CS273348B2 - Method of polycyclic aromatic alkanol derivatives preparation - Google Patents

Abstract

Method of preparation of polycyclic aromatic alkanol derivatives of general formula 2 or monomethyl, or monoethyl derivative of this compound; including ethers of this compound of general formula I containing a maximum of 28 carbon atoms, esters and salts of this compound, where Ar represents <IMAGE> whereas these residues are possibly substituted, R<1> is C1-3 alkyl substituted by the hydroxy group, R<2> is hydrogen, C1-3 alkyl or the hydroxymethyl group, R<3> and R<4> represent hydrogen; methyl or ethyl, whereas R<1>, R<2>, R<3> and R<4> contain a total of five carbon atoms, or a group <IMAGE> where -C-C- is a five or six member ring containing two or three hydroxy groups, R<8> is hydrogen, methyl or hydroxy methyl, R<9> and R<10> represent hydrogen or methyl, R<11> is hydrogen, a reaction of the compound of general formula ArCH2L, where Ar has the abovementioned meaning and L is a cleavable group, hydroxy group, methyl or hydromethyl, whereas R<8>, R<9>, R<10>, R<11> and the -C-C- ring contain a total of less than seven carbon atoms, by with a compound of general formula IV, where R<1> to R<4> have the abovementioned meaning.<IMAGE>

Description

The invention relates to a process for the preparation of polycyclic aromatic alkanol derivatives which have been found to exhibit biocidal activity. In particular, the present invention relates to a process for the preparation of aminoalkanol derivatives comprising a polycarbocyclic aromatic system.

As to the state of the art, it is described in Gazz. Chím. Ital., 93, 118, 1SS3, a process for the preparation of 2-phenylmethylamino-2-methyl-1,3-propanediol, but nowhere does this disclose that it is effective against tumors. Analogues of nitracryn (1-nitro-9 - ((3'-dimethylaminupropyl) amino) acrydine) containing 2-amino-2-methyl-1,3-propanediol and tris (hydroxymethyl) methylamine groups are disclosed in Arzne Forsch Orug Res . 32 II, 1013, 1982, which are said to exhibit anti-tumor efficacy in the form of protective agents in mice.

According to the present invention, a new class of polycarbocyclic aromatic alkanol derivatives has been found which exhibit biocidal activity.

SUMMARY OF THE INVENTION The present invention provides a process for preparing compounds of formula I

Ar - CH 3 NH - C - R ² R ⁴ - C - R ³

AND

OH or monomethyl or monoethyl ethers of these compounds, wherein the compound of formula I including its ethers contains no more than 28 carbon atoms in total, or esters or salts thereof, wherein Ar is selected from the group consisting of:

10 4

WS

T 9 1

0 ·

GS 273348 B2

said radicals being optionally substituted by one or two substituents which together contain a maximum of four carbon atoms and which are the same or different, selected from the group consisting of a halogen atom, a cyano group, a (C1-C3) alkyl group or an alkoxy group containing 1 to? carbon atoms, giving a group S (O) _n R in which n is an integer of 0, 1 or 2, and R represents an alkyl group containing 1 or 2 carbon atoms optionally substituted by a hydroxy or alkoxy group having 1 or 2 carbon atoms, or the radical Ar is optionally substituted by an NR R group containing at most 5 to 7 carbon atoms (wherein the R and R substituents are the same or different and each of these substituents represents an alkyl group having 1 to 3 carbon atoms, or a group 6 7

NR R forms a five-membered or six-membered heterocyclic ring optionally containing one or two additional heteroatoms,

R * is an alkyl group having 1 to 3 carbon atoms, substituted with a hydroxy group,

R is hydrogen, (C 1 -C 3) alkyl or hydroxymethyl,

O Λ

R and R are the same or different substituents, each being a hydrogen atom, a methyl group or an ethyl group, R ¹ , R ² , R ³ and R ⁴ together contain a maximum of five carbon atoms, or:

which - C - C - represents a 5- or 6-membered saturated carbocyclic ring containing two or three hydroxy groups, θ

R is hydrogen, methyl or hydroxymethyl,

10

R and R are the same or different substituents representing hydrogen or methyl,

R ^ js hydrogen, hydroxy, methyl or hydroxymethyl, R ^eighth R ⁹ . R ¹⁰ , R ¹¹ and the - ring together contain less than seven carbon atoms, according to the present invention is to reduce the compound of formula V

Arcon - C - R ^{2 :} 4 * 3

R ⁴ - C - R ³ (A)

AND

OH

4, wherein the substituents Ar, R-R are as defined above, wherein the hydroxy groups are optionally protected and, if necessary, followed by deprotection of said hydroxy groups.

The reduction can be carried out using standard reagents used for the reduction and known in the art for this type of reduction, such as a hydride such as lithium aluminum hydride, the reduction being carried out in an inert solvent such as an ether , such as tetrahydrofuran, at a non-extreme temperature, such as a temperature in the range of 0 to 100 ° C, and usually at the reflux temperature of the ether.

The compounds prepared by the process of the present invention exhibit biocidal activity, the antitumor activity of these compounds being particularly important.

Compounds of formula V may be prepared by reacting a suitable acid of formula

ArCOOH wherein Ar is as defined above, or a suitable reaction derivative of the acid, such as a halide thereof, in an inert solvent with an amine of formula IV (IV) with an amine;

R ¹

OH

4 wherein R @ 1 to R @ 2 is as defined above, wherein optionally the hydroxy groups are protected in the amine, for example when the compound of formula IV is a diol, the protecting group is an isopropylidene group. The compound of formula (V) thus obtained is preferably reduced in situ and, if necessary, deprotected to give a compound of formula (I).

ArCOOH wherein Ar is as defined above may be prepared by methods well known in the art.

In a preferred embodiment of the process of the invention, when the Ar moiety is 1-anthracenyl or 9-anthracenyl, the aromatic system is substituted.

In a preferred embodiment of the invention, the Ar moiety is 6-chrysonyl or 3-fluoroanthenyl or 7-fluoroanthenyl.

Particularly preferred substituents for the aromatic ring are alkyl groups having 1 or 2 carbon atoms or alkoxy groups having 1 or 2 carbon atoms which are optionally substituted by chlorine, hydroxy or methoxy, furthermore S (O) _n R or chlorine, imidazolyl a morpholino group, a cyano group or a bromine atom. Preferred substituents are chloro, 2-chloroethyl group, or OCHgCHgR in which R is hydrogen, hydroxy or methoxyakupinu, or S (0) _n CH ₃ in which n is an integer 0, 1 or 2, said substituents may be attached to any suitable position of the aromatic ring. Preferably, when the Ar moiety is substituted, it is substituted with only one substituent.

In a preferred embodiment of the invention is a group

HO or wherein R represents ^{-3-butylamino} CH? OH, CH (CH ^) OH or CH ^ Ch ^ UH,

R &lt; ⁴ &gt; is hydrogen; 1 to 3 carbon atoms or CH-OH;

R is hydrogen or methyl

In a preferred embodiment of the invention, R is CH 2 OH or CH (CH ₃ ) OH. Suitably, R ¹⁴ is hydrogen, methyl, ethyl or CH 3 OH.

In a preferred embodiment of the invention is a group

R ¹ CH-OH

I 2 ¹ 16

R ⁴ - C - R ³ h - L - R ¹⁵

AND

OH OH wherein R represents a hydrogen atom or a methyl group, and is

R is a hydrogen atom, a methyl group or an ethyl group, preferably the substituent is a methyl group,

The present invention also relates to the preparation of salts derived from the compounds of formula I and the ethers and esters thereof.

The esters and non-pharmaceutically acceptable salts of the compounds of formula (1) are suitable intermediates for the preparation of the compounds of formula (I) according to the invention and the pharmaceutically acceptable salts of these compounds. compounds derived from inorganic acids. Such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as isethionic acid, maleic acid, malonic acid, succinic acid, salycilic acid, tartaric acid, lactic acid, citric acid, formic acid, lactobionic acid, panthethonic acid, further from organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalene-2-sulfonic acid, ascorbic acid and amino acids such as glycine. Suitable salts are hydrochlorides, methanesulfonates and ethanesulfonates, lactates, citrates and isethionates. Preferably, pharmacologically and pharmaceutically acceptable salts are those which are soluble in solvents suitable for parenteral administration, such as hydrochlorides, methanesulfonates and isethionates.

Esters of the compounds of formula (X) prepared by the process of the present invention are derived from acids known in the art which are suitable for the preparation of esters and are usually derived from C 1 -C 6 alkanoic acids such as acetic acid, acid propionic acid, n-butyric acid and iso-butyric acid.

These esters may be prepared from all or some of the hydroxy groups contained in the compound of formula (I).

Specifické Specific examples of compounds of formula X above are:

2 - ((6-chrysenylmethyl) amino) -2-methyl-1,3-propanediol,

2 - ((9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol,

2 - ((1-antracanylmethyl) amino) -2-methyl-1,3-propanediol,

2 - ((10-chloro-9-anthracenylmethylmethylamino) -2-methyl-1,3-propanediol, 2 - ((10-bromo-9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol,

2-methyl-2 - ((10-methyl-9-anthracenylmethyl) amino) -1,3-propanediol,

2-methyl-2 - ((10-methylthio-9-anthracenylmethyl) amino) -1,3-propanediol, 2 - ((10- (2-chloroethyl) -9-anthracenylmethyl) amino) -2-methyl-1, 3-propanediol,

2 - ((10-hydroxymethyl- [9-ant racenylmethyl) amino) -2-ethyl-1,3-propanediol,

10 - ((1,1-bis) hydroxymethyl) ethylamino) methyl-9-anthracenecarbonitrile,

2-methyl-2 - ((10-methylsulfinyl-9-anthracenylmethyl) amino) -1,3-propanediol,

2 - ((10-methoxy-9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol, 2 - ((10-bromo-1-anthracenylmethyl) amino) -2-methyl-1,3-propanediol,

2 - ((4,10-dichloro-9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol,

2 - ((4,5-dichloro-9-vanevacenylmethyl) amino) -2-methyl-1,3-propanediol,

2 - ((2,10-dichloro-9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol, 2 - ((3,10-dichloro-9-antracenylmethyl) amino) -2-methyl 1-1,3-propanediol, 2 - ((3-fluoro-ethylmethyl) amino) -2-methyl-1,3-propanediol,

2-methyl-2 - ((2-triphenylenylmethyl) amino) -1,3-propanediol,

2 - ((4-chloro-9-aminophenylmethyl) amino) -2-methyl-1,3-propanediol, 2 - ((2-chloro-9-anthracenylmethyl) amino) -2-methyl- 1,3-propanediol, 2 - ((10-ethylthio-9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol, 2 - ((10- (2-hydroxyethylthio) -9-anthecenylmethyl) amino) - 2-methyl-1,3-propanediol, 2 - ((2-tert-butyl-10-chloro-9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol, 2 - ((10-chloro- 9-anthracenylmethyl) amino) -2-hydroxymethyl-1,3-propanediol,

2 - ((7-fluoroanthenylmethyl) amino) -2-methyl-1,3-propanediol;

2 - ((10- (2-Hydroxythyloxy) -9-anthracenylmethyl) emino) -2-methyl-1,3-propanediol, 2 - ((10- and thoxy-9-aminophenylmethyl) amino) -2-methyl-1,3-propanediol,

2 - ((10-Butoxy-9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol, 2 - ((10-butyl-9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol, 2 - ((6-chrysenylmethyl) amino-2-hydroxymethyl-1,3-propanediol),

2 - ((6-chlorophenylmethyl) amino-2-ethyl-1,3-propanediol),

2-hydroxymethyl-2 - ((3-fluoranthenylmethyl) amino) -1,3-propanediol,

2-ethyl-2 - ((3-fluoroanthenylmethyl) amino) -1,3-propanediol.

