CS273347B2 - 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 invention relates to a process for the preparation of aminoalkanol derivatives containing a polycarbocyclic aromatic system.

As to the state of the art, it is described in Gazz. Chim. Ital., 93,

118, 1963, the procedure for preparing 2-phenylmethylamino-2-methyl-1,3-propanediol, however, there is no disclosure that this compound exhibits anti-tumor activity. Analogues of nitracryn (1-nitro-9 - ((3'-dimethylaminopropyl) amino) acryidine) containing 2-amino-2-methyl-1,3-propanediol and tris (hydroxymethyl) methylamine groups are disclosed in Arznaim Forsch Drug Ras. 32 II, 1013, I982, which are said to exhibit anti-tumor efficacy in the form of mouse protective agents.

According to the present invention, it has been found that a new class of polycarboxyclic aromatic alkanol derivatives exhibiting biocidal activity.

The process for the preparation of the polycyclic aromatic alkanol derivatives of the general formula X r ¹

2

Ar - CH - NH - C - R 4 1 3

R-C-R (I) i 'or monomethyl nobo monoethyl ethers thereof, wherein the compound of formula I including its ethers contains a maximum of 28 carbon atoms in total, or esters or salts thereof, wherein Ar is selected from the group consisting of :

6

10 4

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 halogen, cyano, (C 1 -C 3) alkyl or (C 1 -C 3) alkyl up to 2 carbon atoms, further a group

5

S (O) R wherein n is an integer of 0, 1 or 2, and R represents an alkyl group having 1 or 2 carbon atoms optionally substituted by a hydroxy or alkoxy group having 1 or 2 carbon atoms, or an Ar moiety is optionally substituted with NRR containing up to 5 carbon atoms, wherein R ° and R ^z are the same or different and each of them represents an alkyl group containing 1 to 3 carbon atoms, or NR R forms a 5- or 6-membered heterocyclyl ring which optionally contains one or two hetero atoms, furthermore, R ^- is alkyl of 1-3 carbon atoms substituted hydroxysku- ·.

pinou,

R is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a hydroxymethyl group;

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

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

R ³ is hydrogen, methyl or hydroxymethyl, g <L0

R 2 and R 2 are the same or different substituents representing hydrogen or methyl, is hydrogen, hydroxy,. methyl, or hydroxymethyl,

H

R, R, R, R and --C - C - ring together contain less than seven carbon atoms, according to the present invention is the reaction of a compound of the formula

In which Ar is as defined above _? and

L is a leaving group, with a compound of formula XV

NH.

OH (IV) wherein R ¹ , R ² , R ³ and R ^{4 are} as previously defined.

Suitable leaving groups are those defined in 0.March.,

Advanced Organic Chemistry, 2nd Edition, pp. 683-895, Mc Graw Hill, New York, 1977.

Such groups include halogen atoms such as chlorine or bromine and sulfonic acid derivatives such as p-toluenesulfonate. The reaction is preferably carried out in a suitable solvent, such as a dipolar aprotic solvent or alcohol, at a non-extreme temperature in the range of 50 to 150 ° C, usually at a temperature in the range of 50 to 100 ° C. Compounds of general formula

ArCHgL may be prepared by known methods in the art.

The compounds prepared by the process of the invention exhibit biocidal activity, in particular having an antitumor effect.

In a preferred embodiment of the present invention wherein Ar is 1-anthracenyl or 9-anthracenyl, the aromatic system is substituted.

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

Especially 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, hydroxyl or methoxy; S (O) _n ^R5 or chloro, imidazolyl A morpholino group, a cyano group or a bromine atom. Preferred substituents are chloro, 2-chloroethyl group 12 12 or group OCHgCHgR <in which R is hydrogen, hydroxy or methoxy, · or a group S (0) _n CH ₃ in which n is an integer 0, 1, or 2.

Said substituents may be attached at any 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 process of the invention is

OH group

R ¹³

OH or

HO wherein R represents a ¹³ ekupinu CHgOH, CH _(CH3) 0H group or GHgCHgOH,

R ¹⁴ is hydrogen, C 1 -C 3 alkyl or CH 3 OH, and

R ¹⁵ is hydrogen or methyl.

In a preferred embodiment, R ^{3 is} CH ₃ OH or CH (CH ₃ ) OH, R ⁴⁴ is suitably hydrogen, methyl, ethyl or CH ₃ OH.

In a preferred embodiment of the invention the group is

R i

- CR ⁴ - CI

OH group

CHgOH

- C i

H - C - R '

AND

OH, 16 wherein R @ ¹⁵ represents a hydrogen atom or a methyl group, and

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 (X) and ethers and esters thereof.

Esters and non-pharmaceutically acceptable salts of the compounds of formula (I) are useful intermediates in the preparation of the compounds of formula (Z) and pharmaceutically acceptable salts of these compounds and are therefore within the scope of the process for preparing the compounds of formula (I). Salts of the compounds of formula I are compounds derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and from organic acids such as isethionic acid, maleic acid, malonic acid, succinic acid, salycilic acid, acid tartaric, lactic acid, citric acid, formic acid, lactobionic acid, and pantothenic acid, further from organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalene-2-sulfonic acid; ascorbic acids and amino acids such as glycine. Suitable salts are hydrochlorides, methanesulfonates and ethanesulfonates, lactates, citrates and isethionates. Preferred are pharmacologically and pharmaceutically acceptable salts, especially those which are soluble in solvents suitable for parantaral 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 well known in the art which are suitable for the preparation of an eater, and are generally derived from C 1 -C 5 alkanoic acids such as acetic acid, acid propionic acid, n-butyric acid and isobutyric acid.

