forming a .beta.-haloalk-2-enyl, e.g., .beta.-haloallyl, ether of a hydroxycoumarin having an active hydrogen in the position ortho to the hydroxy group, and heating the formed ether, preferably in dimethylaniline or like basic amine solvent. An abnormal Claisen rearrangement produces a novel o-hydroxy-(.beta.-haloalk-2-enyl)coumarin inter-mediate which can be dehydrohalogenated directly without isolation to the desired .alpha.-loweralkylfurocoumarin, e.g., .alpha.-methylfurocoumarin.
TC~ELDER- 5 FIELD OF THE INVENTION AND PRIOR ART
This invention relates to a process for making ~-loweralkylfurocoumarins and to novel intermediates produced therein.
Phenols can be converted to ~-methylhenzofurans by a five-step process which involves O-allylation, Claisen rearrangement to an o-allylphenol, acetylation of the phenolic hydroxyl group, addition of halogen to the allylic double bond, and cyclization in an alkaline alcoholic medium.
L. Claisen, Ann., 418, 69 (1919) and Ber., 53, 322 ~1920 That approach has been successfully utilized to convert 7-hydroxycoumarins to a-methylfurocoumarins, K. Do Kaufman, J. ORG. CHEM., _, 117 (1961) and U. S. Patent 3,201,421, including 4,5',8-trimethylpsoralen which was obtained from 4,8-dimethyl--7-hydroxycoumarin in 28~ overall yield. Trimethylpsoralen, under the generic name Trioxsalen, has been extensively used with ultraviolet radiation in the treatment of vitiligo, T. B.
Fitzpatrick, J. A. Parrish, and Mo A. Pathak, in "Sunlight and Man"~ University oE Tokyo Press, Tokyo, Japan, 1974, p.
783-791, and has been recommended in psoriasis therapy, S. W. Becker, Aust. J. Derm., 18, 15-19 (1977). Thus a con-venient and efficient synthesis of ~-loweralkylfurocoumarins.
is of contemporary practical interest.
OBJECTS OF THE INVENTION
It is an object of the invention to provide an improved process for making a-lcweralkylfurocoumarins. It is a further object of the invention to provide novel compounds useful as intermediates in the preparation of a-loweralkylEurocoumarins.
It is another object of the invention to provide novel processes for the production of such intermediates. It is an additional object of the invention to avoid the disadvanta~es ~1-' ~ 5~ TC-~E.R-5 of the prior art and to obtain such advantages which will appear as the description proceeds.
BRIEF DESCRIPTION OF THE_INVENTION
The invention relates to a process which comprises pro-viding a 7-(2Lhalo-loweralk-2Lenyloxy)coumarin having an active hydrogen in the ortho position and heating it, prefer-ably but not necessarily, in a basic tertiary amine solvent, for a time and at a temperature such that a Claisen rearrange-ment is effected. The heating is continued at least until the predominant product is the intermediate (~halo-loweralk-2~enyl)-7-hydroxycoumarin, preferably until the predominant producti~ the ~-loweralkylfurocoumarin, and the reaction is most advantage-ously conducted without isolation of the intermediate product.
Advantageously, the reaction may include the step of heating~
preferabIy in the presence of a hydrogen halide acceptor, a 1,2-dihalo-loweralk-2-ene with a 7~hydroxycoumarin having an active hydrogen in the ortho position. to provide starting material.
The Claisen rearrangement of ~-haloallyl ethers is of a -type known in the art as "abnormal", D. S. Tarbell, Org.
Reactions, 2, 10 (1944). These abnormal rearrangements usually proceed in poor yield. Thus, the rearrangment of ~-bromoallyl phenyl ether has been reported to proceed in 30~ yield in boiling decalin. [J. von Braun, Ann., 449, 264, (1926)]. However, Hurd and Webb [C. D. Hurd and C. N.
Webb, J. Amer. Chem. Soc.j 58, 2190 (1926)] were unable to obtain a pure product from the same rearrangement in decalin or fluorene or by heating without a solvent,but isolated minor amounts of the phenol and the cyclized product a-methyl-benzofuran from the Claisen rearrangement of ~-chloroallyl phenyl ether. It is therefore surprising that, in the process of the invention, there are obtained high yields both of (2~halo-loweralk-2~-enyl)-7-hydroxycoumarin and a-lower-~ 2 TC ELDER-5 alkylfurocoumarin. This is even more surprising in view of the fact that Anderson et al., JCS Chem. Comm., 1974, p. 174, was unable to obtain any cyclized product from chloroallyl phenyl ethers after 48 hours in boiling N,N-diethylaniline.