2 - ((10-chloro-9-anthracenylmethyl) amino) -2-methyl-1,3-pronanediol,

2 - ((3-chloro-9-antracenylmeth ^V L) amino) -2-methyl-1,3-propanediol, (+ -) (2R ^+, 3S *) - 2 - ((6-chrysenylmethy1) amino) - 2-methyl-1, 3-butanedin,

2- ^{((2-ethyl-9-one} antracenylmethy) amino) -2-methyl-1,3-propanediol and 2 - ((3-ethyl-9-antracenylmethyl) amino) -2-methyl-1,3-propanediol (+ -) (2R ⁺ , 3S ⁺ ) -2 - ((9-anthracenylmethyl) amino) -2-methyl-1,3-butanediol, (+ -) (2R *, '3R *) - 2- ( ((6-chryeenyl / methyl) amino) -2-methyl-1,3-butanediol, 2 - (([6-chryeenyl / methyl) amino) -2-ethoxymethyl-1,3-propanediol,

3-Methoxy-2 - (([6-chrysenyl / methyl) emino) -2-methyl-1-propanol, 3-methoxy-2 - (([3-fluoranthenyl / methyl) amino) -2-methyl-1- propanol, (+ -) (2R ⁺ , 36 *) - 2 - ((β-fluoranthenyl / methyl) amino) -2-methyl-1,3-butanediol, 2-ethoxymethyl-2 - ((β-fluoranthanyl) (methyl) amino] -1,3-propanediol,

2 - ((9-anthracenyl / methyl) amino) -2-ethoxymethyl-1,3-propanediol,

2- [3- (6-chryaenylmethyl) amino] -1- (Z, 3-Z) -cyclohexanediol, 2- (3-fluoroanthenylmethyl) amino) -1- (Z, 3-Z-cyclohexanediol),

2 - ((6-chrysenylmethyl) aroino) -2-isopropyl-1,3-propanediol,

2- (3-fluoroanthenylmethyl) amino) -2-isopropyl-1,3-propanediol,

2 - ((6-chloro-phenylmethyl) amino) -2-methyl-1,4-butanediol,

2 - ((3-fluoroanthenylmethyl) amino) -2-methyl-1,4-butanediol, 2 - ((10-chloro-1-anthracenyl / methyl) amino) -3-methyl-2,5-pentanediol,

2 - (([10-chloro-1-anthraconyl / methyl) amino) -2-methyl-1,3-propanediol, meso-3- ([6-chrysenylmethyl] amino) -2,4-pentanediol,

2- (6-chrysenylmethyl) amino) -1,3-propanediol, 1f. 2 - (([12-ethyl-6-chrysenyl] methyl) amino-2-methyl-1,3-propanediol,

2 - (((10- (2-methoxyethoxy) -9-anthracenyl) methyl) amino) -2-methyl-1,3-propanediol,

2-methyl-2 - (((10-morpholino-9-anthracenyl) methyl) amino) -1,3-propanediol,

2 - ((9-anthracenylmethyl) amino) -3-methoxy-2-methyl-1-propanol, ² "(1/ ¹² - ^Chloro - ⁶ " Chrysenyl / methyl) amino) -2-methyl-1,3-propanediol ,

2- (9-anthracenylmethyl) amino) -2-isopropyl-1,3-propanediol,

2- (9-anthracenylmethyl) amino) -2-methyl-1,4-butanediol,

2 - (((10- (1H-xmidazol-1-yl) -9-anthracenyl) methyl) amino) -2-methyl-1,3-propanediol,

2- (4-ethyl-3-fluoroanthenyl) methyl) amino) -2-methyl-1,3-propanediol, ² '((12-ethoxy-6-chrysenyl / methyl) amino) -2-methyl-1, 3-propanediol, (1), (2), 3Z] -2- (9-anthracenylmethyl) amino-1,3-cyclohexanediol,

2 - (((4-chloro-10-hydroxyethoxy) (9-anthracenyl) methyl) amino) -2-methyl-1,3-propanediol,

2 - ((4-ethyl-3-fluoroanthenyl / methyl) amino) -2-methyl-1,3-propanediol, and salts and esters thereof.

Of these specific exemplary compounds of formula (I) prepared by the process of the present invention, the most preferred compounds are 2 - ((S-chrysenylraethyl) amino) -2-methyl-1,3-propanediol, ^2- (3-fluoranthenylmethyl) amino- 2-methyl-1,3-propanediol,

2 - ((10- (2-hydroxyethyloxy) -9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol.

The compounds of formula I prepared by the process of the present invention exhibit biocidal activity, which is manifested in that they are toxic to certain cells in living organisms that are harmful to mammals, such as pathogenic cells and tumor cells. This toxicity to pathogenic organisms has been shown to be effective against viruses (e.g. Herpes simplex), bacteria (e.g. Mycoplasma smegmatis and Streptococcus Pyogenes), fungi (e.g. Candida albicans), protozoa (e.g. Eimeria tenella) and worms (e.g. Nippostrongylus brasiliensis). The antitumor activity of the compounds of the formula I has been demonstrated in a number of conclusive tests and, in particular, efficacy against ascitic leukemia PS88 / 0. Efficacy against ascytic tumors, including PSB8 / 0, is apparent from the reduction in tumor cell numbers in mammals, such as mice with these ascitic tumors, and their subsequent increase in survival compared to the untreated group also these tumors. The anti-tumor efficacy is also further evident from detecting a reduction in the size of certain solid tumors after treatment of mice with the compounds of the present invention as compared to the untreated group, which also appear to be tumors. In view of the above, the compounds of formula I have been shown to be effective against mouse tumors, P3B8 / O lymphocytic leukemia, L1210 lymphocytic leukemia, B16 mslanotic melanoma, ΡΘ15 mastocytoma, phobrosarcoma MDAY / D2, colon adenocarcinoma 38 , rhabdomyosarcoma M5Q76, and against Lewis plin carcinoma,

Efficacy in one or more of these tumor assays has been suggested to suggest anti-tumor efficacy in humans as well (see A. Goldin et al. Methods of Cancer Research, VTDeVita, 3r, and 3. Busch, 16,165, Academie). Pres3 (1979).

There are PS88 / O species that are resistant to the following clinically used agents: cytosine arablnoside, doxorubidine, cyclophosphamide, L-phenylalanine mustard, methotrexate, 5-fluorouracil, actinomycin 0, cis-platin, and bis-chloroethylnitrosourea. The compounds of formula (1) prepared by the process of the invention exhibit potential efficacy against these drug resistant tumors, as evidenced by the P388 / 0 assay procedures described above,

The compounds of formula (Z) have also been shown to be effective against human cancers, particularly tumor cells, in primary stomach cultures, pancreas, telitis, cancer cells CSCS 273348 B2 marrow and colon tumors. The term tumor as used herein is synonymous with a malignant tumor or, more generally, a cancer, unless expressly stated otherwise. It is known in the art to compare the prevention of colony formation of cancer cells, i.e., multiplication of these cells by drugs, with clinical antitumor efficacy in humans (see DD Von Hoff et al., Cancer Chemotherapy and Pharmacology 6, 265). 1980); With _the Salmon and DD Von Hoff, Seminars in Oncology, 8, 387/1981 /.

The compounds of formula I prepared according to the invention, which have been found to have antitumor activity, are inserted in vitro between DNA molecules. This property is determined! by viscometric methods, using the W.D. Wilson et al., Nucleis Acids Research 4, 2697 (1954), with the log P value as determined by C. Hanshe and A, Leoa in the Substituent Constants for Correlation Analysis in Chemistry and Siology, 3ohn Wiley and Sons, New York 1979. ranging from -2 to +2.5.

In the treatment of tumors in animals, including mammals, and in particular in the treatment of tumors in humans, an effective, non-toxic amount of a compound of formula I, an ether or ester thereof, or an acid addition salt thereof is administered.

The amount of the compound of formula (X) required to produce an effect as a biocidal agent will, of course, depend on a number of circumstances and will ultimately be determined by examination of a physician or veterinarian. Factors to be considered when determining this amount include the condition to be treated, the mode of administration of the medicament, the nature of the composition, the mammalian body weight, the surface area, the aged and the general condition of the patient, and a compound that to be administered. A suitable effective anti-tumor dose is from about 0.1 to about 120 milligrams / kg body weight, preferably from about 1.5 to about 50 milligrams / kg body weight, for example 10 to 30 milligrams. / kg body weight. The total daily dose may be administered as a single dose, in the form of multiple doses, such as two to six times daily, or by intravenous infusion for a selected period. For example, for a 75 kilometer mammal, the dosage amount can range from about 8 to about 9,000 milligrams per day, with a typical daily dose of about 2000 milligrams per day. If multiple discrete doses are determined in the treatment, treatment with the usual doses of 500 milligrams of the compound of formula I administered four times a day in the form of tablets, capsules, liquid preparations (e.g. syrup) or injection can be performed.

Although the active compounds prepared by the process of the invention may be defined as whether the compounds of formula (I) or the ethers, esters or salts thereof may be administered as the raw chemical itself, it is preferable to prepare pharmaceutical preparations from the active compounds. Compositions intended for medical use contain the active ingredient together with one or more pharmaceutically acceptable carriers and optionally other therapeutic adjuvants. The carrier (s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

The compounds prepared by the process of the present invention may be formulated into a pharmaceutical composition comprising a compound of Formula I (in the form of a free basic compound, an ether, an ester, or a pharmaceutically acceptable acid addition salt thereof) together with a pharmaceutically acceptable carrier.

In a process for preparing a pharmaceutical composition, a compound of formula I or an ether, ester or pharmaceutically acceptable salt thereof is combined with a pharmaceutically acceptable carrier.

Although it is believed that the antitumor effect of the compounds of formula (I) prepared by the process of the present invention is derived from the free base form, it is often desirable to administer an acid addition salt thereof.

The above compositions are in a form suitable for oral, rectal or parenteral administration (including subcutaneous, intramuscular or intravenous administration).

The compositions containing the compounds of formula (I) prepared by the process of the present invention may be formulated in a unit dosage form, and may be prepared by any of the known methods in the art.

In all of these processes, the active compound is combined with a carrier that functions as one or more excipients. In general, the compositions are prepared by uniformly and intensively contacting the active ingredient with a liquid carrier therefor, or with a finely divided solid carrier, or both, and then, if necessary, shaping the product into forms of the desired composition.

These compositions suitable for oral administration may take the form of discrete units such as capsules, capsules, tablets or lozenges, each containing a predetermined amount of the active ingredient, in the form of powders or granules, or in the form of a suspension in an aqueous liquid or in a non-aqueous liquid, such as syrups, elixirs, emulsions or inhalations.

Tablets may be prepared by compression or molding, optionally together with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredient in the form of a free-flowing agent, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent, in a suitable device. Molded tablets may be prepared by molding a mixture of the active compound in powder form together with any suitable carrier in a suitable machine.

Syrups may be prepared by adding the active compound to a concentrated aqueous sugar solution such as 3-sucrose, and other ingredients may also be added to the syrup. Such additives may be, for example, flavorings, sugar crystallization retardants or agents which increase the solubility of any component, such as a polyhydric alcohol, for example glycerol or sorbitol.

Formulations for rectal administration may be in the form of suppositories with a commonly used carrier, such as cocoa butter.

Formulations for parenteral administration typically comprise a sterile aqueous preparation of the active ingredient, which is preferably isotonic with the blood of the recipient. These compositions, in a suitable embodiment, comprise a solution of a pharmaceutically and pharmacologically acceptable acid addition salt derived from a compound of Formula I that is isotonic with the blood of the recipient. Thus, these compositions generally comprise distilled water, 5) a solution of dextrosis in distilled water or saline, and a pharmaceutically and pharmacologically acceptable acid addition salt derived from a compound of formula (I) having suitable solubility in these compounds. solvents such as isethionate salt and methanesulfonate salt, the methanesulfonate salt being preferred.

In addition to the aforementioned additives, the compositions may further comprise one or more excipients selected from the group consisting of diluents, buffering agents, flavoring agents, binders, surfactants, reinforcing agents, lubricants, preservatives (including antioxidants) and the like.

The following are non-limiting practical examples of the process of the present invention, and are given for purposes of illustration only. All temperatures are given in ° C.

General remarks;

All solvents used were reagent grade in these examples, and were used without further purification with the following exceptions. Tetrahydrofuran was dewatered by distillation with sodium / potassium mixtures under a nitrogen atmosphere and used immediately. Toluene (PhCH ^) was distilled from CaH ₂ under nitrogen and stored over molecular sieves 3A. The chemicals used were reagent grade and were used without re-purification unless otherwise indicated. For the first substances listed, the full name and address of the supplier of reagents and chemicals is given. Then only the abbreviations are used.

Preparative high pressure liquid chromatography was carried out on a Waters Prep LC (System 500A) using two 500 grams SiO 2 silica gel unless otherwise noted. The SiO ₂ cartridges used for the purification contained silica gel for flash chromatography (E. Merck, silica gel 60, 230-400 mesh). A sintered glass funnel of appropriate volume was filled with approximately 3/4 of SiO2, tapping only on the outer wall of the funnel. A sample of the filter paper was then placed on the top surface of SiO ₂ and a solution of the substance to be cleaned was impregnated on the top surface. By gentle suction applied to the filter vessel, faster elution of the solvent through the cartridge can be achieved. It is also possible to combine fractions of different grain size and make further adjustments if desired.

Appropriate methods were used to perform elemental analyzes of the compounds of formula I prepared by the poem of the present invention. In the case where elemental analyzes have been performed, for intermediates or starting materials, the analyzed elements are referred to for example (C, Η, N) or (C, H, Cl), etc. In all the analyzes below the experimentally determined values are different from calculated values within + θ »4% ·

Preparation of the starting compounds

Example A

- chrysencarbaldehyde.