These esters may be prepared from all or only some of the hydroxy groups contained in the compound of formula (X), as specific examples of the compounds of formula (I) above, and the following compounds:

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

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

2 - ((1-anthracenylmethyl) amino) -2-methyl-1,3-propanedibl,

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

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

2-methyl-2 - ((10-methyl-9-anthraoanylmethyl) amino) -1,3-propanediamine;

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-anthraenylmethyl) amino) -2-methyl-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 - ((Lo-bromo-l-antracenylmethyl) amino) -2-methyl-l, 3-propanediol, 2 - {(4 ^and 10-dichloro-9-antracenylmethyl) amino) -2-methyl-LT3 -propandiQj. ² ((4 »5-dichloro-9-antracenylnethyl) amino) -2 -methyl-1,3-propandio1, 2 - ^((2-f 10 diohIor-9-antracenylmethyl) amino) -2- methyl-1,3-propanediol, 2 - ((3, 10-dichloro-9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol, 2 - ((3-fluoroantrylmethyl) amino) -2-methyl -l, '3-p ropanediol,'

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

2 - ({4-chloro-9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol;

2 - ({2-chloro-9-anthracanylmethyl) amino-2-methyl-1,3-propanediol,

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

2 - ((10- (2-hydroxyethylthio) -9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol, 2 - ((2-tert-butyl-10-chloro-9-anthracenylmethyl) amino) - 2-methyl-1,3-propanediol, 2 - ((10-chloro-9-anthracanylmethyl) amino) -2-hydroxymethyl-1,3-propanediol,

2 - ((7-fluo ranthenylmethyl) amino) -2-methyl-1,3-p rop ^Andiol,!

2 - ((10- (2-hydroxyethyloxy) -9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol; 2 - ((10-ethoxy-9-anthracenylmethyl) 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 - ((S-chrysanylmethylamino) amino) -2-ethyl-1,3-propanediol,

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

2-ethyl-2 - ((3-fluoroanthanylmethyl) amino) -1,3-propanediol, 2 - ((10-chloro-9-anthracenylmethyl) amino) -2-ethyl-1,3-propanediol, 2- ( (3-chloro-9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol, (+ -} (2R *, - 3S ⁺ ) -2 - ((6-chrysenylmethyl) amino) -2-methyl- 1,3-butanediol,

2 - ((2-ethyl-9-anthracenylmethyl) amino) -2-methyl-1,3-propanediol and 2 - ((3-ethyl-9-anthracenylmethyl) amino) -2-methyl-1, 3-propanediol, (+ -) (2R ⁺ , 3S ⁺ ) -2 - ((9-anthracenylmethyl) amino) -2-methyl-1,3-butanediol, (+ -) (2R ⁺ , 3R ⁺ ) - 2 - ((6-chrysanyl / methyl) amino) -2-methyl-1,3-butanediol, ² ((8 'ohrysenyl / methyl) amino) -2-ethoxymethyl-1,3-propanediol,

3-Methoxy-2 - (((S-chryeenyl) methyl) amino) -2-methyl-1-propanol;

3-methoxy-2 - ((3-fluoranthenyl / methyl) amino) -2-methyl-1-propanol, (+ -) (2R ⁺ , 2S ⁺ ) -2 - ((3-fluoranthenyl / methyl) amino) -2-methyl-1,3-butanediol, 2-ethoxymethyl-2 - ((β-fluoroanthanyl / methyl) amino) -1,3-propanediol,

2 - ((/ 9-antracanyl / methyl) amino) -2-ethoxymethyl-1,3-beta ropandiol 2 - $ - ((6-chrysenylmethyl) amino) -l-í6,3 ^{Z-cyclohexanediol,!}

2- $ - ((3-fluoroanthanylmethyl) amino) -1- [eta] < 3 &gt; -3-cyclohexanediol, 2 - ((6-chrysenylmethyl) amino) -2-isopropyl-1,3-propanediol, 2- ( (3-fluoroanthanylmethyl) amino) -2-isopropyl-1,3-propanediol, 2 - ((6-chrysanylmethyl) amino) -2-methyl-1,4-butanediol,

2 - ((3-fluoroanthenylmethyl) amino) -2-methyl-1,4-butanediol,

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

2 - ((6-chlorophenylmethyl) amino) -1,3-propanediol, 2 - (([1,2-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) -l, ^{3-propanediol,} 2 - (/ 9-antracenylmethyl / amino) -3-methoxy-2-methyl-propanol, '2 - ((/ 12-chloro-S-chrysenyl / methyl (amino) -2-methyl-1,3-propanediol;

2 - ((9-nitrophenylmethyl) amino) -2-isopropyl-1,3-propanediol;

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

2 - (((10- (1H-imidazol-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-5-chlorophenyl) methyl) amino) -2-methyl-1,3-propanediol, (1Z, 2R, 3R) -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-fluoranthenyl) 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 - ((6-chrysenylmethyl) amino) -2-methyl-1,3-propanediol, 2 - ((3-fluoranthenylmethyl)) amino-2-methyl-1,3-propanediol and 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 characterized by being 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 formula (I) has been demonstrated in a number of conclusive tests, and in particular ascitic leukemia P88 / 0 activity, ascitic tumor activity, including P388 / 0, is evident from a reduction in tumor cell numbers in mammals such as mice in which these ascitic tumors occur and their subsequent increase in the survival period as compared to the untreated group · the group in which these tumors also occur, The anti-tumor efficacy is also further evident from detecting the reduction in the size of certain solid tumors after treatment in mice with of the present invention as compared to the untreated group, in which these tumors also occur. In view of the above, the compounds of formula (I) have been shown to be effective against mouse tumors against lymphocytic leukemia P388 / 0, lymphocytic leukemia L1210, 1 melanotic melanoma BIS, mastocytoma P815, MDAY / D2 fibrosarcoma, colon adenocarcinoma 38, rhabdomyosarcoma M5076, and against Lewis lung carcinoma.