To obtain a cyclized product, namely, a 2-methylbenzo [b] furan, it was necessary for Anderson et al. to treat the ortho-chloroallyl phenol under acidic conditions in a separate step. Thus, the discovery that 7-(2'halo-loweralk-2'enyloxy)~
coumarins can be converted directly to ~alkylfurocoumarins, in the presence of an acid-binding agen~, and especially most conveniently by boiling in N,N-diloweralkylaniline or like basic solvent, is entirely unexpected.
The invention is particularly directed to the preparation of trimethylpsoralen and analogues -thereof from a (2'-halo--loweralk-2Lenyl)-7-hydroxycoumarin having a reactive hydrogen in the 6- position and a substituent in the 8- position effective to block the formation of isopsoralenes. In this process, both tile starting compound, that is, a 7-(2'-halo--loweralk-2Lenyloxy)coumarin having an active hydrogen in the 6~ position and a blocking group in the 8- position and the 6~(2Lhalo-loweralk-2'-enyl)-7-hydroxycoumarin are novel intermediates which are readily converted to the corres-ponding psoralenecompounds on heating in a N,N-diloweralkyl-aniline or like tertiary amine solvent for a time and at a temperature such that rearrangement and cyclization is effected.
The isopsoralenes are prepared in a like manner from 7-(2Lhalo-loweralk-2~enyloxy)coumarins havin~ an active hydrogen in the 8- position. The starting ether for this conversion was prepared by Shamshurin et al., Trudy Uzbekskogo Gosudarst Univ. ~N.S.), No. 25, Khim., No. 1, 1-8 (1941), but its conversion either to a (2Lhalo-loweralk-2~enyl)-7--hydroxycoumarin or to an ~-loweralkylfurocoumarin has not been ~3--reported.
The process of the invention may be illustrated by the following flow diagram:
~() R6CH=CX-CHR50 . ' o R3 ~ -)-R RG-CH=CX--CHRsX R ~ ~
R ~' Hydrogen Halide Acceptor 3 ~ -R
R4=blocking group R~-hydrog~n ~3 =H
R4 R6CH-CX=~}Rs ~0~ 10~
R5CH2CX-CHR -I~)-R R--~-R
R2 Rl E~2 R~
~6 R 4 R5C~H2 ~\
~6 ~ R3--~J~J--R
2 1 1~2 R
In Formula I, R, R1, R2~ R3, and R4 can be hydrogen, alkyl, and lower-alXoxy, provided at least one o~ R3 and R4 -:
is hydrogen. In Formula II, additionally, R5 and R6 can be hydro~en or lower-alkyl. In Formula III, R4 must :be a ~locking group, that is, other than hydroyen and, for the con-:' version to compound IV, the R~ must be hydrogen, in which case R3 can be hydrogen also. The X is halo~en, advanta~eously, chlorine or bromine. Compounds I, V, and VI are known compounds, as is compound II where Rl is methyl and all of the other R's are hydrogen. Compounds III and IV are novel intermediates useful in the production of compounds V
and VI, and compound II, except for the case noted above, is a novel compound useful as an intermediate in the production of compounds III and V.
Suitable known startin~ compounds of Formula I :include:
7-hydroxycoumarin, 7-hydroxy-4-me thylcoumarin r 7 hydroxy-8-methylcoumarin, 7-hydroxy-4,8-dimethylcoumarin, 7-hydroxy-3,6-die-thyl-4-methylcoumarin, 7-hydroxy-4-methyl-6-octadecylcoumarin, 7-hydroxy-3,4,5-trime-thyl-8-propylcoumarin, 7-hydroxy-5-methoxy-4-methylcoumarin, 7-hydroxy-8-methoxycoumarin, and 7-hydroxy-8-methoxy-4-methylcoumarin, Representative examples of known 1,2-dihalo-loweralk-enes suitable for use in the process include:
2,3-dichloropropene, 2,3-dibromopropene, 2~3-dichloro-1-pentene, 1,2-dichloro-2-pentene,
3,4-dibromo-2-pentene, 2,3-dichloro-1-butene, 1,2-dichloro-2-butene, 1,2-dibromo-2-decene, 2,3-dibromo-1-hexene, 1,2-dibromo-2~hexene, 3,4-dibromo-6-methyl-2-hep-tene, and 3,4-dibromo-2-nonene.