In a five-liter three-necked flask equipped with a mechanical overhead stirrer, a thermometer, a cooler and a nitrogen inlet, 100 grams of chrysene (equivalent to 0.438 moles) and o-dichlorobenzene of 2500 milliliters were charged. The liquid was then heated, the contents heated until large lumps of solid matter had dissolved (at 80 ° C), and then the liquid was quenched to give fine crystals. After further cooling with salt and ice to 5 ° C, tin tetrachloride SnCl ₄ (purity 98%, 228.2 g, 0.876 mol, 102.4 ml) was added in one portion. No temperature changes occurred during this treatment. The temperature of the flask was kept below 5 ° C while N, N-dichloromethyl methyl ether (70.48 g, 0.613 mol, 55.45 ml) was added dropwise over one hour. The resulting suspension was slowly warmed to 40 ° C over 4 hours and then stirred for 16 hours. During heating and at the initial stage of the reaction at 40 ° C, considerable evolution of HCl gas occurred. The reaction was then cooled to 10 ° C and hydrolyzed by carefully adding one liter of cold water. After four hours, the layers were separated, the organic layer was filtered, dried over anhydrous Na2SO4 (100 g) and filtered again. The clear yellow solution was then divided into two aliquots which were passed through a 50C gram silica gel cartridge by flash chromatography (silica gel 60, 230-400 mesh), using toluene as the elution solvent as a 500 mL fraction. In this way, unreacted chrysene (3 grams) was separated from the aldehyde and the more polar product. The aldehyde-containing fractions were combined and the toluene was centrifuged off. Crystals were formed during this process, and the crystals were periodically removed by filtration. After drying in a vacuum oven at 60 ° C, the final yield of 6-chrysocarbaldehyde was 89.46 grams (corresponding to 79.7%), the product having a melting point ranging from 167 to 19.6 ° C.

Example B

10-methylthio-9-arthracenecarbaldehyde.

In the procedure of this example, the method of V. Rogo11 vika et al., See Zh. Org., Khim. 3, 1315 (1959), as follows: 10-chloro-9-ananacenecarbaldehyde (28.0 mL) was charged to a 2-liter three-necked flask equipped with a stir bar, cooler, addition funnel, thermometer, nitrogen inlet, and bubbler. gram (equivalent to 0.116 mol) and DMF ⁱⁿ 1 liter. The solid dissolved as soon as the reaction mixture was heated to 60 ° C. The addition funnel was charged with a solution of sodium sulfide Na 2 S (28 grams, equivalent to 0.116 mol) in 30 mL of water. This solution was then rapidly added to the flask, accompanied by significant spraying of the solution to form a purple thiolate. The reaction mixture was stirred for 45 minutes at 65 ° C and then cooled to 30 ° C (using an ice bath). Methyl iodide CHgI (27.38 grams, equivalent to 0.193 moles) was added dropwise over 5 minutes. The color of the solution changed from dark purple to yellow after three hours. One liter of water was then added to the reaction mixture after 15 minutes. The yellow solid was collected by filtration, then dissolved in hot toluene (500 mL), dried over MgSO4, and finally filtered through Celite (Trade Mark). A larger volume of toluene was removed, and the resulting oil was stirred vigorously with 200 mL hexane to give a pale yellow solid. This material was dried at 50 ° C to give 10.04 g (86% yield) of 10-methylthio-9-anthracenecarbaldehyde, mp 98.5-99 ° C (H, S).

Example C

10- (2-chloroethyl) -9-anthracenecarbaldehyde.

The Vilsmeier method was used in the procedure of this example, see LFFieser, Org. Son. Coli., Vol., III, 98 (1955), starting with 9-vinylanthracene, from which 10- (2-chloroethyl) -9-anthracenecarbaldehyde was prepared with a melting point of 158-159 ° C (PhCH _3). (CH ₃ OH), (C, H, Cl).

Example D

1, 10-dichloro-9-anthracenecarbaldehyde; and 4, 10-dichloro-9-anthracenecarbaldehyde.

The procedure of VIRogovik et al., See Zh. Org. Khim. 3, 1315 (1967), starting from 1-chloroanthraquinone, to give a mixture of 10,10-dichloro-9-anthracenecarbaldehyde and 4,10-dichloro-9-anthracenecarbaldehyde. The compounds were separated by preparative liquid chromatography under high pressure, using toluene as eluent, to give 3.05 g (14% yield) of 10, 10-dichloro-9-anthracenecarbaldehyde, m.p. range of from 180.5 to 183 ° C (Rf = 0.64, Si0 _2, PhCHg), (C, H, C1) and 0.59 g (corresponding to a yield of 3%)

4.10-dichloro-9-anthracenecarbaldehyde, m.p. 167-170 ° C (Rp = 0.57, SiO ₂ , PhCH ₃ ), (C, H, Cl).

Example E 10-bromo-9-anthracenecarbaldehyde.

Prepared from 9,10-dibromantracene (20 grams, corresponding to 60 moles) using a modified method of R. Kuhn and H. Fischer, cf. Chem. Ber. 94, 3060 (1961). The mixture was cooled to -78 ° C, after which n-butyllithium nBuLi was added. The resulting reaction mixture was warmed to ambient temperature over one hour and then heated to reflux until all of the starting crystalline material had dissolved. The mixture was recooled to -78 ° C before dimathylformamide DMF was added as a single addition. The container volume was then

CS 273348 Q2 was allowed to warm to ambient temperature and was then quenched with 1M hydrogen bromide solution (200 mL). The biphasic system was extracted with CH 2 Cl 2 (3 x 500 mL). The extracts were combined, dried over MgSO 4, filtered, and the solvent was removed to give the crude material. This material was purified by preparative high pressure liquid chromatography using toluene as the eluting solvent.

After removal of the solvent, 13.05 g (75%) of 10-bromo-9-anthracenecarbaldehyde having a melting point of 215 to 216.5 ° C was obtained (melting point 218 ° C by P. Kuhn and H. Fischer, Chem., Ber. 94, 3050 (1961), (C, H, Br).

Example F

4,5-dichloro-9-anthracenecarbaldehyde.

The process was based on 1,8-dichloroanthracene prepared by the method of H.O. House et al. (see 3. Org. Chem. 38, 1167, 1973), which was further formulated according to the method of Example A (except that CH 2 Cl 2 was used as the reaction solvent) to yield 4,5-dichloro-3-anthracenecarbaldehyde, the melting point of which ranges from 218 to 220 ° C; PhCHg / CH3OH values and elemental analysis values (C, H, Cl) correspond to theory; the melting point value reported in the literature is &lt; 224-226 ° C, see 6.L. Stogryn, 3.Med, 17 , 563 (1974).

Example 1 G Formylation of fluoranthene.

In this example, fluoranthene (100 grams corresponding to 0.49 moles) was formulated as described in Example A except that CH 2 Cl 2 was used as the reaction solvent. The crude material obtained was passed through a 1000 g SiO 2 silica gel cartridge using toluene as the eluting solvent (3 L). The thus obtained fractions containing the aldehyde mixtures were combined and the solvent was removed, yielding 115 grams of a euro yellow oil. This raterial was dissolved in 500 mL of CH 2 Cl 2 and then diluted with hexane to a volume of one liter. This gave a yellow precipitate which was isolated by filtration. The fixed share it was. 3-fluoroanthene-carbaldehyde was crystallized from CH 2 Cl 2 / hexane / CH 2 Cl 2 / hexane and dried at 50 ° C to give 45.7 g of pure material. The obtained filtrate was added to the remaining unpurified material and the solvent was removed. The remaining material was chromatographed using a 1000 gram silica gel packed SiO, using PhCH ₃ toluene as eluent.

From this material were obtained by this procedure three aldehyde (including a plurality of 3-isomer) The total isolated yield of the compounds, their analysis and the characteristics of chromatographic analysis TLC (Si0g / PhCH ₃₎ of these aldehydes are listed as follows:

I. 3-fluoranthenkarbaldehyd: amount obtained 68.73 grams (51% yield), melting range from 103 to 104.5 ° C (R _f = 0.27, the values of elemental analysis / C, H / match theory, the literature reports a melting point of 98 to 99 ° C (see N. Campbell and NH Wilson, Chem. and Ind., 1114, 1970).

II. 7-fluoroanthenecarbaldehyde: 2.10 g (corresponding to 2% yield), mp 139-141 ° C, elemental analysis (C, H) consistent with theory, Rf = 0.38

III. 8-fluoroanthene carbaldehyde: 24.8 g (22% yield), mp 91.5-93 ° C, elemental analysis (C, H) consistent with theory, Rf = 0.19.

Example H

4-chloro-9-anthracenecarbaldehyde.

Starting from 1-chloroanthracene, which was prepared from 1-chloro-anthraquinone according to the method of H.O. House et al. (see 3.

Org. Chem. 38, 1167 (1973), the 1-chloroanthracene was formulated in the same manner as in Example A except that CH 2 Cl 2 was used as the reaction solvent to give 4-chloro-9-anthracenecarbaldehyde. Melting point of this product ranged from 129 to 131 ° C (PhCHg / CHgOH), elemental analysis values were consistent with theory (C, H, Cl).

Example I

10-methylsulfinyl-9-anthracenecarbaldehyde.

10-methylthio-9-anthracenecarbaldehyde (see Example B, 12.0 g, equivalent to 48 mmol) and 450 ml of dichloromethane CH were added to a 1 liter round bottom flask equipped with an addition funnel and stir bar. The resulting solution was then cooled to 5 ° C with an ice bath. A solution of 9.64 g of MCPBA (85%), equivalent to 48 mmol, in 350 ml of CH 2 Cl 2 was added dropwise over 1 hour. The reaction mixture was warmed to ambient temperature for one hour and washed with 5% sodium bicarbonate solution (2 x 500 mL), dried over sodium sulfate, filtered, concentrated to 500 ml and then passed through SiO2 (250 g) using 5 liters of toluene. The title compound was then eluted from SiO ₂ using EtOAc (2 L) as eluent. The volume of the solvent was then reduced to 100 ml and then filtered to 700 ml with hexane. The yellow solid was filtered and dried at 50 ° C to give 11.98 g (94% yield) of 10-methylsulfinyl-9-anthracenecarbaldehyde, m.p. Noc: 2 ° C. The results of elemental analysis (C, H, S) were consistent with the theory.

Example 3

2-triphenylcarbaldehyde.

In this example, the same molding procedure was used as in Example A except that the reaction temperature was 85 ° C, starting from triphenylene and the end product was 2-triphenylenecarbaldehyde with a melting point ranging from 160 to 161.5 Deň: 32 ° C. The values (CHgClg / CHgOH) and the values of elemental analysis (C, H) corresponded to theoretical values.

Example K

10-methoxy-9-anthracenecarbaldehyde.

According to this example, a 15-crown-5 in an amount of 25.89 grams, corresponding to 0.119 moles, of sodium methoxide NaOCHg in an amount of 7.62 grams, was placed in a 2-liter round-bottom flask equipped with a distillation head, a thermometer and a condenser. corresponding to 0.141 mol, and methanol in 50 ml. After 5 minutes, 10.4-chloro-9-anthracenecarbaldehyde (28.4 g, equivalent to 0.118 mol) and 900 ml of dry toluene were added to the clear colorless solution. Then, the solvent was distilled off at a head temperature of 108 ° C (evaporating solvent volume was 300 ml). A longer volume of dry toluene was then added, adjusting the total volume to one liter. The reaction mixture was heated at reflux for four hours, then cooled and poured onto a large SiO ₂ silica gel (1000 grams) in a sintered glass funnel. The crude product was chromatographed using toluene (5L) as eluent.

The 250 ml fractions containing the product were combined (total volume was about 3 liters) and then the solvent was reduced to 500 ml. The shiny gold crystals thus obtained were filtered off, and after drying at 50 DEG C., 15.6 g of material were collected. The volume of the filtrate was then reduced to 200 milliliters, the product dropped out of solution, filtered and washed to yield 6.1 grams of additional material. The two products were combined, yielding 22.51 g (81% yield) of 10-methoxy-9-anthracenecarbaldehyde, which material was used without further purification. The recrystalline was lured by analytically pure material, the melting point of which was in the range of 164.5 to 166.5 ° C. PhCHg value and analyzed values (C, H) corresponded to theoretical values. The melting point of 155 ° C is reported in the literature. 3.B. Conant and M, Bramann,

3. Amer. Chem _o Soc. 50, 2305 (1928).

Example L

10-formyl-9-anthracenecarbonitrile.

In a 25 milliliters round-bottomed flask equipped with a thermometer, a condenser, a duct, a bubbler, and a stir bar was added 5 grams of 10-chloro-9-anthraldehyde corresponding to 21 mmol. CuCN (2.14 g, 24 mmol), 100 ml of N-methylpyrrolidinone, DMF (15 ml) and 0.08 g of DMF (0.08 g) 0.01 mmol. The mixture was then heated to 170 ° C and stirred for 15 hours under a nitrogen atmosphere. After

1.5 hours the mixture became homogeneous. The reaction was cooled to 70 ° C and the reaction mixture was poured into a solution consisting of 16 grams of FeCl 3 · 6H ₂ O hexahydrate and 70 ml of 1.0 M hydrochloric acid in 400 ml of water. The resulting resulting mixture was stirred at 60-70 ° C for one hour, filtered and the crude orange solid collected. This material was dissolved in one liter of hot toluene and the solution was poured onto a small silica cartridge ₂ S10 (100 g). The filtrate was concentrated to milliliters with sweat and then diluted with hexane (200 mL). This gave an orange solid which was collected by filtration and dried to give 3.17 g (68% yield) of 10-formyl-9-anthecenecarbonitrile, m.p. Deň: 32 ° C. The values of elemental analysis (C, H, N) corresponded to the theory.