efficacy in one or more of these tumor assays has been suggested to suggest anti-tumor efficacy also in humans (see A, Goldin et al. Methods of Cancer Research, ed. VTOeVita, 3r., with O.Busch, 16,165, Academic Press NY 1979

There are P388 / 0 species that are resistant to the following clinically used agents: cytosine arabinoside, doxorubidine, cyclophosphamide L-phenylalanine mustard, methotrexate, 5-fluorouracil, actinomycin D, cis-platin, and bie-chloroethylnitrosourea. Compounds of formula (I) prepared by the process of the invention; exhibit potential efficacy against these drug resistant tumors, as evidenced by the P388 / 0 assay procedures set forth above.

The compounds of formula (X) have also been shown to be effective against human cancers, particularly tumor cells in primary stomach cultures, pancreas, telitis, cancer of plasma cells. bone marrow and colon tumors. The above term tumor is a mini-synonym for malignant tumor or more generally cancer, unless explicitly stated otherwise. Prior art is known to compare the prevention of tumor cell colony formation, 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))} S. Salmon et al., D, Von Hoff, Seminars in Oncology, 8 (377/1981),

Compounds of formula I which have been found to have antitumor activity are introduced in vitro between ONA molecules. This property is determined by viscomatic methods using WD, Wilson et al. / Nucleis Acids Research 4/2697/1954, and the log P value, as determined by C. Hansh and A. Leo in the Substituent Constants for correlatxone analysis in Chemistry and Biology, Oohn Wiley &amp; Sons, New York, 1979, ranges 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) prepared by the process of the invention, an ether or ester thereof or an acid addition salt thereof is administered.

The amount of the compound of formula (I) prepared by the process of the invention required to achieve the desired effect as a biocidal agent will, of course, depend on many circumstances and is ultimately 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 age and general condition of the patient, and the compound to be administered. A suitable effective anti-cancer dose is in the range of about 0.1 to about 120 railigrams / kg body weight, preferably about 1.5 to about 50 milligrams / kg, for example 10 to 30 milligrams / kg. . 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 may range from about 8 up to about 9000 milligrams per day (with a typical daily dose of about 2000 milligrams per day) (If multiple discrete doses are determined in the treatment, treatment can be carried out with the usual doses of 500 milligrams of the compound of formula 1). · Capsules, liquid preparations (eg syrup) or injection.

Although the active compounds prepared by the process of the present invention (defined herein as the compounds of Formula X or the ethers, esters, or salts thereof) can be administered as the raw chemical itself, it is preferred to prepare pharmaceutical compositions from the active compounds. Compositions intended for medical use contain the active ingredient together with one or more pharmaceutically acceptable carriers and optionally other theraputic additives. The carrier or substances must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The compounds prepared by the process of the invention may be formulated into a pharmaceutical composition comprising a compound of formula I (in the form of a free base 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 of the above compound of formula (X),

The above formulations are in a form suitable for oral, rectal or parenteral administration (including aubcutaneous, intramuacular or intravenous administration).

These compositions containing a compound of formula (I) may be formulated in a unit dosage form and may be prepared by any of the known methods of pharmacy. In all these processes, the active compound is combined with a carrier which functions as one or vioe excipients. In general, the compositions are prepared by uniformly and intensively contacting the active ingredient with a liquid carrier which is a carrier, or with a finely divided solid carrier, or both, and then, if necessary, shaping the product into forms of the desired device *

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, ¹ emulsion or inhalation.

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 compound as a free tekoucí.látky ¹ such as a powder or granules, optionally mixed with a binder material), lubricant, inert diluent *, 'a surfactant or dispersing agent, ^- in a suitable machine. 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 solution of a sugar, for example sucrose, and additional additive (s) may also be added to the syrup. Such additives may be, for example, flavoring agents, sugar crystallization retardants, or agents which increase the solubility of any component, such as a polyhydric alcohol, for example glycerol or sorbitol.

The compositions 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 preferably contain a solution of a pharmaceutically and pharmacologically acceptable acid addition salt derived from a compound of Formula I which is isotonic with the blood of the recipient. Thus, such compositions typically contain distilled water, a 5% dextrose solution. in distilled water or in saline, and a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of formula I having suitable solubility in such solvents, such as isethionate salt and methanesulfonate salt, preferably methanesulfonate salt.

In addition to the abovementioned additives, the compositions may further comprise one or more adjuvants 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 examples of the practice of the present invention, and are intended to illustrate the invention in more detail. All temperatures are given in Celsius scale *

General remarks:

All solvents used were reagent grade in these examples and were used without further purification with the following exceptions. Tetrahydrofuran was stripped of water by distillation using a mixture of sodium and potassium under a nitrogen atmosphere, and then used immediately. Toluene (^ J PhOH was distilled from CaH ₂ under nitrogen and stored over molecular sieves 38 Chemicals used were reagent grade and were used without přečišřování ,! unless otherwise indicated. For the first of the substances js the entire name and address of the suppliers of the reagents and chemicals, then only the abbreviations * g are used

Preparative high pressure liquid chromatography was performed on a Waters Prep LC (System 500A) using two 500 grams SiOg silica gel unless otherwise specified. SiOg cartridges used for purification contained flash chromatography silica gel (E. Merck, silica gel). 60, 230-400 mesh) The funnel of a sintered glass of suitable volume was filled with approximately 3/4 of SiO ₂ , tapping only on the outer wall of the funnel.