Representative examples of compounds II (flow diagram on page 4) which can be prepared from the foregoing or similar known starting materials, are as follows:
4,8-dimethyl-7-(2'-bromoallyloxy)coumarin, 4,8-dimethyl-7-(2'-chloroallyloxy)coumarin, 4-methyl-7--(2'-bromoallyloxy)coumarin, 7~ ethyl-2'-chloroallyloxY)coumarin, 7-(11-methyl-2'-bromobut-2'-enyloxy)-3,4,5-trimethyl-8-propylcoumarin, 7~ isobutyl-2'~bromobut~2'-enyloxy)-4-methyl-6-octadecylcoumarin, 7-(2'-bromodec-2)-enyloxy)-8-methoxycoumarin, 7-(2'-bromoallyloxy)-8-methoxycoumarin, 7-(2'-chloroallyloxy)coumarin, 7-(2'-chloropent-2'-enyloxy)-4,8-dimethylcoumarin, and 7~(2' bromoallyloxy)-8-methylcoumarin.
Representative examples of compounds III (flow diagram) which can be prepared by the abnormal Claisen reaction from the foregoing and similar starting materials, are as follows:
6-(2'-chloroallyl)-4,8~dimethyl-7-hydroxycoumarin, 6-(2'-bromoallyl)-g,8-dimethyl-7-hydroxycoumarin, 6-(2'-bromoallyl)-7-hydroxy-8-methoxycoumarin, 6-(1'-ethyl-2'-chloroallyl)-4,8-dimethyl-7-hydroxy-coumarin, 6-(1'-methyl-2'-bromobut-2'-enyl3-7-hydroxy-3,4,5-trimethyl-8-propylcoumarin, .. ~
6-(2'-bromoallyl)-7-hydroxy-8 methylcoumarin, and 6~ heptyl-2~-Dromoallyl)-7-hydroxy-B-methoxycoumarin-Representative examples of compounds IV (flow diagram)which can be made rom the foregoing and similar s-tarting materials are as follows:
8-(2'-bromoallyl)-7-hydroxy-4-methylcoumarin, 8-(2'-chloroallyl)-7-hydroxycoumarin, 8-(21-chloropent-2'enyl)-7-hydroxycoumarin, and 8-(2'-bromo-1',5'dimethylhex-2'enyl)-7-hydroxy-6-octadecylcoumarin.
Representative examples of compounds V (flow diagram) which can be made by cyclization from the examples of compounds III listed in the foregoing are:
5'-methyl-8-methoxypsoralen, 4'-ethyl-4,5',8-trimethylpsoralen, 5'-ethyl-3,4~4'5-tetramethyl-8-propylpsoralen, 5',8-dimethylpsoralen, and 4'-heptyl-8-methoxy-5'-methylpsoral~en.
Representative examples of compounds VI (flow diagram) which can be made by cyclization from the examples of compounds IV listed in the foregoing are:
4,5'-dimethylisopsoralen, 5'-methylisopsoralen, 5'-propylisopsoralen, and 5'-isopentyl-6-octadecyl-4'-methylisopsoralen~
The solvent employed for the reaction is not critical;
in fact, a fusion process may be used if desired. An acid-binding agent, e.g., a hydrogen halide acceptor, is generally ~ TC-ELDER-5 employed in the cyclization step of the invention, i.e., Compound III -~ V or IV -~ VI. The solvent in said cyclization reaction preferably comprises or consists of a tertiary amine which is i-tself a hydrogen halide acceptor.
Preferred such tertiary amines are N,N-diloweralkylanilines.
The temperature of heating is not critical but should not be so high as to produce undesirable side effects or so low that the reaction proceeds at an uneconomically slow rate.
~olvents having boiling points of 190C or higher are therefore preferredl and the boilin~ points of such solvents are gen-erally satisfactory for carrying out the reaction. Atmos-pheric pressure is ordinarily employed, but increased pressures may be used to permit efficient use of lower-boiling solvents.
Likewise, reduced pressures may be employed to permit efficient use oE higher-boiling solvents, all as will be apparent to one skilled in the art.