Example M

9,10,10-Dihydro-9,10-dioxo-1-anthracanecarboxylic acid.

In this example, the practice to benzanthrone (technical grade) was purified by chromatography, using silica gel Flattened S10 ₂ and toluene as the eluent (83% yield). The melting temperature ranged from 172 to

172.5 ° C (melting point in the literature ranges from 170 to 171 ° C, see 0. Bally and R. Shcoll, Ber. 44,1 1658 (1911)).

The purified benzanthrone (63.7 g, 0.277 mol) was dissolved in 15 ml of glacial acetic acid at 90 ° C and stirred with a mechanical stirrer. After cooling the solution to 80 [deg.] C., 200 grams of CrOg solid, corresponding to 2 moles, was added in the form of five-gram portions mixed at an interval of about 4 hours. The axothermic reaction was maintained at a temperature of about 80 ° C to release CO _2. After the evolution of carbon dioxide had ceased and the reaction temperature dropped, the heating mantle was reused and the reaction mixture was stirred for a period of time. overnight. Water (1.5 L) was added to the dark green solution. The reaction mixture was filtered to collect a dark brown solid, which was washed with 200 mL CH 2 OH methanol for 15 washes until the wash liquid was colorless. The soaked solid was redissolved in two liters of hot methoxyethanol and then filtered through Celite (trade name) to separate a solid black residue. The volume of the solution was then reduced to i1 75 ml (a solid solid formed) and the mixture was diluted with 100 ml of methanol CH 3 OH to give the product. It was filtered to give 32.0 g (46% yield) of the gold-brown 9,10-dihydro-9,10-dioxo-1-anthracenecarboxylic acid, the melting point of the product being ranging from 287 to 289 ° C. Values of elementary analysis; (C, H) corresponded to theory (melting point is in the range of 293 to 294 ° C according to literature, see Chemistry of Carbon Compound IXIb, ed. EH Rodd, 1419 (1956), Elsevier, New York).

1-anthracanecarboxylic acid.

In the preparation of this compound, 9, 10-dihydro-9,10-dioxo-1-anthracenecarboxylic acid (90 grams, equivalent to 0.357 mole) and zinc dust were charged into a five-liter three-necked flask equipped with a condenser, thermometer and stirrer built in above. 250 grams, corresponding to 3.82 moles, and CuSO4 pentahydrate. 5 g of 5 g, and a 28% NH4 OH solution of 2500 ml. The mixture thus prepared was slowly aabitaed and heating was continued until a dark red color of the solution appeared as the temperature reached 85 ° C. After 3.5 hours the solution became yellow. The reaction mixture was then heated for an additional 1 hour, then cooled and excess zinc was filtered off. The filter cake thus formed was washed with most of the ammonium hydroxide (100 ml) and then discarded. The filtrate was carefully acidified to pH 1 with concentrated hydrochloric acid which was added in small portions over one hour to give a light green precipitate which was collected by filtration. The solid was washed with water (200 mL) and recrystallized from methoxyethanol / water (with little hydrochloric acid), filtered, and dried at 75 ° C. The process yielded 65 grams (82%) of 1-anthracenecarboxylic acid with a melting point of 249-250 ° C. The values of elemental analysis (C, H) corresponded to theoretical values (melting point 245 ° C in the literature, see Chemistry of Carbon Compound XXXb, ed. EH Rodd, 1373, 1956, Elsevier / New York), (l-enthryl) methanol.

In a 500 milliliter two-necked flask equipped with a condenser, an addition funnel and nitrogen inlet, and a stirring rod, 1-anthracene carboxylic acid (6.888 g, 31 mmol) was charged, and dry tetrahydrofuran THF (250 mL). A 1M solution of boron hydride BH ₃ in tetrahydrofuran (50 mL, equivalent to 50 mmol) was prepared via a funnel via tube. The boron hydride solution was added at one hour interval and the solution was stirred overnight at ambient temperature. Methanol (CH 2 OH) was then added and the addition was continued until hydrogen evolution ceased. Water (5 ml) was added to the flask, followed by 5 ml of 1N hydrochloric acid. The solvents were then removed. The solid was recrystallized from ethyl acetate-hexane to give 4.5 g (67% yield) of (1-anthryl) -methanol, mp 124-125 ° C. C. The elemental analysis (C, H) values corresponded to theoretical values, the melting point value reported in the literature being in the range from 124 ° C to 125 ° C, see FIG. S. Akiyma et al

Bull

Chem, Soc. 35 1962

1- anthracene carbaldehyde.

In the preparation of this compound proceeded so » 'ae into a two liter round bottom flask," which was equipped with a condenser and magnetic stirrer, was added ¹ (1-anthryl) methanol in an amount of 21.0 g, equivalent to 0.10 mol, dichloromethane CH 2 Cl 2 at 1200 ml; and pyridine chlorochromate PCC at 32.33 g, corresponding to 0.15 mol. The mixture was then heated under reflux for 5 hours. The reaction mixture was cooled and then filtered through a silica gel cartridge (400 grams) using toluene as the elution solvent. The solution was concentrated to give 16 g of crude product. The material was purified using a high pressure liquid chromatography method using toluene as the eluent. The solvent was removed and the pure material was recrystallized from toluene-hexane to give 14.0 g (67% yield) of 1-anthracene-carbaldehyde. T _e mperature point of this product ae is in the range from 130 to 131.5 ° C, and in the literature cited melting points in the range of 126.5 to 127.5 ° C, viz. PH, Gore O, Chem, Soc. 1616, ^1, 1959,

Example N (10-bromo-1-anthryl) methanol.

According to this example, 10-bromo-1-anthracenecarboxylic acid was prepared from 1-anthracenecarboxylic acid (see Example M) according to the method of E. Bartnett,

3.W, Cook and H, H, Grainger, 'see. Ber. 57 B, 1775 (1924), 'reduced using a hydride of boron BHG in tetrahydrofuran as described in 18C · was treated to afford (Lo-bromo-l-anthryl) methanol with a melting point ranging from 125 to 127 ° C ₀ EtOAc / hexane values and elemental analysis values. (C, H, Br) correspond to theoretical values,

10-bromo-1-anthracenecarbaldehyde,

The same procedure was followed as in Example M, oxidizing (10-bromo-1-anthryl) methanol with pyridine chlorochroman PCC to give 10-bromo-1-anthracenecarbaldshyd melting at 134.5-135.5 ° C. C, PhCHg (hexane) and elemental analysis (C, H, Br) values corresponded to theoretical values.

Example O

2-chloro-9-anthracenecarbaldehyde and 3-chloro-9-anthracenecarbaldehyde,

In the procedure of this example, 2-chloroanthracene was prepared from 2-chloroanthraquinone by the method of H.O.House et al. (See 3. Org. Chem, 38,

1167, 1973), formulated in the same manner. As described in Example A, except that CH 2 Cl 2 was used as the reaction solvent in this case,

A 4: 1 mixture of 2-chloro-9-anthracenecarbaldehyde and 3-chloro-9-anthracenecarbaldehyde (87% yield) was obtained. Trituration of this material with methanol preferably crystallized 2-chloro-8-anthracenecarbaldehyde, from which, after further crystallization from toluene / hexane, a pure 2-chloro isomer was obtained with a melting point of 149-150 ° C. The values for elemental analysis (C, H, Cl) corresponded to theoretical values (melting point ranges from 148 to 150 ° C in the literature, see United Kingdom Patent No. 1,149,557). The filtrate obtained from said CH 3 OH-trituration ( R (0.48, silica, SiO ₂ , toluene (CH ₂ )) was further purified by preparative high pressure liquid chromatography to give pure 3-chloro-9-anthraldehyde, m.p. Mp 122-123.5 ° C. Values PhCHg / haxan values and elemental analysis / C, H, Cl / correspond to the theoretical values (R _f 0.48, N, 'Si0 ₂ · PhCHg /,

CS 273348 82

Example P 10-ethylthio-9-anthracenecarbaldehyde.

The procedure of Example B was followed using 10-chloro-9-anthracenecarbaldehyde and ethyl iodide to give an oily product which, after solidification, yielded 10-ethylthio-9-anthracenecarbaldehyde, m.p. from 74 to 75? 5 ° C · Elemental analysis values (C, H, S) corresponded to theoretical values.

Example Q

10 - ((2-hydroxyethyl) thio) -9-anthracenecarbaldehyde.

The procedure of Example B was followed except that the alkylation reaction was carried out for one hour at 65 ° C, with 10-chloro-9-anthracenecarbaldehyde and 2-iodoethanol. prepared 10 - ((2-hydroxysthyl) thio) -9-anthracenecarbaldshyd. The melting point of this product was in the range of 103 to 104 ° C. The values of PhCHg / hexane and values of elemental analysis / Ο, Ή, δ / corresponded to theoretical values.

Example R

2,10-dichloroanthracenecarbaldehyde and 3,10-dichloro-9-anthracenecarbaldehyde.

In the process of this embodiment by the method of _O VI Rogovika et al. (cf. Zh. Org. Khim. 3, 1315, 1967), starting from 2-chloroentrachinone, and in this way a mixture (in a ratio of about 1 to 1) of 2,10-dichloroantracenecarbaldehyde and 3,10-dichloroantracenecarbaldshyde ( 68% yield). This laugh was then split? using a preparative high-pressure liquid chromatography method employing an aspiration-recycle technique to yield 2,10-dichloro-9-anthracenescarbaldehyde, m.p.

175.5 to 176.5 ° C (values (PhCH 2)) and elemental analysis values (C, H, Cl) corresponded to theoretical values, and 3,10-dichloro-9-anthracenecarbaldehyde, melting point in the range of 173.5 to 176.5 ° C. 175 ° C (PhCHg values and elemental analysis values (C, H, Cl) corresponded to theoretical values). The untreated residue of the above mixture was used as a mixture of the above compounds for further purposes.

Example S

10-ethoxy-9-ananecarboxaldehyde.

The procedure of Example K was followed except that sodium methoxide and NaOCHg / CHgOH were replaced by sodium ethoxide NeOEt and ethanol, starting from 10-chloro-9. 10-sthoxy-9-anthracenecarbaldehyde having a melting point of 88-90 ° C (CH 2 Cl 2 / hexane, elemental analysis (C, H) as in the formula).

Example T

10- (2-hydroxyethyloxy) -9-anthracenecarbaldehyde.

According to this embodiment, a three-liter, two-necked vessel was fitted with a thermometer? cooler, ⁴ stir bar and nitrogen inlet, and bubbler were inserted into the vessel. 25 g of potassium butylate corresponding to 0 (22 moles), 1500 ml of athylene glycol and 50 g of 10-chloro-9-anthraldehyde, corresponding to 0.077 moles, and the mixture was stirred at 100 ° C. Then, 5 grams (equivalent to 45 mmol) of potassium tert-butylate was added and stirring was continued for a further 0.5 hours, the reaction mixture was cooled and then poured into 1500 ml of cold water. The yellow solid was dissolved in one liter of CH ₂ Cl ₂ and passed through a 100 g eilicagal cartridge (CH ₂ Cl ₂ o), followed by stirring for 10 minutes. This dichloromethane was removed and the desired material was eluted with 12 L EtOAc / EtOAc. were combined and the solvent removed to give, after drying at 50 ° C, 10- (2-hydroxyethyloxy) -9-anthracenecarbaldehyde in an amount of 28.82 g (53% yield), m.p. from 142 to 144 ° C (CH 2 Cl 2 / hexane, elemental analysis (C, H) was consistent with the compound).

EXAMPLE U 10-Methylsulfonyl-9-anthracanecarbaldehyde.

10-methylthio-9-anthracenecarbaldehyde (4.50 g, 17/83 mmol) was dissolved in CH ₂ Cl ₂ (100 mL) and cooled to 0 °. C with the help of an ice bath.

This solution was stirred with a magnetic stirrer, then a solution of m-chloroperbenzoic acid (technical grade, purity 85 amount of 7.08 grams, corresponding to 35/76 mmol) in 250 ml of dichloromethane CH ₂ was added dropwise over 15 minutes. C1 ₂ «the ice bath was removed and the clear solution was stirred for 2 hours. The solution was washed successively with 10% NagSgOg (500 mL) and saturated Na ₂ CO ₃ (2 x 100 mL).

The solvent was removed and the crude material was passed through a small volume (200 ml) silica gel in a sintered glass funnel using CH ₂ Cl ₂ as eluent (500 ml). The solvent was removed, giving rise to a euro / product which was rekrystalovón from dichloromethane and ethanol, CH ₂ Cl ₂ / EtOH and was treated to afford 9-10me.thylsulfonyl antracankarbaldehyd melting point ranging from 215-217 ° C (value elemental analyzes (C / H / S) corresponded to the indicated compound).

AND

ExampleV

10- (2-methoxyethoxy) -9-anthracenecarbaldehyde.