A sample of the filter paper was then placed on top of the SiO 2 and the solution to be cleaned was impregnated on the top. Slightly sucked! applied to the filter vessel, faster elution of solvent by said cartridge can be achieved. It is also possible to combine fractions of different grain size and make further adjustments if desired.

To carry out elemental analyzes of the compounds of formula (I): prepared according to the examples below, the corresponding methods were used. In case they were pro-. elemental analyzes are performed for intermediates or starting materials /, these analyzed elements are referred to for example (C, H, N) or (C, H, C1), etc. In all the analyzes below, the experimentally determined values are different from the calculated values in range + 0.4%.

Preparation of starting compounds:

Example A

6-chrysocarbaldehyde.

In a five-liter three-necked flask equipped with a mechanical overhead stirrer, a thermometer / cooler and a nitrogen inlet, 100 grams of chrysene (0.438 mol) and o-dichlorobenzene of 2500 milliliters were charged. The liquid was then heated (the contents were heated until the large lumps of solids dissolved (at 80 ° C) and then cooled rapidly). to give fine crystals. After further cooling with salt and ice to 5 ° C, SnCl 2 (purity 98%, < 228/2 grams, 0.875 mol, 102.4 ml) was added in one portion. No temperature changes occurred during this treatment. The vessel temperature was maintained below 5 ° C by the addition of δ, J-dichloromethyl methyl ether (70/48 g / 0.613 mol, 55.45 ml) 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 in 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 sodium sulfate (100 g) and filtered again. The clear yellow solution was then divided into two portions which were passed through a 500 gram silica gel cartridge by flash chromatography (silica gel 60, 230-400 mesh) using toluene as the eluting solvent as fractions of 500 ml. 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 removed. During this process, crystals were formed and these 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% yield) and had a melting point of 167-196 ° C.

Example 1 a d B

10-methylthio-9-anthracenecarbaldehyde

In the case of this example, the method of V. Rogo was modified. vika et al., see Zh. Org. Khim. 3, 1315 (1969) as follows: into a 2-liter three-necked flask equipped with a stir bar, cooler / additional infusion—

10-chloro-9-anthracenecarbaldehyde (23.0 grams, equivalent to 0.116 mol) and DMF in 1 liter were charged with a thermometer, nitrogen inlet and bubbler * The solids dissolved as soon as the reaction mixture was heated to 60 ° C. The additional label was filled with a solution of sodium sulfide Na ₂ S (28 grams, equivalent to 0.116 mol) in 30 milliliters of water. This solution was then quickly 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) _. Then methyl iodide CHgX (27.36 grams, equivalent to 0.193) was added to the flask. mole) 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. This afforded a yellow solid ⁸ was separated by filtration and then was dissolved in hot toluene with a volume of 500 ml, then was dried over MgSO ^, and finally filtered using Celite (trade mark). More toluene was removed and the resulting oily substance was vigorously stirred with 200 mL hexane to give a pale yellow solid. This material was dried at 50 ° C to give 25.04 g (86% yield) of 10-methylthio-9-anthracenecarbaldehyde, mp 98.5-99 ° C. , H, S / ·

Example 10- (2-chloroethyl) -9-an tracenecarbaldehyde.

The Vilsmeier method was used in the procedure of D.F.Flsssr, Org. Son. Coli. Vol. III, 98 (1955), starting from 9-vinylantracene, from which 10- (2-chloroethyl) -9-anthracenecarbaldehyde of melting point 158 DEG-159 DEG C. was prepared; (C, H, Cl).

Example D 1, 10-dichloro-9-anthracenecarbaldehyde and 4,10-dichloro-9-anthracenecarbaldehyde.

The procedure of V.I. Rogovika et al. Zh. Org. Khim. 3, 1315 (1967), starting material

1-chloroanthraquinone to give a mixture of 1, 10-dichloro-9-anthracenecarbaldehyde and 4,10-dichloro-9-anthracene carbaldehyde. These compounds were separated by preparative liquid chromatography under high pressure using toluene as the elution solvent, to give 3.05 g (14% yield) of 1,1-dichloro-9-anthracenecarbaldehyde, m.p.

180.5-183 ° C (Rf a 0.64, SiO 2, PhCHg), (C, H, Cl), and 0.59 grams (corresponding to a 3% yield) of 4, 10-dichloro-9-anthraoencarbaldehyde; melting at 167 to 170 ° C, (R _f> 0, (57 ', S10 _2, PhCHg) / C, H, C1 /.

Example E

10-bromo-9-anthracene rbaldehyde.