Representative solvents for Step 1 (II -~ III or IV
(flow diagram) are as follows:
a. No solvent is required. Many Claisen rearranqements carried out without a solventr i.e., by sirnply heating a compound of Formula II at ca. 200C, (at which temperature it melts).
b. decalin c. fluorene d. diphenyl ether e. diethyleneglycol monoethyl ether f. ethyl benzoate g. butyl ether h. 1,2,4--trichlorobenzene i. p-tolunitrile TC~ELDER-5 5i2 In general, any conventional organic solvent which is non-reactive with the reactant~ and reaction products under conditions of the reaction may be employed, when a solvent is utilized, as will be apparent -to one skilled in the art.
Representa-tive acid-binding agents for S-tep 2 (III -~ V or IV -~ VI (flow diagram) are as follows:
A. Representative solids which can be used in conjunction with solvents a through d above are:
a. potassium or sodium carbonate b. calcium oxide c. barium hydroxide d. potassium or sodium bicarbonate e. potassium or sodium acetate B. Representative basic solvents which can be substituted for or used in conjunction with those solvents a through d in khe foregoing are as follows:
a. N,N-dimethylaniline b~ N,N-diethylaniline (or other N,N-diloweralkylaniline) c. p-toluidine d. collidine e. tributylamine f. N,N-dimethylmesidine g. morpholine h. 2,4-lutidine i. quinoline j. methylpiperazine k. methylpiperidine Basic solvents of this type are especially preferred when it is clesired to proceed directly from Compound II
_9_ TC -El.l)E R- S
to Compound V or from Compound Il to Compound VI without isolation of an intermediate.
DETAILED DESCRIPTION OF THE INVENTION
The following Preparations and Examples are given by way of illustration only, and are not to be construed as limiting.
EXAMPLE I: Preparation of 4,5',8-Trimethylpsoralene Part l-A: 4,8-Dimethyl-7-(2'bromoallyloxy)coumarin -A mixture of 4,8-dimethyl-7-hydroxycoumarin (2.00g., 10.5 m mole), anhydrous potassium carbonate (2.9g., 21 m mole), freshly-distilled 2,3-dibromopropene (2.50 g., 12.6 m mole, b.p. 42-44C/ll torr), and acetone (75 ml.) was stirred and heated under reflux for six hours. Inorganic salts were filtered rom the cooled solution and washed with acetone. Evaporation of the combined filtrate and washingunder reduced pressure left a nearly colorless residue t3.52 g., m.p. 128.5-131C) of 4,8-dimethyl-7-(2'-bromoallyloxy)coumarin, that smelled faintly of 2,3-dibromopropene. Recrystallization of a sample (1.00 q.) from methanol gave colorless needles (0.84 g., 91~ y:ield) of m.p. 130-132C. Another recrystallization gave an analytical sample of m.p. 131-131.5C.
A al. Calcd. for Cl4HI303Br: C, 54.39; H, 4.24; Br, 25.85.
Found: C, 54.32; H, 4.24; Br, 26.07.
Part l-B: 4,5',8-Trimethylpsoralene A mix-ture of 4,8-dimethyl-7-(2~bromoallyloxy)coumarin (200 mg., n.65 m mole, m.p. 130-132C) and freshly-distilled ~,N-diethylaniline (5.0 ml.) was stirred under a nitro~en atmosphere and heated under reflux for twenty-four hours at .~ . . .
-- TC-~I,DER -S
an oil bath temperature of 225+ 2C. An ether solution of the dark-brown reaction mixture was filtered, and the filtra-te was washed with several portions of 5% aq. sodium hydroxide and one portion of 6M hydrochloric acidO After drying (MgSO4), the ether solution was concentrated under reduced pressure to a tan residue (131 mg., 88% yield, m. pO 222-228C). Recrystal-lization of 120 mg. from 95~ ethanol gave 4,5',8-trimethyl-psoralene as fine needles (82 mg., 60% yield) of m.p. 232.5-233.5C (rptd~- m.p. 234C). The melting point of a commercial sample was 230-232C when~determined simultaneously. The infrared spectra of the two samples were identical.