According to this example, the target was. potassium butylate KOtBu at 8/2 grams corresponding to 0.162 moles in 1000 ml of methoxyethanol (treated with 10-chloro-9-orthraldehyde at 25 grams) corresponding to 0/104 moles and this mixture was then heated at reflux temperature for 2 hours. The cooled reaction mixture was then diluted with water (5 L) and the oily matter was stirred for 2 hours until the product solidified. The filtered solid was chromatographed using 500 g of SiO ₂ silica gel and CH 2 Cl 2 as eluent. 26.9 g (92% yield) of 10- (2-methoxyethoxy) -8-anthracenecarboxaldehyde, m.p. 87 DEG-88 DEG C. (elemental analysis / Cl, N), were obtained. (corresponding to the above compound, CHCl2 / hexane / Rf &gt; 0.16, SiO2 ₎ ,

CH ₂ Cl ₂ ) ·

Example W

10-mo rfolin-9-an t-racencarbaldehyde ·

10-chloro-9-anthracanecarboxaldehyde (25 grams, equivalent to 0.104 mol / mol morpholine (technical grade), 500 ml) was heated at 55 ° C under nitrogen for 17 hours. The reaction mixture was then poured into 2 L of water. The precipitate / was filtered off and then chromatographed on silica gel packed Si0 ₂ in an amount of 1 kilogram, using toluene in an amount of 4 liters, as the initial eluting solvent to remove starting material and byproducts. The orange layer of product was eluted with CH 2 Cl 2 (CH 2 Cl 2) to give 10.58 g (35% yield) of 10-morpholine-9-anthracenecarboxaldehyde, mp 182-184 ° C, softening 175 ° C (the values of elemental analysis (CHN) correspond to said compound; system Rf «0.16, SiO _2, CH ₂ or _{the second}

Example X

12-chloro-6-chryanecarbaldehyde.

In this example, 6-chloro-chrysene (70 grams, corresponding to 0.265 moles) was formulated in the same manner as in Example IA, except that CH ₂ Cl ₂ was used at 2500 milliliters as the reaction solvent. The product was chromatographed on SiO _2, 1 kg, eluting with ethyl acetate to give 19.1 g (25% yield) of 12-chloro-6. - chrysocarbaldahyd at a melting point of 255 to 257 ° C; (EtOAc system, R f 0.42, SiO 2, toluene).

Example Y 10- (imidazol-1-yl) -9-anthracenecarbaldehyde.

A solution of 10-chloro-9-anthaldehyde of 15 grams corresponding to 0.062 moles, imidazole of 10.2 grams corresponding to 0.15 moles and DMF of 300 milliliters was treated at 55 ° C. ° C target with 7.9 g of KtB butyl acetate, equivalent to 0.07 mol, and then stirred for 30 minutes. The reaction mixture was poured into 0.1 M sodium hydroxide solution (1500 ml). This gave a precipitate which was filtered off and then chromatographed on cartridge 8ilikagelu SiO ₂ 500 g, using dichloromethane _CH2 & ₂ with a volume of three liters as the initial eluting solvent to remove starting material and byproducts * The yellow product was eluted with EtOAc (2 L) to give 12.99 g (73% yield) of 10- (imidazol-1-yl) -9-anthracenecarbaldehyde at a temperature of 12%. mp 194-196 ° C; (elemental analysis values (C, H, N) were consistent with the indicated compound; EtOAc systems, Rf 0.38 / SiO ₂ , EtOAc) ·

Example Z 2-ethylanthracene.

A 5-liter three-necked flask was equipped with a condenser, thermometer, and stirrer built in from above, containing 2-ethylanthraquinone of 120 grams corresponding to 0.51 mole, zinc dust in 300 grams, corresponding to 4.59 moles, calcium sulfate pentahydrate CaSO4. 5 g of 3 g, and 28% ammonium hydroxide solution of 2800 ml. The temperature of the mixture was then raised until the initial dark red color was changed (interval about 5 hours). The reaction mixture was then filtered. The filtrate was extracted with ethyl acetate, and the solid zinc was also extracted with ethyl acetate. The ethyl acetate solutions were combined and the solvent was removed. The residue thus obtained was heated to reflux with a mixture of concentrated hydrochloric acid (10 ml) and n-propanol (1200 ml) for two hours. After cooling, a solid precipitate was obtained, which was filtered and washed with absolute ethanol (100 ml) and then dried to give 40 g (38% yield) of 2-athylantracene. The values of melting temperature and elemental analysis (c, H) correspond to theory.

2-ethylantracene-9-carbaldehyde and 3-ethylantracene-9-carbaldehyde. ·

The 2-ethylaotracene was 40 grams, corresponding

0.194 moles were formulated in the same manner as in Example A except that CH ₂ Cl ₂ was used as the reaction solvent in an amount of 500 ml. The product was chromatographed using SiO 2 on silica gel and toluene PhCHg eluting with 43.68 g (96% yield) of a 2-ethylenedracone-9-kerbaldehyde and 3 mixture. -othylantracon-9-carbaldehyde.

ExampleAA

3,5-Diphenyl-7α (ZH) -ethoxymethyl-1H, 3H, 5H-oxazole 23,4-C7-oxazole ·

In this example, a 60% dispersion of sodium hydride in mineral oil (34.0 grams corresponding to 0.86 mole) was first mechanically stirred, then washed with dry hexane to remove the oil, and then suspended in dry DMF (300 mL). To this mixture was added a solution of 3,5-diphenyl-1H, 3H, 5H-oxazole, 7-oxazole-7α (7H) -methanol, at a rate of 0.72, corresponding to 0.7 mole, prepared according to the procedure of O.Pierce et al, see OACS 73 2595, 1951, in 300 ml of dry dlmethylformamide OMF, the reaction mixture being maintained at a temperature of 30 to 35 ° C. The salt suspension was then stirred at ambient temperature for 60 minutes, then diluted with 200 mL dry dimethylformamide pMF to facilitate stirring, then cooled and treated with ethyl iodide (in excess) to maintain the reaction temperature at room temperature. rozmez! from 20 to 35 ° C. The mixture was stirred at ambient temperature for 2 hours and then carefully treated with 30 ml of absolute ethanol. The resulting mixture was diluted with Et2O (2.5 L) and the solid was filtered off. The solvent was then removed using a rotary evaporator to attract 229.5 grams of a yellow oil containing both the starting material and the desired product. Thereafter, a solution of the oil in chloroform was emitted with 200 g of SiO2 and the solvent was removed. The resulting solid was then placed in a silica gel column ₂ S10 (800 g). Elution with EtOAc / hexane ethyl acetate / hexane (1: 3.5) gave 139.7 g (61.3% yield) of 3,5-diphanyl-7α (7H) -ethoxymethyl-1H, 3H. 5H-oxazole / -3,4-c-oxazole. The analytical sample was attracted by recrystallization from hexane. The melting point of the product thus obtained was in the range of 83.5 ° C to 85 ° C, the elemental analysis values (C, H, N) corresponding to the compound. All of the material so obtained was used without further purification.

!

2-Amino-2-ethoxymethoxy-1,3-propanediol hydrochloride 1/4 HgO.

3,5-Diphenyl-7α (7H) -ethoxymethyl-1H, 3H, 5H-oxazole-3,4-c-oxazole, 136 g, corresponding to 0.42 mole, was dissolved in 6N hydrochloric acid (400 ml), and the resulting solution was stirred for 1.5 hours at ambient temperature. After extraction with diethyl ether (2 x 200 mL) to remove benzaldehyde, the aqueous solution was concentrated on a rotary evaporator to give a colorless oil. The product was then cooled in an ice bath to remove crystals and facilitate crystallization. This gave a solid podium which was diluted with β cold CH 2 CN, then filtered, washed with diethyl ether and dried in a vacuum oven at ambient temperature to give 71 grams (89% yield) of 2-amino- 2-ethoxymethyl-1,3-propanediol in the form of the hydrochloride. 1/4 H ₂ 0. M.P. e product obtained ranged from 78 to 79 ° C, the values of elemental analysis corresponded /CHCl.N/ compound.

.EN 273348 82 p

Example AB

4- [3- (3-hydroxyethyl) -3-biphenyl-1-oxaeplro] (4.0) decene;

In this example, the solution of 2-amino-2-methyl-1,3-propanediol was in an amount

303.4 g, corresponding to 3.0 mol, based on cyclohoxanone at 294.5 g, corresponding to 3.0 mol, and toluene PhCHg at 400 ml, heated at reflux for about 2 hours with the isotropic removal of water. After cooling, the stage crystallized from toluene, which ^! it was recrystallized twice from hexane to give 444.4 grams of 4-aza-3-hydroxymethyl-3-1-oxaepiro [4.5] decane (corresponding to 80% yield), the temperature of this product being in the range of from 52 to 54 ° C, the elemental analysis (C, H, N) was consistent with the indicated compound.

sodium hydride NaH in mineral oil at 75 grams corresponding to 1.9 moles, and the stirring was performed mechanically and the mixture was washed with dry huxan to remove the oil and then suspended in dry DMF (200 ml). A solution of 4-aza-3-hydroxymethyl-3-methyl-1-oxaapiro [4.5] decane in an amount of 27.8 grams, corresponding to 1.5 moles, in dry dimetbylformamide OMF was then added. 200 ml while maintaining the temperature of the reaction mixture at 30 to 35 ° C. Subsequently, small amounts of dimethylformamide OMF, only necessary to facilitate stirring, were added. The mixture was stirred at ambient temperature for 1.5 hours, then cooled and treated with methyl iodide (234.2 grams, 102.7 mL) corresponding to 1.65 moles, maintaining the annual temperature between 20 and 30 ° C. The mixture was stirred for 2 hours at ambient temperature and then slowly treated with absolute ethanol (40 ml) and finally diluted with dry Et2O diethyl ether (3 L). The reaction mixture was filtered and the solvent removed on a rotary evaporator. The residue was fractionally distilled to give 209.7 g (70.3% yield) of 4-aza-3-methoxymethyl-3-methyl- 1-oxaepiro (4,5) decane as a colorless liquid boiling at 114 ° C / 14 mm; values of elemental analysis corresponded to the mentioned compound,

AND

2-Amino-3-methoxy-2-methyl-1-propanol. A solution of 4-aza-3-methoxy-methyl-3-methyl-1-oxapiro (4,5) decane was 299 grams. equivalent to 1.5 mol, and 500 ml of 6H hydrochloric acid, heated at reflux for 60 minutes. After cooling, they formed two layers, the upper layer containing cyclohexanone and was removed by extraction with EtgO diethyl ether (2 x 400 ml). The lower aqueous layer was concentrated on a rotary evaporator to give a eirup mass, which was then treated with 50% sodium hydroxide, which was used in excess. The resulting slurry was extracted with diethyl ether / EtOH / CH 2 Cl 2 (4 x 500 mL), then again with CH 2 Cl 2 (500 mL). The solvent was removed on a rotary evaporator to give 198 g of a light oil. Fractional distillation of this oil gave 166 g (93% yield) of 2-amino-3-methoxymethyl-1-propanol as a colorless oil. The boiling point of the product thus obtained was 94 [deg.] C. (17 mm &lt; 3 &gt;).

This compound was prepared by the method of F. Lichtenthaler (see Ber, 96,

851, 1963), the melting point of the thus prepared product ee being in the range from 175 to 177 ° Cj.

dř

CS 273340 82, melting point ranges from 175 to 177 ° C, F. Lichtenthaler, Ber.

96, 851 (1963).

Example AD (k

2-Isopropyl-2-nitro-1,3-propondiol

A solution of 2-methyl-1-nitropropane in an amount of 38.7 grams, corresponding to 0.375 mole, was prepared according to the procedure of N. Kornblum, B. Tunge and H. Ungnad, cf. 3. Am. Chám. Soc., 1954, 7, 3029, and longer N? ₃ in an amount of 3.79 grams, corresponding to 0.0375 mol, in 50 mL methanol, added dropwise to a 37% aqueous formaldehyde solution 76.2 g, corresponding to 0.938 moles, at a rate such that the temperature of the reaction mixture did not exceed 30 DEG C. After 72 hours, the solution was concentrated using larger amounts and the residue was dissolved in 250 ml of water. This solution was then continuously extracted for 1 hour with CH 1 Cl 2 dichloromethane.

The dichloromethane solution was dried over MgSO4, filtered, and concentrated to give 53.3 g of 2-isopropyl-2-nitro-1,3-propanediol as a white off-white solid (yield). 87%). The melting point of the entrapped product ee was in the range of 67-72 ° C (melting point in the literature is in the range of 87-88 ° C, see, 8M Vanderbilt and HB Haas, Ind. Eng. Chem. 32, 34, 1940). In our experience, this process failed to attempt to prepare the desired compound.

»> ·

2-Amino-2-isopropyl-1,3-propanediol acetate.

The same procedure was used as in Example AM, starting from 2-isopropyl-2-nitro-1,3-propondiol, resulting in 2-amino-2-isopropyl-1-acetate. 3-propanediol, which was obtained with a yield of 98%, the melting point of this product α being in the range of 155 to 155.5 ° C (synthesis of this compound as the free base is reported by HS Broadbent et al, in 3. Hetorocyolic Chom 13, 337 (1975)), the melting point of this compound being in the range of from 70 to 72 ° C.

F

Example AE Ethyl N-banzylidene-L-alaninate.