Prepared from 9,10-dibromantracene (20 g, 60 mmol) using a modified method of R. Kuhn and H. Fischer, cf. Chem. Ber. 94, 3060 (1961). The mixture was cooled to -78 ° C and n-butyllithium nBuLio 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 cooled to -78 ° C before DMF (as a single addition) was added. The flask was then warmed to ambient temperature and then quenched with 1 M hydrogen bromide solution (200 mL). The biphasic system was extracted with CH 2 Cl 2 (3 x 500 mL) and the combined extracts were dried over MgSO 4, filtered, and the solvent was removed to give crude material. This material was purified by preparative liquid chromatography. under high pressure using toluene as the eluting solvent. After removal of the solvent, 13.06 g (76% yield) of 10-bromo-9-anthracenecarbaldehyde having a melting point of 215 to 216.5 ° C (literature: melting point 218 ° C, P. Kuhn and H) was obtained. Fischer, Chem., 94, 3060 (1961), obtained (C, H, Br).

Example F

4,5-Dichloro-9-an tracenecarbaldehyde.

The procedure 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-9-anthracene-carbaldehyde, the melting point of which was in the range of 1: 1; from 218 to 220 ° C, the PhCHg / CHgOH and elemental analysis (C, H, Cl) values were consistent with the theory; melting point ranges from 224 to 226 ° C in the literature, see E.L, Stogryn, 3rd Med. Chem. 17, 563 (1974).

Example G

Formylation of fluoranthene.

The fluoranthene (100 grams corresponding to 0.49 moles) was formulated as in Example A e 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 fractions containing the aldehyde mixtures were combined and the solvent was removed, yielding 1X5 grams of a crude yellow oil. This material was dissolved in 500 mL of CH 2 Cl 2 dichloromethane and then diluted with hexane to one liter. This gave a yellow precipitate which was isolated by filtration. The solid, 3-fluoroanthene-carbaldehyde, was crystallized with CH 2 Cl 2 / hexane / CH 2 Cl 2 / hexane then 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 1000 g of SiO ₂ silica gel using toluene PhCHg as eluent. Three aldehydes (including a larger amount of the 3-isomer) were obtained from this material. The total isolated amounts of the individual compounds, their analysis and the characteristics of the thin layer chromatographic analysis (SiO2 / PhCH3) of these aldehydes are given in the following:

I. 3-fluoroanthenecarbaldehyde: 68.73 g (61% yield), mp 103-104.5 ° C (Rf = 0.27, elemental analysis (C, H) consistent with theory, the literature reports a melting point of 98 to 99 ° C (see N. Campbell and NH Wilaon, Chem. and Ind., 1114, 1970).

XI. 7-fluoroanthancarbaldehyde: 2.10 g (corresponding to a yield of 2%), melting point 139-141 ° C, elemental analysis (C, H) consistent with theory,

Rf = 0.38.

III. 8-fluoroanthancarbaldehyde: 24.8 g (22% yield), m.p. from gi, 5 to 93 ° C, elemental analysis (C, H) values are consistent with theory, R f = 0.19.

Example H

4-chloro-9-anthracenecarbaldehyde.

Starting from 1-chloroanthracene prepared from 1-chloroanthraquinone according to the method of H.O. House et al. (Cf.

Org. Chem., 38, 1167, 1973), wherein the 1-chloroanthracan 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, (PhCH ₃ / CH ₃ OH), elemental analysis values were consistent with theory (C, H, Cl).

EXAMPLE 11 10-Methylsulfinyl-9-anthracenecarbaldehyde.

10-Methylthio-9-anthracenecarbaldehyde (see Example S, 12.0 g, equivalent to 48 mmol) and 450 ml of CH 2 Cl 2 were charged in a 1 liter round bottom flask equipped with an addition funnel and stir bar. . The resulting solution was 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 an 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 Na ₂ SO ₄ , filtered, concentrated to 500 mL. It was passed through silica gel SiOg (250 g) using toluene (5 L) as eluent. The desired material was then eluted from SiO ₂ using ethyl acetate (2L) 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; from 182 to 184 ° C. The results of elemental analysis (C, H, S) were consistent with the theory.

Example 3

2-triphenylcarbaldehyde.

In this example, the same formylation procedure was used as in Example A except that the reaction temperature was 85 ° C, starting from triphenylene and the final product was 2-triphenylenecarbaldehyde, mp 160-161.5 ° C. C. Values (CHgClg / CHgOH) and elemental analysis (C, H) values corresponded to theoretical values.

Example K 10-methoxy-9-anthracenecarbaldehyde.

According to this example, a 2 liter round bottom flask equipped with a head, thermometer and condenser was placed. 15-crown-5 at 25.89 grams corresponding to 0.119 mol, followed by sodium methoxide NaOCH3 at 7.62 grams corresponding to 0.141 mol, and methanol at 50 ml. After 5 minutes, 10.4-chloro-9-anthracenecarbaldehyde (28.4 g, 0.118 mol) and 900 ml of dry toluene were added to this clear colorless solution. Then, the solvent was distilled off at a head temperature of 108 ° C (evaporating solvent volume was 300 ml). An additional volume of dry toluene was added to bring the total volume to one liter. The reaction mixture was refluxed for four hours, then cooled and poured onto a large SiO ₂ silica cartridge (1000 grams) in a sintered glass funnel. The crude product was chromatographed using toluene (5L) as eluent. The 250 ml fractions thus obtained containing the product were combined (total volume obtained was about 3 liters) and then the solvent volume was reduced to 500 ml. The shiny, gold crystals thus obtained were filtered off, and after drying at 50 ° C, 15.6 g of material were obtained. The filtrate volume was then reduced to 200 ml and a further portion of the product precipitated from the solution, which was filtered and dried to give 6.1 g of additional material. The two products were combined to give 22.51 g (81% yield) of 10-methoxy-9-anthracenecarbaldehyde, which material was used without further purification. Recrystallization yielded an analytically pure material having a melting point of 164.5 ° C to 166.5 ° C. The PhCH3 value and the analyzed values (C, H) corresponded to theoretical values. (Melting point 165 ° C, see B. B. Conant and M. Bramann, 3 * Amer. Chem. Soc. 50, 2305, 1928).