EXAMPLE II Preparation of 4,5',8-Trimethylpsoralene Part 2~ 4,8-Dimethyl-7-(2Lchloroallyloxy)coumarin A mixture of ",8-dimethyl-7-hydroxycoumarin (8.00 g., 42.1~m mole); anhydrous potassium carbonate (18.1 gO, 130 m mole);-2,3-dichloropropene (33.6 g., 302 m mole); and acetone (600 ml~.) was stirred and heated under reflux for twenty-four hours. The reaction mixtur~ was concentrated to ca. 200 ml., filtered, and the inorganic salts were washed with acetone.
, . .
Evaporation of the combined filtrate and washing under reduced :
pressure left a tan-colored residue (11.30 g.). Recrystal-lization from aqueous methanol gave a 77% yield of 4,8-dimethyl--7-~2Lchloroallyloxy)coumarin as small, off--white needles (8.55 g., m.p. 117.5-120C). Another recrystallization did not change the m.p. but gave an analytical sample.
Anal. Calcd. for Cl4Hl3O3Cl: Cr 63.52; H, 4.95; Cl, 13.39.
Found: C, 63.39; H, 5.12; Cl, 13.52.
Part 2-B: 4,5',8-Trimethylpsoralene A mixture of 4,8-dimethyl 7-(2'chloroallyloxy)coumarin (500mg., 1.89 m mole) and N,N-diethylaniline (5.0 ml) was protected by an "Aquasorb" (TM)~ brand of phosphorous pentoxide drying tube, while being heated under xeflux for twenty-four hours at an oil bath temperature of 220-225C. Treatment of the reaction mixture as described in part l-B gave some black, ether-insoluble material which was discarded. The desired 4,5',8-trimethylpsoralene was obtained as a tan solid (154 mg., 41.6% yield), which was re-crystallized from 95% ethanol to obtain light tan needles (53 mg., 14~ yield) of m.p. 233C (rptd: m.p. 234C). Its infrared spectrum was identical to that of a commercial sample.
EXAMPLE III-Preparation of 4,8-Dimethyl~6-(2'-bromoallyl)-7-hydroxycoumarin A mixture of 4r8-dimethyl-7-(2Lbromoallyloxy)coumarin (l.OO g., 3.24 m mole) and freshly distilled N,N-diethylaniline (5.0 ml.) was protected by an "Aquasorb" (TM) tube while being stirred and heated under reflux for three hours at an oil bath temperature of 225+ 3C. An ether solution of the dark brown reaction~ mixture was filtered to remove a black solid (ca. 1~ mq.), extracted with several portions of 5~ aqueous sodium hydroxide, washed several times with 6M hydrochloric acid, dried (MgSO4), and concentrated to a tan solid (0.43 g., m.p. 114-125C) which was probably impure starting material. The alkaline extracts were acidified with concentrated hydrochloric ac:id toobtain 4,8-di-methyl-6-(2~bromoallyl)-7-hydroxycoumarin as an off-white solid (0.53g., 53% yield, m.p. 154-161C) that was collected by ether extraction. Recrystallization from aqueous ethanol, followed by another recrystallization from benzene, gave an analytical sample of m.p. 175-176C.
35;2 Anal. Calcd. for Cl4HI3O3Br: C, 54.39; H, 4.24; Br, 25.85.
Found: C, 54.83; H, 4.39; Br, 25.87 ll~atinc~ the 4,8-dimcthy]-~)-(2Lbromoallyl)-7-hydroxycoumarin in the ~resence of a hydroc3en halide acceptor, for exam~)le, N,N-dlmethylaniline or sym-collidine, converts it to 4,5', 8--trimethylpsoralene.
EXAMPLE IV-Preparation of .
in mixture of 4,8-dimethyl-7- (2'chloroallyloxy) coumarin ~500 mg., 1.89 m mole ) and N,N-diethylaniline (5.0 ml.) was protected by an "Aquasorb" (TM) tube while refluxing for nine--teen hours at an oil bath temperature of 220-225C. The cooled mixture was treated as described in Example III to obtain 4,8-dimethyl-6-(2Lchloroallyl)-7-hydroxycoumarin as a tan solid (307 mg., 61% yield, m.p. 135-163C) from the acidified alkaline extracts. Recrystallization from benzene using active carbon~gave small yellow needles (183 mg., 37% yield, m.p. 172-176C).
Anal. Calcd. for ClljHl3O3Cl: C, 63.52; H, 4.95; Cl, 13.39.
Found: C, 63.62; H, 4 75; Cl, 13.42.