In this exemplary embodiment, N-benzylldan-L-alaninate and ethyl were prepared according to the general method of S. Sarkka et al., Set forth in Org. Chem. 41, 249 (1976), the boiling point of this compound ranged from 98-100 ° C (0.4 mm), the literature cited b.p. 100 ₄ ° C (0.3 mm), see Fig. A * Calcayai et al., Syntheals 445, 1981.

2- (2-iodoethoxy) tetrahydro-2H-pyran.

In this embodiment, freshly distilled dihydropyrene (59.0 grams, equivalent to 0.7 mol) was added dropwise to a cooled solution of iodoethanol (98 grams, equivalent to 0.57 mol) in a 1 liter EtgO diethyl ether containing 0.1 g of p-toluenesulfonic acid. The solution was stirred for 1 hour at 5 ° C. Solid K2CO3 (5 g) was added to the reaction mixture, and the suspension was stirred for an additional hour at ambient temperature. The reaction mixture was filtered and the separated solids were washed with 1 L of Et 2 O. The organic solutions were combined and concentrated on a rotary evaporator (in a vessel washed with 1% NET 4 in water). The thus obtained crude 2- (2-iodathoxy) tetrahydro-2H-pyran in an amount of 100 grams (corresponding to a yield of 68.9%) was used without further purification.

. AM

Λ »

Ethyl 2-benzylideneamino-2-methyl-4- (tetrahydro-2H-pyran-2-yl) oxybutyrate.

First, lithium diisopropylamide solution * was prepared by dropwise addition of n-butyllithium n-BuLi (1.6 M in hexane, 228 mL, equivalent to 0.365 mol) to the solution of diisopropylamine in an amount of

51.6 grn, corresponding to 0.51 mol, in a mixture of 700 ml dry tetrahydrofuran THF and 40 ml dry HMPa while maintaining the temperature at 30-40 ° C. The solution was cooled to a solution of -70 ° C, and to this solution was added dropwise a solution of ethyl N-benzylidene-L-alaninate (74.9 grams, equivalent to 0.365 moles), allowing the reaction mixture to warm to -20 ° C over a period of time. a few minutes * The red digest obtained in this way was cooled to -70 C

In a further procedure, 2- (2-iodoethoxy) -tetrohydro-2H-pyrrone (98.1 g, equivalent to 0.383 mol) was then added to the solution prepared as described above at a rate such that the temperature in the reaction mixture did not exceed -55 ° C. The solution was allowed to warm slowly to ambient temperature and stirred for 14 hours. The volume was then reduced to 300 ml with a stream of dry nitrogen over a few hours to facilitate the final work-up. sodium chloride solution (800 ml) and diluted with EtgO diethyl ether to order 800 ml. The diethyl ether was then removed and the aqueous layer was extracted with 500 mL hexane. The diethyl ether and hexane layers thus obtained were then combined and dried over Na ₂ SO ₄ . The solution was filtered and the solvent removed to give 124 grams of a crude red oil. Distillation of the flask into the flask (glass flask were washed with 1% aqueous NETGEM --N) at a bath temperature of 210 ° C and 0.3 mm, attracted by 95 g of ethyl ^2-f bonzyli denamtno-2-methyl-4 - (/ tetrahydro-2H-pyran-2-yl / oxy) butyrate, which was then homogeneous in pc and the product showed acceptable NMR and mass spectrum values. The product was stored under nitrogen in a freezer and used without further purification.

Ethyl 2-benzylideneamino-2-methyl-4- ((tetrahydro-2H-pyran-2-yl) oxy) butyrate.

A solution of ethyl 2-benzylideneamino-2-methyl-4- ((tetrahydro-2H-pyran-2-yl) oxy) butyrate in an amount of 100.0 grams, corresponding to 0.03 moles, in THF tetrahydrofuran was added. 100 milliliters was slowly added to the 22.77 g of lithium aluminum hydride slurry, equivalent to 0.6 mole, which was rapidly stirred in dry 1 L tetrahydrofuran, maintaining the rate of addition to maintain a slight reflux. After the addition was complete, the mixture was heated to reflux for 4 hours. The reaction mixture was cooled and treated successively with water (23 ml), 15 N sodium hydroxide solution (23 ml) and again with water (45 ml). A solid podium was formed which was collected by filtration and then washed with THF (200 mL). The organic layers were combined and concentrated on a rotary evaporator to give ethyl 2-benzylideneamino-2-methyl-4w ((tetrahydro-2H-pyran-2-yl) oxy) butyrate at 81.1 g. corresponding to a yield of 92.0% and this product was in the form of a thick oil which was used for further purification purposes.

r,

2-Benzylamino-2-methyl-1,4-butanediol. In this preparation, the crude ethyl 2-benzylideneamino-2-rotliyl-4 - ((t-trihydro-2H-pyran-2-yl)) oxy) butyrate in an amount of 80/1 grams, corresponding to 0.273 moles, was dissolved in 3 ml of 120 ml hydrochloric acid.

After three minutes, the mixture was washed with Et 2 O (200 mL). The resulting aqueous solution was concentrated using a rotary evaporator to give a thick oil which was cooled and basified with an excess of 50% sodium hydroxide. The oily amine thus formed was extracted with Et2O (3 x 200 mL) and the combined ethyl ether extracts were combined to give 63.6 g of a thick oil. Distillation yielded 49.8 g (94% yield) of 2-benzylamino-2-methyl-1,4-butanediol as a light yellow oil. The heat of the filament thus ee ranged from 160 to 170 ° C at 0.35 mm. The elemental analysis values (C, H, N) corresponded to the compound,

2-omino-2-methyl-1,4-butondiol in the hydrochloride form.

In the preparation of this compound, 2-benzylamino-2-methyl-1,4-butylene was added in an amount of

31.08 g (0.149 mol) dissolved in 95% ethanol (240 ml) containing 21 ml concentrated hydrochloric acid (0.125 mol) and 5% palladium on charcoal (10 ml). 1.0 grams, followed by reduction in a Parr apparatus at 0.275 MPa for 37 hours at ambient temperature. The catalyst was removed by filtration and the solvent was removed on a rotary evaporator (60 ° C bath) to scare 20.91 grams of 2-amino-2-methyl-1,4-butanediol hydrochloride. (yield: 90.2%) and was a clear, thick, colorless oil with acceptable NMR and mass spectra. This product was used without further purification. This compound is reported in the form of its acetate salt (see, G, Cardillo et al., Chem * Comm, 1308, 1982), but no values are given for this compound.

Example AF

10-chloroanthracan-1-carboxylic acid.

1-anthroleic acid, 24 grams corresponding to 0.108 moles, was treated with 24 grams corresponding to 0.18 moles, N-chloro-succinimidamide, in N-methylpyrrolidinone, and the mixture was heated under a nitrogen atmosphere at 90 ° C. ° C for 1.5 hours. The soaked reaction mixture was diluted with 3.5 liters of water, filtered, dried and the precipitate obtained was recrystallized from ethyl acetate EtOA _c to yield 16.41 g (59% yield) of 10-chloroantracanil. The melting point of this product was in the range of 257 DEG to 277 DEG C. and the elemental analysis values (C, H, C1) corresponded to the compound.

10-Chloroanthracene-1-carboxylate-stearate.

The compound was prepared by adding 10-chloroantrecene-1-carboxylic acid at 17.3 grams, corresponding to 0.0674 moles, longer concentrated sulfuric acid at 1.0 milliliters, and absolute ethanol at a rate of 1.0 ml. 500 milliliters were heated together under reflux for 3 days using 488 Soxhlet extractors to remove water. The solvent was then removed and partitioned between EtOAc / EtOAc and saturated sodium bicarbonate. The solvent was removed from the organic layer to give 14.86 g (77%) of ethyl 10-chloro-anthracene-1-carboxylate, which was used without further purification.

10-chloro-1-anthracenemethanol,

For the preparation of the above compound ss, starting from a solution of 10-chloroantracsin-1-carboxylate of ethylnose in an amount. 14.86 g, 0.052 mol in tetrahydrofuran is THF množetvi 300 ml, the solution was treated with lithium borohydride _LiBH4 1.14 The quantities in grams, \ corresponds 0.052 mol, and heated under reflux for 16 hours . The reaction mixture was poured into ice

CS 273348 82 water and acidified to pH 2 with hydrochloric acid. This gave a solid pod which was filtered, washed with water (500 ml), dried and finally chromatographed on a SiO ₂ silica gel (500 g), ethyl acetate of EtOAc as eluent. The used solvent was removed on a rotary evaporator, yielding a solid which was crystallized from carbon tetrachloride Cl _4, wherein in this embodiment, yielding 10.3 grams (yield 81% strength) of 10-chloro-l- anthracenemethanol having a melting point of 138-140 ° C for the elemental analysis / C,

H, Cl) corresponding to said compound,

10-chloroanthracene-1-carbaldehyde

8.8 g (0.036 mole) of 10-chloro-1-entracenemethanol was dissolved in 200 ml of CH ₂ Cl ₂ , and then treated with BaMnO 2 at 15 g, corresponds to 0.059 moles, which was carried out for 3 days and then rapidly refluxed. The reaction mixture was filtered and the filtrate was worked up to dryness. The residue was chromatographed, using preparative liquid chromatography conducted under pressure vyeokého PhCHg using toluene as an elution solvent, ¹ an eluent to give 6.0 grams (69% yield) of slightly impure 10-chloro- anthracene-1-carboxaldehyde, which was then used for further purposes without further purification.

Example 1 AG

3-nitro-2,4-pentadiol.

The solution of nitromethane (73.3 grams, corresponding to 1.2 moles) and acetaldehyde (158.6 grams, corresponding to 3.6 moles) was cooled in an ice bath. 80 ml of water and 0.40 g of calcium hydroxide were then added to the flask. The mixture was stirred under nitrogen for 8 hours, then neutralized with carbon dioxide and filtered. The filtrate was extracted continuously with CH ₂ O ₂ in one liter for 6 hours. The dichloromethane extract was concentrated in vacuo to give 114.6 g (77% yield) of crude 3-nitro-2,4-pentanediol as a pale yellow syrup. This material was unstable and was used for other purposes without further purification. The synthesis and isolation of this product as a raw material is also reported by Z. Eckstein and T. Urbanskira, cf. Roczniki Chem. 26, 571 (1952).

(2H ([eta] &lt; 4 &gt;-( 5C, 6C)) -4,6-dimethyl-5-nitro-2-phenyl-1,3-dioxane.

A solution of the crude mixture of 3-nitro-2,4-pentanedioles of 115 grams, corresponding to 0.77 moles prepared by the above process, and benzoldohydride of 81.7 grams, corresponding to 0.77 mole, and 1.28 grams of p-toluene sulfonic acid in 400 ml of benzene, heated at reflux for 1.5 hours with azeotropic removal of water. Removal of the solvent under vacuum gave a crude product (i.e. a complex emesis) which was dissolved in absolute ethanol at 150 ml. After keeping the mixture at ambient temperature for 36 hours, a portion of the crystals was collected and dried to give 25.8 g of 5: 1 (NMR) of the desired product and further isomer is elemental. analysis (C, H, N) was consistent with theory. Pure 2 &lt; 6.4 < 6.5 < 6 &gt; -6,6-4,6-dimethyl-5-nitro-2-phenyl-1,3-dioxane was obtained after recrystallization from absolute ethanol, the melting point of the product thus obtained. and ranged from 117.5 to 118 ° C; elemental analysis values (C, 1 H, N) were consistent with the indicated compound.

EN '273348 82

Meso-3-amino-2,4-pentanediol acetate.

The preparation of this compound was carried out from (2, 4, 6, 5, 6, 6, 4) -4,6-dimethyl-5-nitro-2-phenyl-1,3-dioxane in the same manner as in the Example. The reaction mixture was recrystallized from 95% ethanol, the meso-3-emino-2,4-pontanediol acetate having a melting point ranging from 100% ethanol. 108.5 to 109.5 ° Cj values of elemental analysis (C, H, N) corresponded to the mentioned material ·

Example AH

12-Oethyl-6-chryeencarbaldehyde ·

According to this example, 6-ethylchryeen (60 grams, corresponding to 0.234 moles) was formulated according to the procedure described in Example A, except that CH ₂ Cl ₂ was used as the reaction solvent in an amount of 1000 ml. The crude material was chromatographed on a 1 kg SiOg silica gel to give 50.38 g (70% yield) of 12-ethyl-6-ohryeenecarbaldehyde, m.p. from 138 to 139 ° C, elemental analysis (C, H) was consistent with the title compound.

Example AX

10- (imidazol-1-yl) -9-anthracanecarbaldehyde.

A 10-chloro-9-anthaldehyde solution of 15 grams corresponding to 0.062 mol, longer an imidazole of 10.2 grams corresponding to 0.15 mol and dimethylformamide OMF of 300 milliliters at 55 ° C treated with 7.9 g of KOtBu potassium tert-butylate corresponding to 0.07 mol, and this /

the mixture was then stirred for 30 minutes. The reaction mixture was then poured into a 1.5 M NaOH solution (1.5 L) to give a precipitate which was filtered off and chromatographed on SiO 2 silica gel (500 grams), starting with an eluting solvent. CH ₂ Cl ₂ dichloromethane (3 L) was used to remove the starting material and by-products. The yellowed product was then eluted with EtOAc (2 L) to remove 12.29 grams of solvent after drying and drying. (corresponding to a yield of 73%) of 10- (imidazol-1-yl) -9-anthracenocorbaldehyde with a melting point ranging from 194 to 196 ° C using an EtOAc system, elemental analysis (Ο, Ηί ') values consistent with the title compound.