Example L 10-formyl-9-anthracanecarbonitrile.

In a 25 ml round bottom flask equipped with a thermometer, a condenser, a nitrogen inlet and a bubbler, and with a stir bar, 10 grams of chloro-9-anthaldehyde was added at 5 grams corresponding to 21 mmol. CuCN copper cyanide (2.14 g, equivalent to 24 mmol) gave 100-ml N-methylpyrrolidinone, DMF (15 ml) and bis (triphenylphosphine) palladium dichloride (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. Then the reaction was cooled to 70 ° C and the reaction mixture was poured into a solution consisting of 16 grams of FeCl 3 · hexahydrate ·

HgO and 70 ml of 1.0 M hydrochloric acid in 400 ml of water. The resulting reaction 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 charge of SiO 2 silica gel (100 grams). The filtrate was concentrated to 75 mL and 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, mp 270-275 ° C. . The values of elemental analysis (C, H, N) corresponded to the theory.

Example M

S, 10-dihydro-9,10-dioxo-1-anthracenecarboxylic acid.

The procedure was such that benzanthrone (technical grade) was purified by chromatography using silica gel SiO ₂ and toluene as the eluent (83% yield). Melting point was 172-172.5 ° C. C (melting point reported in the literature is from 170 to 171 ° C, see 0. Bally and R.

Shcoll, Ber. 44, 1656 (1911).

The purified benzanthrone (63.7 g, 0.277 mole) was dissolved in 15 ml of glacial acetic acid at 90 ° C and stirred with a mechanical stirrer. After cooling the solution to 80 ° C, 200 grams of CrO ₃ solids, corresponding to 2 moles, were added in the form of five-grams, mixed at about 4 hours. The exothermic reaction was maintained at a temperature of about 80 ° C, releasing carbon dioxide. After the evolution of carbon dioxide ceased and the reaction temperature dropped, the heater jacket was reused and the reaction mixture was then stirred 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, and the wash was continued until the wash was colorless. The solid thus obtained was redissolved in two liters of hot methoxyethanol, and then the mixture was filtered through Celite (Trade Mark) to separate a solid black residue. The volume of the solution was then reduced to about 75 mL (some solid formed) and the mixture was diluted with 100 mL of CH 2 OH to give the product. It was filtered to give 32.0 grams (46% yield) of the gold-brown 9,10-dihydro-9,10-dioxo-1-anthracenecarboxylic acid, m.p. The range of elemental analysis (C, H) was consistent with theory (according to literature, the melting point is in the range of 293 to 294 ° C, see Chemistry of Carbon Compounds IIXb, ed. EH Rodd, 1419, 1956, Elsevier, New York).

.alpha.-anthracenecarboxylic acid.

To prepare this compound, 9.10-dihydro-9,10-dioxo-1-anthracenecarboxylic acid (90 grams, equivalent to 0.357 moles) was charged to a 5 L three-necked flask fitted with a condenser, thermometer, and stirrer incorporated from above. zinc dust in an amount of 250 g, corresponding to 3.82 mol, further sulfate pentahydrate měcfného CuS0 _4, 5 HgO, 5 g, and 28% solution of ammonium hydroxide NH? OH in an amount of 2500 ml. The mixture was warmed slowly and heating continued until a dark red color of the solution appeared as the temperature reached 85 ° C. After 3.5 hours the solution turned yellow, and the reaction mixture was then heated for One hour, then cooled and excess zinc was filtered off. The filter cake was washed with more ammonium hydroxide (100 mL) and discarded. The filtrate was carefully acidified to pH 1 with concentrated hydrochloric acid, which was added in small portions over an hour, to give a light green precipitate which was collected by filtration. The solid was washed with water (200 mL) and recrystallized from a mixture of msthoxyethanol and water (with little hydrochloric acid added), filtered, and dried at 75 ° C as above. 65 grams (corresponding to a yield of 82%) of 1-anthraocarboxylic acid, having a melting point of 249-250 ° C was obtained. The elemental analysis (C, H) values corresponded to theoretical values (the melting point reported in the literature is 245 ° C). , see Chemistry of Carbon Compounds Illb, ed. EH Rodd, 1373, 1956, Elsevier, New York).

(1-anthryl) methanol.

In a 500 mL 2-neck two-necked flask equipped with a condenser, an addition funnel with nitrogen inlet, and a stir bar, charged with 1-anthracene carboxylic acid (6.88 g, 31 mmol) and dry tetrahydrofuran THF 250 ml. A solution of 1M boron hydride BH ₃ in tetrahydrofuran (50 ml, corresponding to 50 mmol) was prepared in an addition funnel by tube. The boron hydride solution was added at one hour interval and the solution was stirred overnight at ambient temperature. Methanol CH 3 OH was then added to the reaction until hydrogen evolution ceased. Water (5 ml) was added to the flask, followed by 5 ml of 1N hydrochloric acid. The solvents were removed and 100 ml of toluene was added to the flask. The toluene used was also removed. The solid was recrystallized from ethyl acetate / hexane to give 4.3 g (67% yield) of (1-anthryl) -methanol, mp 124-125 ° C. Elemental analysis (C, H) values were theoretical, with the melting point reported in the literature in the range from 124 to 125 ° C, see 5. Akiyama et al. Bull Chem. Soc. Oap. 35, 1962.