Eleating the 4,8-dimethyl-6-(2'-chloroallyl)-7-hydroxycoumarin in the presence of a hydrogen halide acceptor, for example, N,N-dimethylaniline or sym-collidiner converts it to 4,5', 8-trimethylpsoralene.
EXAMPLE V-Preparation of 4,5'-Dimethylisopsoralene Part l-A: 4-Methyl-7 (2'bromoallyloxy)coumarin _ _ 4-Methyl-7-hydroxycoumarin (2.00 9., 11.4 m mole) was refluxed with freshly-distilled 2,3-dibromopropene (2.72 g., 13.6 m mole), anhydrous potassium carbonate (3.15 g., 22.8 m mole), and acetone (80 ml.) for four hours. The reaction TC-ELD]ER 5
mix-ture was treated as described for -the preparation of Example I~ Part l-A to obtain 4-methyl-7-(2~bromoallyloxy) coumarin as an off-white solid (3.70 g.) that contained some excess 2,3~dibromopropene. Recrystallization of a portion (500 mg.) ~rom ligroin (b.p. 100-120C) ~ave needles (394 m~., 89~o yield) of m.p. 109.5-110.5C. An analytical sample of m.p. llO-111C was obtained by recrystallization from methanol.
Anal. Calcd. for Cl3HllO3Br: C, 52.97; H,3.75; Br, 27.08.
Found: C, 52.98; H, 3.80; Br, 27.18.
Part l-B: 4,5'-Dimethylisopsoralene Rearrangement and cyclization of 4-methyl-7-(2'bromo-allyloxy)coumarin (500 mg., 1.69 m mole) was carried out as described in Example I, Part l-B, except that N,N-dimethyl-anillne (12.5 ml.) was used instead of the diethyl homo]og.
The same purification procedure gave 4,5'-dimethy~isopsora-lene as a tan solid (289 mg., 80% yield) of m.p. 173-179.5C.
Recrystallization from methanol using active carbon afforded light tan needles (161 mg. r 45% yield) of m.p. 182.5-184C
(rptd.: m.p. 182-183C). The infrared spectra of this sample and that of an authentic sample were iaentical.
EXAMPLE VI~Preparation of 4-Methyl~8-(2~bromoallyl)-7-hydroxycoumarin A mixture of 4-methyl-7-(2'-bromoallyloxy)coumarin (500 mg.) and freshly-distilled N,N-diethylaniline (12.5 ml.) was stirred under a nitrogen atmosphere and heated under reflux for five hours at an oil bath temperature of ca. 225C.
An ether solution of the reaction mixture was extracted with several portions of 5% aqueous sodium hydroxide, which were acldified and re-extracted wi.th ether to obtain 4-methyl-TC-EI.DER-5 f~
-8-(2'-bromoallyl)-7-hydroxycoumarin as an off-white solid (206 mg.). Recrystallization from 95~ ethanol gave fine, off-white needles (102 mg ~ 20% yield) of m.p. ~01-202C.
Another recrys-tallization gave an analytical sample of m.p. 204.5-205~C.
Anal. Calcd. for Cl3H~O3Br: C, 52.97; H, 3.75; Br, 27.08 Found: C, 52.97; H, 3.75; Br, 26.56.
Heating the 4-methyl-8-(2'bromoallyl)-7-hydroxycoumarin in the presence o E a hydrogen halide acceptor, for example, N,N-dimethylaniline or sym-collidine, converts it to 4,5'-dimethylisopsoralene.
E MPLES ~II THROUGH XVI-Additional Preparations In the same manner as given in the foregoing examples, by the reaction of starting compounds having Formula I with selected 1,2-dihaloloweralkenes, additional compounds having Formula II are produced and converted to end products having Formulas V and VI, preferably without isolation of -the inter-mediate compounds of Formulas III and IV, respectively, all according to the reaction se~uence fully set forth on page 4 hereof and employing, as starting materials of Formula I, those compounds set forth on page 5 hereof; as reactant 1,2-dihaloloweralkenes, those compounds set forth on pages 5 and 6 hereof; thus to prepare compounds of Formula II as set forth on page 6 hereoE, as well as compounds of Formula III as set forth on pages 6 and 7 hereof, and compounds o:E Formula IV as set forth on page 7 hereof, which latter ty~e of compounds of Formulas III and IV are preferably not isolated, but converted directly in situ, according to the foregoing examples, to the end products being compounds of Formulas V and VI, also as set I'C-ELDER-5 ~f~
forth on page 7 hereof. The procedure employed is substantially as set forth in the foregoing examples, as well as reaction conditions and work-up for procurement of the final end products in each case. The end products in each case are the compounds of Formulas V and VI set forth on page 7 hereof.