Example AO 12-ethoxychrysan-6-carbaldehyde *

6-Ethoxychryeen (48 grams, equivalent to 0.176 mole) was formulated using the same procedure as in Example A except that CH ₂ Cl ₂ in dichloromethane was used as the reaction solvent. 1000 ml. After separation, the crude material was chromatographed on SiO ₂ silica gel (500 grams) using dichloromethane as eluent to give 33.7 grams (64% yield) after removal of the solvent and drying (corresponding to 64% yield) 12-ethoxychrylene-6- of carbaldehyde, melting at 173.5 to 175 ° C, elemental analysis (C, H) values corresponding to said compound.

Example AK ”

4-chloro-10- (2-hydroxyethoxy) -9-anthracene-carbbaldahyd,

The isomeric mixture of 1-chloro-9-anthaldehyde and 4-chloro-9-anthaldehyde was 36.8 g (0/133 mol) in ethylene glycol (1000 ml) and tetrahydrofuran TiiF (200 ml). · Treated with a target, with potassium butylate KOtBu in an amount of 12/5 grams, corresponding to 0.11 mol, and then

The mixture was heated to 80 ° C and heated at this temperature for 14 hours. The reaction mixture soaked was poured into water (2 L). The precipitated fraction was filtered, washed with water (500 ml), sucked dry, and then chromatographed on a SiOg silica gel (500 grams), eluting with CH 2 Cl 2 as the starting material, by centrifuging off the starting material. and by-products. The desired product was then eluted with ethyl acetate: ethyl acetate, yielding 3 grams (7.5% yield) of 4-chloro-10 (2-hydroxy-ethoxy) -9-anthracenkerbeldshyde, m.p. 141-145 ° C; values of elemental analysis (C, H, C1) corresponded to the given elucant.

Example AL

Formylation of 3-ethylfluoranthene.

70 g (0.304 mol) of 3-ethylfluoranthan were formulated in the same manner as described in Procedure IA except that one liter of CH 2 Cl 2 was used as the reaction solvent. The material was chromatographed on a 1 kg SiOg cartridge to give three separately purified products, each of which was precisely purified by preparative high pressure liquid chromatography using toluene PhCHg as the eluting solvent. Each of the three products was an isomeric mixture as shown below.

a) 3-athylfluoranthen-7-carbaldehyde and 4-athylfluoranthen-7-carbaldehyde, as obtained in an amount of 5.0 g (yield 6%) / (R 0 _f <55 · Si0 ₂ - PhCHg) Elemental analysis value j ! (C, H) correspond to the product obtained;

(b) 4-ethylfluoranthan-3-carbaldehyde and 4-ethylfluoranthan-2-carbaldehyde, obtained in quantities

4.7 g (6%) (Rf "0.49" Si0 ₂ PhCHg) elemental analysis values / C, H / correspond to said product;

(c) 3-ethylfluoranthene-8-carbaldehyde and 4-ethylfluoranthene-8-carbaldehyde,

47.3 g (60% yield), (Rf &lt; 0.38, SiOg, PhCHg); values of elementary analysis / C,

H) correspond to said product;

d) 4-ethylfluoranthene-3-carbaldehyde.

The above mixture b) was recrystallized twice from CH 2 Cl 2 / hexane (4.7 g) to give 1.83 g (2% yield) of 3-ethylfluoranthene) 4-ethylfluoranthene-3. -carbaldehyde, m.p. 113.5-116 ° C; elemental analysis (C, H) values were consistent with the product.

Example AM

3-methyl-3-nitro-2,4-pentanediol.

Solid NaOH (285 mg, 7.15 mmol) was added to 59.6 g (0.50 mol) of 3-nitro-2-butanol, acetaldehyde (132 g, equivalent to 1.50 mol) in anhydrous DMSO (100 mL) was added. The reaction was then carried out with stirring the reaction mixture under nitrogen atmosphere for 5 days. Glacial acetic acid (0.5 ml) was added to the solution. The solvent was then removed on a rotary evaporator (at a bath temperature of 45 ° C) to give a yellow liquid. The liquid was then diluted with 200 mL of water and the solution was extracted with CH 2 Cl 2 (5 x 200 mL). The combined dichloromethane extracts were then washed successively with water (500 ml) and saturated sodium chloride solution (50 ml), followed by drying with magnesium airane and finally filtration. The volatiles were removed from the filtrate under vacuum (first using a suction fan and at 0.1 mm, bath temperature ranging from 50 to 135 ° C) to give a viscous yellow liquid of 53.0 grams (yield corresponding to The liquid was then mixed with 50 ml of 1: 1 acetic acid / hexane acetone / hexane acetone / hexane and flash chromatographed on SiQg ^{0 for} 1.5 kg (silica gel 60, 230-400). eluting with 1: 1 acetic acid / hexane EtOAc / hexane as the elution solvent, collecting 500 mL fractions. Combine the appropriate fractions and remove the solvent on a rotary evaporator as above. , obtained

43.5 g (corresponding to a yield of 53%) of the dia-stereoisomeric mixture of 3-methyl-3-nitro-2,4-pontenedioles (two possible forms of β d, 1-p6r, readily separable by NMR in DMSO-d ⁶ ), ( + -) - (2K ⁺ , 3RS, 4R ⁺ ) -3-nitro-3-methyl-2,4-pentanediol and meso-3-nitro-3-methyl-2,4-pontanediol.

The separation of the para-stereoisomers was achieved by chromatographic treatment. From an initial fraction of 500 ml, 13.1 gm of one of meso-3-nitro-3-methyl-2,4-pentendolol was obtained in the form of a colorless solid fly, which had a melting point of 60 to 61 ° C. C, the elemental unulysis values (C, H, N) corresponding to said compound. The remaining fractions were intoxicated to give 36.3 grams of iso-azine containing both the mzo- and id-1-compounds. Recrystallization from a 2: 1 EtOAc / hexane ethyl acetate / hexane mixture and a mixture volume of 300 mL gave 27.8 grams of (+ -) - (2R ⁺ 3RS, 4R ⁺ ) -3-nitro- 3-methyl-2,4-pentanediol and other mszi-3-nitro-3-methyl-2,4-pentanedioles at a ratio of 4 sec., The melting point of this product being in the range of 79 to 86 ° C. analyzes (C, H, N) were consistent with theory. The above two compounds were then used without further purification, (+ -) - (2R ⁺ , 3RS, 4R ⁺ ) -3-amino-3-methyl-2,4-pentanediol in the form of acetate.

To prepare this compound, a solution of 3-methyl-3-nitro-2,4-pentanediol in an amount of 16.3 g, equivalent to 0.1 mole, was a mixture of d, l-steam and one. the meso form shown above in a ratio of 4: 1 in 95% ethanol at 150 ml added glacial acetic acid at 19 ml and 10% palladium on activated carbon Pd / C at 2, 0 grams. The reduction was carried out in a Parr apparatus at 50 psi hydrogen for 70 hours at ambient temperature and after completion of the reaction the catalyst was removed by filtration using a Millipore filter (TM). The solvent was removed under vacuum at at ambient temperature for 2 days. The colorless, viscous syrup was dissolved in absolute ethanol (30 ml).

Thereafter, the solution was heated and, after the addition of anhydrous diethyl ether EtgO in an amount of 100 ml 9e, became cloudy. The mixture was then placed in a refrigerator. Within two days, colorless crystals formed, which were filtered, washed with diethyl ether and then dried in a vacuum oven at ambient temperature. The yield of pure acetate (+ -) - (2R ⁺ t 3RS, 4R *) - 3-amino-3-methyl-2,4-pentanediol (which was confirmed by NMR in DMSO-d ^5), according to this embodiment 12.8 g the melting point of this product was from 110.5 to 112 ° C; the elemental analysis (C, H, N) of this product corresponded to the compound, U.S. Pat. No. 5,221,272 (cf. CA 85: 177498) discloses 3 -amino-3'-methyl-2,4-pentanediol as an intermediate, but no details are given in this material regarding the synthesis of this compound, the physical properties or the stereochemistry of the compound,

Meso-3-amino-3-methyl-2,4-pentanediol acetate.

To prepare this compound, the same procedure as above was used starting from meso-3-mono-3'-nitro-2,4-pentanediol (not analyzed) to give meso-3-amino-3 acetate. - methyl-2,4-pentanediol (53% yield); the melting point being in the range of 137 to 138 ° C; elementary analysis / C,

H, N / confirmed the compound. »

AND

Example AN (+ -) (2R ⁺ , 3S ⁺ ) -2-methyl-2-nitro-1,3-ibutanediol (A) and (+ -) (2R ⁺ , 3R *) - 2-methyl-2-nitro , 3-butanediol (B),

The preparation was carried out by adding to the mixture 2-nitro-1-propanol 63.0 grams corresponding to 0.60 mol and acetaldehyde 39.6 grams corresponding to 0.90 mol. which was cooled in an ice bath under nitrogen, cold water (40 ml) and calcium hydroxide (200 mg) were added. The mixture was allowed to warm to ambient temperature over two hours and then stirred for 68 hours. The resulting solution was neutralized with excess carbon dioxide. The resulting mixture was stirred for one hour and then filtered using a Millipore filter (TM). The filtered filtrate was concentrated in vacuo at 35 ° C to give a viscous syrup residue which partially crystallized upon drying under vacuum ( 0.1 mm, ambient temperature, 48 hours run time) and then this mixture was triturated with cold Et 2 O (35 mL). White solid crystals were formed, which were collected by filtration, then washed with cold Et 2 O 3 x 15 mL, and finally dried under vacuum at 0.1 mm at ambient temperature. 34.1 g of material was obtained which was analyzed by NMR as diastereoisomer A (purity less than 97%, racemic mixture). After recrystallization, the purity of the diastereomeric product was less than 99%, with a melting point of 78.5 to 81 ° C (melting point 78 ° C in the literature, cf. Bell 1, 482 in Henry). , Bull, Soc, Chlm. Fr, (3) 15 → 1244).

Thereafter, the original filtrate (including the wash) was concentrated under vacuum to give a light yellow liquid which was subjected to flash chromatography as follows. The sample was mixed with 1: 2 hexane / ethyl acetate / hexane (1: 2) 100 mL, and loaded onto a silica gel 60 column (1500-400 mesh). The column was then eluted with hexane: ethyl acetate: hexane: EtOAc 2: 1, 12L, then ε

hexane / ethyl acetate (6L; hexane / EtOAc = 6L), collecting 500 mL fractions. The corresponding fractions were combined. The pure product was obtained from the last 8 liters. The yield of this step was

38.7 grams, the resulting material being a viscous syrup and analyzed by NMR method. As a 1: 1 mixture of the two racemic diastereoisomers A and B &lt; 1 &gt;

The 1: 1 diastereomeric mixture (prepared as described above) was combined to give a total weight of 57 grams, and then subjected to a sequential liquid-liquid partition between water and ethyl acetate / EtOAc and pure product A (99% pure by NMR method using preparative liquid chromatography under high pressure using 3.5% aqueous acetonitrile as the mobile phase) was obtained as described above. the yield of this product was 24.9 grams (k ' = > 4.3j elemental analysis (C, H, N) corresponding to said compound) and B at 15.8 grams (k ' H, N (corresponding to said compound) as a colorless viscous liquid.

(+ -) (2R ⁺ , 4S ⁺ , 5R ⁺ ) -4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane and (+ -) (2R ⁺ , 4S ⁺ , 5S ⁺ ) 4 5-Dimethyl-5-nitro-2-phenyl-1,3-dioxane

The relative configuration of the two diastereoisomeric pairs (A and B) was determined by comparative NMR analysis with the corresponding benzaldehyde-derived acetals. In this way, product A was 1.49 grams, corresponding to 0.01 mole, and banzal *

CS ¢ 73349 82 of 1.06 g equivalent to 0.01 mol of condensed benzene in the presence of a catalytic amount of p-toluenesulfonic acid with azeotropic separation of water (see H. Piotrowska * B. Serafin T. Urbanski method, Tstrahedron 109 379 (1963).

The mixture was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, and the benzene was removed on a rotary evaporator to give a light yellow solid. Dissolution of this product in ethanol at 0 ° C yielded an oil which was isolated by decanting the mother liquor and drying under vacuum (0.1 mm, ambient temperature). 1.48 g (corresponding to yield) were obtained. 62%) (+ -) (2R ⁺ , 4S ⁺ , 5R ⁺ ) -4,5-dimethyl-5-nitro-2-fanyl-1,3-dloxane Elemental analysis of this product (C, H, N) was as described compound.

In a similar manner (+ -) (28 ⁺ , 4S ⁺ , 5S *) - 4,5-dimethyl-5-nitro-2-phenyl-1,3-dloxene was prepared from product B and benzaldehyde in 74 elemental analysis / C , H, N / corresponds to the compound,

(+ -) (2R ⁺ , 3R ⁺ ) -2-amino-2-methyl-1,3-butanediol acetate.