1-anthracenecarbaldehyde.

To prepare this compound, (1-anthryl) methanol was added to a 2 liter round bottom flask equipped with a condenser and a magnetic stirrer in an amount of 21.0 grams, equivalent to 0.10 mol, followed by dichloromethane CH 2 Cl 2. 1200 ml and pyridine chlorochromate PCC 32.33 g, corresponding to 0.15 mol. The mixture was then heated under reflux for 5 hours. The reaction mixture was then cooled and then filtered through a 400 g silica gel cartridge using toluene as the elution solvent. The first one liter portion of the solution was concentrated to give 15 grams 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. Melting point: 130-131 5 ° C, the melting point value reported in the literature being in the range from 126.5 to 127.5 ° C, see PH Gore 3, Chem. Soc. 1616 (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 procedure of 6. Barnett,

3.W. Cook and H.H. Grainger, see. Ber. 57 B, 1775 (1924), reduced using boron hydride θ in tetrahydrofuran as described in 18 ° C to afford (10-bromo-1-anthryl) methanol having a melting point of 125 to 127 ° C. EtOAo (hexane) and elemental analysis (C, H, Br) values were consistent with theoretical values.

10-bromo-1-anthracenecarbaldehyde.

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

Example 0

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 HO House et al. (see 3. Org. Chem. 38, 1167, 1973), formulated in the same manner as in Example A except that CH 2 Cl 2 was used as the reaction solvent in this case. A mixture of 2-chloro-9-anthracanecarbaldehyde and 3-chloro-9-anthracanecarbaldehyde in a ratio of 4: 1 (in 87% yield) was obtained by trituration of this material with preferential crystallization of 2-chloro-8-anthracenecarbaldehyde from methanol. The title compound is obtained after further crystallization from a mixture of toluene and hexane to give pure 2-chloro isomer having a melting point of 149-150 ° C. The values for elemental analysis (C, H, Cl) corresponded to theoretical values (the melting point reported in the literature is in the range from 148 to 150 ° C; United Kingdom Patent No. 1,149,557). The filtrate obtained from CH 3 OH-trituration (R _f 0.48, silica gel SiO ₂ , toluene PhCHg) was further purified by preparative high pressure liquid chromatography to give pure 3-chloro-9-anthaldehyde. m.p. 122-123.5 ° C. Values PhOH ^ / hexane and the values of elementary analysis / C, H, C1 / correspond to the theoretical values (R _f 0.48, SiO, PhCHg).

CS 273347 82

Example P 10-ethylthio-9-anthracenecarbaldehyde.

The procedure of Example B was followed using 10-ethyl-thio-9-anthracene-carbaldehyde, m.p. 74-75.5 ° C. Values of elemental analysis (C, H, S) corresponded to theoretical values ·

Example Q10 - ([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, starting from 10-chloro-9-anthracenecarbaldehyde and 2-iodoethanol. prepared 10 - ((2-hydroxyethyl) thio) -9-anthracenecarbaldehyde. The melting point of this product was in the range of 103 to 104 ° C. PhCH ₃ values (hexane with elemental analysis values (C, H, S) corresponded to theoretical values.

Example R

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

The method of VX Rogovik et al. (Zh. Org. Khim 3, 1315, 1967), starting from 2-chloroanthraquinone, and in this way a mixture (in a ratio of about 1 t 1) of 2,10-dichloroantracenecarbaldehyde and 3,10-dichloroantracenecarbaldehyde (in yield) was prepared. 68%). The mixture was separated using a high pressure preparative liquid chromatography method using an etiquette of the recycle technique to yield 2,10-dichloro-9-anthracene-carbaldshyd melting in the range of 175, 5 ° C to 176.5 ° C (PhCHg values and elemental analysis values were consistent with theoretical values of (C, H, Cl) and 3,110-dichloro-9-anthracenecarbaldehyde with a melting point of 173.5 to 175 ° C ( values (PhCH ₃ ) 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-anthracenecarbaldehyde.

The procedure of Example K was followed except that sodium methoxide and NaOCH 3 / CH 2 OH were replaced with NaOEt and ethanol starting from 10- chloro-9-anthaldic anhydride, to give 10-ethoxy-9-anthraconecarbaldehyde, m.p. 88 DEG-90 DEG C. (CHCl2 / hexane: elemental analysis (C, H) was as shown).

Example T

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

A three-liter two-necked flask was fitted with a thermometer, a condenser, a stir bar, a nitrogen inlet, and a bubbler, and a target was inserted into the vessel. 25 g of potassium butylate corresponding to 0.22 mol, followed by ethylene glycol of 1500 ml and 10-chloro-9-anthraldehyde of 50 g corresponding to 0.207 mol. The mixture was stirred at 100 ° C for 1.5 hours. A further 5 grams (corresponding to 45 mmol) of tarc was then added. potassium butylate and stirring was continued for an additional 0.5 hour. The reaction mixture was cooled and then poured into 1500 ml of cold water, then stirred for 10 minutes, after which the precipitated podium was separated by filtration. The resulting yellow solid was dissolved in one liter of CH ₂ Cl ₂ and this solution was passed through a plug of silica gel with a weight of 100 g, using a volume of CH₂Cl₂ 9 liters. This dichloromethane was removed and the desired material was eluted with ethyl acetate 12% EtOAc. The corresponding fractions were collected and the solvent was removed, after drying at 50 ° C, 10- (2-hydroxyethyloxy) -9-anthracenecarbaldehyde in 28.82 g (53% yield), mp 142-144 ° C (CH 2 Cl 2 / hexane, elemental analysis (C, H) consistent with the compound).