As used herein, loweralkyl means such radicals con-taining up to and including eight carbon atoms, such as me-thyl, ethyl, propyl, butyl, amyl, hexyl, heptyl and octyl, and loweralkoxy means such radicals of the formula -O-loweralkyl.
It is to be understood that the inven-tion is not to be limited to the exact details of operation or structure shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art.
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
-17- (Claims page 1)
-19- (Claims page 3)
Priority Applications (2)
|Application Number||Priority Date||Filing Date||Title|
|US06020935 US4216154A (en)||1979-03-15||1979-03-15||Process for making α-loweralkylfurocoumarins|
Applications Claiming Priority (1)
|Application Number||Priority Date||Filing Date||Title|
|CA 408196 CA1163642A (en)||1979-03-15||1982-07-27||6-or 8-haloalkyl substituted 7-hydroxycoumarins|
|Publication Number||Publication Date|
|CA1146952A true CA1146952A (en)||1983-05-24|
Family Applications (1)
|Application Number||Title||Priority Date||Filing Date|
|CA 346784 Expired CA1146952A (en)||1979-03-15||1980-02-29||Process for making alpha-loweralkylfurocoumarins and novel intermediates produced therein|
Country Status (7)
|US (1)||US4216154A (en)|
|BE (1)||BE882236A (en)|
|CA (1)||CA1146952A (en)|
|DE (1)||DE3009508A1 (en)|
|FR (1)||FR2451379B1 (en)|
|GB (1)||GB2047686B (en)|
|NL (1)||NL8001517A (en)|
Families Citing this family (11)
|Publication number||Priority date||Publication date||Assignee||Title|
|GB2128997B (en) *||1982-10-18||1985-12-24||Consiglio Nazionale Ricerche||Process for producing alkylangelicins|
|JPH05501713A (en) *||1989-10-26||1993-04-02|
|US6420570B1 (en)||1993-06-28||2002-07-16||Cerus Corporation||Psoralen compounds|
|US5593823A (en) *||1993-06-28||1997-01-14||Cerus Corporation||Method for inactivating pathogens in blood using photoactivation of 4'-primary amino-substituted psoralens|
|US6004742A (en) *||1993-06-28||1999-12-21||Cerus Corporation||Method for inactivation of pathogens in platelets using 4' and 5' primary amino-substituted psoralens|
|US5712085A (en) *||1993-06-28||1998-01-27||Cerus Corporation||5'-(4-amino-2-oxa)butye-4,4', 8-trinethylpsoralen in synthetic medium|
|US6004741A (en) *||1993-06-28||1999-12-21||Cerus Corporation||Method for the photoactivation of 4' and 5' primary aminoalkyl psoralens in platelet preparations|
|US5871900A (en) *||1993-06-28||1999-02-16||Cerus Corporation||Method of inactivating pathogens in biological fluids using photoactivated 5-primaryamino psoralens|
|US5399719A (en) *||1993-06-28||1995-03-21||Steritech, Inc.||Compounds for the photodecontamination of pathogens in blood|
|US20020115585A1 (en) *||1996-06-07||2002-08-22||Hei Derek J.||Method and devices for the removal of psoralens from blood products|
|DE69819360T2 (en)||1997-11-20||2004-08-19||Cerus Corp., Concord||New psoralens for inactivation of pathogenic|
Family Cites Families (1)
|Publication number||Priority date||Publication date||Assignee||Title|
|US3201421A (en) *||1962-05-09||1965-08-17||Dept Of Chemistry||Preparation of alkyl psoralens|
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|Kaufman||Synthetic Furocoumarins. I. A new synthesis of methyl-substituted psoralenes and isopsoralenes|
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|Sasaki et al.||as-Triazine Chemistry. III. 1, 2 The Structures of the Monoxide of 3-Methoxy-and 3-Phenoxy-5, 6-diphenyl-as-triazine|
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|US3201421A (en)||Preparation of alkyl psoralens|