This compound was připrovono of _f (<-) (2R ^{+, +} 3R) -2-motbyl-2-nitro-l, 3-butanediol, using the same procedure as in example AM, and this compound was obtained by s $ těžekm97 elemental analysis (C, H, N) was consistent with the title compound, with a melting point of 117-121 ° C;

(+ -) (2R ⁺ , 3S ⁺ ) -2-amino-2-methyl-1,3-butanediol acetate.

This compound was prepared from (+ -) (2R ⁺ , 3S ⁺ ) -2-methyl-2-nitro-1,3-butanediol using the same procedure as in Example AM to obtain a yield of 93% The elemental analysis values (C, H, N) corresponded to the compound, the melting point of this product being from 163 to 165 ° C, (+ -) (2R ⁺ , 3R ⁺ ) -2-amino-2-methyl- 1,3-butanedioloetate,

This compound was prepared from (+ -) (2R ⁺ , 3R ⁺ ) -2-methyl-2-nitro-1,3-butanediol using the same procedure as in Example AM, and was obtained in 97 yield. elemental analyzes (C, H, N) were consistent with the title compound, m.p. 117-121 ° C, (+ -) (2R ⁺ , 3S ⁺ ) -2-amino-2-methyl-1-carboxylic acid; 3-Butanediol in the form of acetate.

This compound was prepared from (+ -) (2R ⁺ , 3S ⁺ ) -2-methyl-2-nitro-1,3-butanediol using the same procedure as in Example AM and was obtained in 93 yield. Elemental analyzes: (C, H, N) were consistent with the title compound, m.p. from 163 to 165 ° C.

EXAMPLE 2 Preparation of 2 - ((6-chryaanylmethyl) imino) -2-methyl-1,3-propanediol,

A, Chrysene-6-carboxylic acid.

In a round-bottomed flask equipped with a condenser, nitrogen bubbler and magnetic stirrer, was added chrysene-6-carbaldehyde (Cambridge Chemical, Inc, 10.0 grams corresponding to 39 mmol) and glacial acetic acid HOAc in 1000 ml. The reaction was heated to 50 ° C. To the reaction mixture was then added dropwise a solution of bromine Br ₂ (Aldrich

6.2 g (39 mmol, 2.0 ml) in glacial acetic acid HOAc,

The reaction mixture was then heated to BO &lt; 0 &gt; C and held at this temperature for 1 hour, then treated with water (1 ml) and cooled. A solid was obtained, which was filtered and washed with water. The solid was then recrystallized twice with tetrahydrofuran / toluene THF / PhCHg in a ratio of 1: 1.

And then twice from tetrahydrofuran THF, after drying 3.3 g of ohrysen-6-carboxylic acid 9 having a melting point greater than 305 ° C; (C, H).

8. 6-Chryeenoyl chloride.

In a round bottom flask equipped with a condenser, a nitrogen bubbler and a magnetic stirrer, was added chrysene-S-carboxylic acid (obtained as described in Embodiment A above, 3.3 g, equivalent to 13 mmol). and thionyl chloride SO ₂ (Aldrich, excess amount, 100 mL). After gently warming the reaction mixture was heated in the temperature of the solvent raft under reflux for 2 hours, then cooled and excess thionyl chloride SOC1 ₂ was removed. The crude solid was then suspended 2x in toluene PhCHg (200 mL) and the solvent was removed on a rotary evaporator. This gave a crude material (3.5 g) which was used for the next step without further purification.

Co N- (2- (1,3-dihydroxy-2-methyl) propyl) -hensenecarboxamide.

In a round-bottomed flask equipped with a condenser, nitrogen bubbler and magnetic stir bar was charged 6-chrysenoyl chloride (Step B compound, 3.50 g, 12 mmol), giving 2-amino- 2-methyl-1,3-propanediol (Aldrich, 2.53 g, equivalent to 24 mmol) and dry tetrahydrofuran THF (200 mL). The mixture was heated at reflux for 4 hours. During this time a white solid formed. The reaction mixture was poured into water (500 mL) and filtered. The solid was then dissolved in EtOAc (700 mL), washed with water (3 x 500 mL), brine (2 x 500 mL), dried over Na ₂ SO _4, and concentrated. to give 4.12 g of a crude white solid. This solid was dissolved in EtOAc (500 mL) and filtered through a medium quality frit sintered glass funnel and then concentrated to 200 mL. The hot solution was diluted to 400 mL with hexane. This gave crystals which were filtered and recrystallized from EtOAc / hexane ethyl acetate / hexane, then filtered and dried in a vacuum oven to give 2.06 g (47.8% yield) of N- ( 2- (1,3-dihydroxy-2-methyl) propyl) chrysocarboxamine, m.p. 170 DEG-171 DEG C. (C, H, N),

D. 2 · ((6-Chrysenylmethyl) amino) -2-methyl-1,3-propanediol methanesulfonate.

In a round bottom flask equipped with a condenser, nitrogen bubbler, and magnetic stir bar was charged N- (2- (1,3-dihydroxy-2-methyl) propyl) -chrysocarboxamide (a compound obtained according to the above step). C, 1.0 g (2.8 mmol) and dry THF (100 mL). Solid LiAlH 4 (alpha, 0.53 g, 14 mmol) was charged in several portions. The color of the reaction mixture rapidly changed to a dark brown color while simultaneously evolving gas. The reaction mixture was stirred overnight at ambient temperature and then refluxed for 14 hours. The reaction mixture was then quenched by the addition of saturated Na ₂ SO ₄ solution (10 mL) followed by the addition of water (50 mL). The reaction mixture was then extracted with EtOAc (3 x 200 mL). The ethyl acetate layers were combined, washed with water (200 mL), saturated aqueous sodium chloride (3 x 200 mL), dried with K ₂ CO ₃ , filtered and concentrated to give a needle-like solid. This substance κ

CS 273348 Β2 was then dissolved in absolute ethanol EtOH (25 mL) and CH 2 SO 4 H (alpha, 0.5 mL), heated and filtered. The resulting liquid was then diluted to a volume of 500 mL with hexane, filtered and recrystallized twice with a mixture of absolute ethanol and diethyl ether EtOH / EtgO to give 0.21 g (16.9% yield) of 2 - ((6-chrysenylmethyl) emino) -2-methyl-1,3-propenediol in the form of methanesulfonate, m.p. 227-228 ° C (dec.), (C, H, N, S)

Example 2

Examples of resources. ¹

A. Tablet:

Compound of Formula I (as hydrochloride) 500.0 mg pregelatinized maize starch 60.0 mg sodium starch glycolate 136.0 mg Magnesium Otonate 4.0 mg.

The compound of formula (Ie) is finely divided with perfect emission by a powdered excipient, which is pregelatinized starch and sodium starch glycolate. This powder is then moistened with pure water to form a granule. These granules are then dried and emitted with magnesium stearate. This may then be formulated as tablets having a weight of approximately 600 milligrams.

II. Tablets;

Compound of Formula I > 500.0 mg cornstarch ^? 70.0 mg laktozo 83.8 mg Magnesium stoate 4.2 mg polyvinylpyrrolidone _{: t} 14.0 mg stearic acid 28.0 mg.

Compound of Formula (I) oe finely comminutes and perfectly and is emitted with a bland excipient which is corn starch and lectose. The powder obtained is moistened with a solution of polyvinylpyrrolidone, further dissolved in pure water and denatured alcohol to form granules. These granules are then dried and emitted with powdered atearic acid and magnesium stearate. The mixture is then compressed to form tablets of approximately 700 milligrams.

C, Bands:

Compound of Formula I 500.0 mg corn starch 50.0 mg magnesium stearate 3.0 mg.

The compound of formula (I) 9b is finely pulverized and then βθ emission with a pulverulent corn husk moistened with danoturonic alcohol to thicken the powder. The dried powder 8e is then mixed with atearic acid and filled into gelatinous liquids and hard shell.

O, Syrup:

compound of formula I ethanol glycerin sucrose flavoring colorant preservative pure water

250.0 mg 250.0 mg 500.0 mg 3500.0 mg q, s g.e.

0.1% 5.0 ml.

add-in to '4 * ·'>

The compound of formula (I) is dissolved in ethanol, glycerin and a portion of pure water, sucrose and preservative are dissolved in a second portion of hot pure water, and then a coloring agent is added to dissolve it. The two solutions are then emitted and cooled, after which the flavoring agent is added. The resulting syrup was properly milled with the field ·

U. Injokcot compound of formula X glycerin preservative hydrochloric acid or sodium hydroxide water for injections

5.0 mg addition to achieve the desired isotonicity of 0.1% as needed to adjust the pH of the supplement to 1 ml.

The compound of formula I and the preservative are added to glycerin and water for injection. The pH is then adjusted with hydrochloric acid or sodium hydroxide, water for injection is added to the total volume, and the solution is

This solution is then sterilized by filtration using a 0.22 micron filter membrane and is not aseptically filled into sterile 10 ml ampoules or vials.

Claims (5)

P ff Ε O Μ Ε T OF THE INVENTION 1. A process for the preparation of polycyclic aromatic alkanol derivatives of the general formula Is ArCH - NH - C - R 2. A process according to claim 1, wherein the corresponding starting materials are used to form a compound of formula (I) wherein Ar is 6-chrysenyl, 7-fluoranthenyl or substituted 1-anthracenyl or 9-anthracenyl and the other substituents are as defined above. 3. A process according to any one of claims 1 to 2, wherein the corresponding starting materials are used to form a compound of formula I wherein Ar is substituted by a C1-C2 alkyl group or a C1-C2 alkoxy group which optionally substituted with chlorine, hydroxy or methoxy or S (O) _n R ⁵ or chloro, imidazolyl, morpholino, cyano or bromo, with the preferred eubetituents being chloro, 2-chloroethyl or OCH ⁸ CH ⁸ R ¹² in which R is hydrogen, hydroxy or methoxy; or a S (O) _n CH _{3 group} in which π is an integer of 0, 1 or 2 and the other substituents are as defined above. 3 4 R and R are the same or different substituents, each of which is hydrogen, methyl or ethyl, 12 3 4 R, R, R and R contain a total of up to five carbon atoms, or the group j in which - C - C - is a 5- or 6-membered saturated carbocyclic ring containing two or three hydroxyl groups, r is hydrogen, methyl or hydroxymethyl , r ⁹ _and R 10 are the same or different eubstituents, each of which is a hydrogen atom, a nobo methyl group, r ¹¹ is a hydrogen atom, a hydroxy group, a methyl group or a hydroxymethyl group, the ring together containing the total R®, R®, R ^10, R ¹¹ and · C-C of less than seven carbon atoms, the compound of formula Vt is reduced AND Arcon - C - R ² OH (V) in which the substituents Ar, R 1 to R ⁴ are as defined above, and the hydroxy groups are optionally protected, followed, if necessary, by removal of the hydroxy protecting groups. 4. A process as claimed in claim 1, wherein the compound of formula I is used in which I is used, wherein AND OH where aubetituontom R R yeah It is or CH is OH, and K is ¹⁵ Jo CHgOH group, CH _(CH3) 0H or CH ₂ CH ₂ 0H, hydrogen, alkyl group containing 1 to 3 carbon atoms, hydrogen Nobo methyl group. CS 27334B B2 4 ¹ 3 R-C-R ³ (I) OH or a monomethyl or monoethyl derivative thereof, including ethers of the compound of formula I having a total of up to 20 carbon atoms, esters and a salt thereof, wherein Ar is a radical selected from the group consisting of: by © OW <* · CS > 273340 B2 wherein these residues are optionally substituted with one or two substituents together comprising a total of up to four carbon atoms and having the same or no difference, selected from the group consisting of halogen, cyano, alkyl of 1 to 3 atoms or an alkoxy group having 1 to 3 carbon atoms, each of which is optionally substituted by a hydroxy or alkoxy group having 1 to 2 carbon atoms, further a halogen substituted alkyl group having 1 or 2 carbon atoms, or an alkoxy group having 1 or 2 carbon atoms S (O) _n R ⁵ in which n is an integer of 0, 1 or 2 and R ⁸ represents an alkyl group containing 1 or 2 carbon atoms optionally substituted by a hydroxy or alkoxy group containing 1 or 2 atoms or the Ar moiety is optionally substituted with an NR @ ⁷ R @ ⁷ group which contains a carbon atom 5 carbon atoms, and R ⁸ and R ⁷ They are the same or different substituents, each of which represents an alkyl group of f Ύ containing 1 to 3 carbon atoms or the NR R group forms a 5- or 6-membered heterocyclic ring optionally containing one or two additional hetero atoms, R '' is an alkyl group containing 1 to 3 carbon atoms substituted by a hydroxy group, R is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a hydroxymethyl group, 5. A process according to item 1 of the corresponding starting materials up to 4, which is used to form a compound of formula (I) wherein the group R * 1 CH _o OH 1 1 2 - C - R - C - R ^{16 1} 3 - C - R ^J I Yeah H - C - R ¹⁵ 1 1 OH IN 1 OH wherein R is hydrogen or methyl and R ( ⁶⁾ is hydrogen, methyl or ethyl