Example

10-methylsulfonyl-9-anthracenecarbaldehyde.

10-methylthio-9-anthracenecarbaldehyde, 4.50 g, corresponding to 17.83 mmol, was dissolved in CH 2 Cl 2 at 10 mL, and the solution was cooled to 0 ° C under stirring. help ice bath. The solution was stirred magnetically and then treated dropwise over 15 minutes with a solution of m-chloroperbenzoic acid (technical grade, 85% purity, 7.08 grams, corresponding to 35.76 mmol) in 250 mL of CH 2 Cl 2. ^. The ice bath was then removed and the clear solution was stirred for 2 hours. The solution was washed sequentially 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 silica gel packed, small volume (200 ml) in a sintered glass funnel, using dichloromethane CH ₂ C1 ₂ as eluting solvent (500 milliliter). The solvent was removed, .přičemž a crude which was crystallized from dichloromethane and ethanol, CH ₂ Cl ₂ / EtOH and was treated to afford the LO-methylsulfonyl-9-antracenkarbaldehyd melting point ranging from 216-217 ° C ( elemental analysis values (C, H, S) corresponded to the indicated compound).

ExampleV

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

According to this exemplary embodiment, the target was. potassium butylate KOtBu in amounts

8.2 g (0.162 mole) in methoxyethanol (1000 ml) treated with 10-chloro-9-orthraldehyde (25 g), equivalent to 0.104 mole, and the mixture was refluxed 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 (corresponding to 92% yield) of 10- (2-methoxyethoxy) -8-anthracenecarboxaldehyde, m.p. 87 DEG-88 DEG C. (elemental anelysis values / C, N) were obtained according to the procedure. (corresponding to the title compound, CH ₂ Cl ₂ / hexane, R _{f =} 0.16, SiO ₂ , CH ₂ Cl ₂ ).

Example W

10-rao rfolin-9-an t racencarbaldehyde

10-chloro-9-anthracenecarboxaldehyde, 25 grams, equivalent to 0.104 mol, in morpholine (technical grade) at 500 ml, was heated at 55 ° C under nitrogen for 17 hours. The reaction mixture was then poured into 2 L of water. A precipitate was formed, which was filtered off and then chromatographed on a silica gel of SiO ₂ (1 kg) using toluene (4 L) as the starting material to remove the starting material and by-products. The orange layer of the product was eluted with CH 2 Cl 2 dichloromethane (2 L) to give 10.58 g (35% yield) of 10-morpholine-9-anthracene CS 273347 B2 carboxaldehyde, m.p. 182-184 ° C. C, softening at 175 ° C (elemental analysis (C, H, N) were consistent with the above-mentioned compound, system R f = 0.16, sieve ₂ , <gh ₂ or c ₂ ).

Example X

12-chloro-6-chrysocarbaldehyde ·

In this example, 6-chlorotrysene (70 grams, corresponding to 0.265 moles) was formulated in the same manner as in Example 1A ^; except that CH 2 Cl 2 in 2500 mL was used as the reaction solvent. The obtained liquid product was chromatographed on silica gel Si0 ₂ weighing 1 kilogram, using EtOAc as eluent, ¹ and this procedure was obtained 19.1 g (corresponding to a yield of 25% strength), 12-chloro- -6-chrysocarbaldehyde, m.p. 255-257 ° C (EtOAc system,? 0.42, SiO 4, toluene).

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

A solution of 10-chloro-9-anthaldehyde (15 grams, corresponding to 0.062 moles), imidazole (10.2 grams, 0.15 moles) and dimethylformamide DMF (300 mls) was treated at 55 ° C. ° C target with potassium butylate KOtBu in an amount of 7.9 g corresponding to 0.07 mol, and then the mixture was stirred for 30 minutes. The reaction mixture was poured into 0.1 M sodium hydroxide solution (1500 ml). The precipitate was filtered and then chromatographed on SiO ₂ silica gel (500 grams) using 3 L CH 2 Cl 2 as the starting eluent to remove the starting material and by-products.

The yellow product layer was eluted with EtOAc (2 L) to give 12.29 g (73% yield) of 10- (imidazol-1-yl) -9-anthracenecarbaldehyde, m.p. in the range from 194 to 195 ° C (elemental analysis values / C, H, N / match said compound system EtOAc, R> = 0.38, Si0 _2, EtOAc).

Example

2-ethylanthracene.

A 5-liter three-necked container was used; equipped with a condenser, a thermometer and an overhead stirrer, which was charged with 2-ethylanthraquinone of 120 grams corresponding to 0.151 moles, and zinc dust of 300 grams corresponding to 4.59 mole, calcium sulfate pentahydrate CaSO ₄ . 5 H ₂ 0 in an amount of 3 g ,: and 28% solution of ammonium hydroxide in an amount of 2800 ml. The temperature was then raised eměei, 'until the initial dark red coloration is changed (interval of about 6 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 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 100 ml of absolute ethanol and then dried. 40 grams (corresponding to a yield of 38%) of 2-ethylanthracene were obtained, the melting point values and elemental analysis (C, H) being consistent with the theory,

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

In this embodiment, 2-ethylanthracene in an amount of 40 grams, corresponding to 0.194 mole, was formulated in the same manner as in Example A, with the difference.

The reaction mixture was treated with CH 2 Cl 2 (500 mL) as reaction solvent. The product was chromatographed using SiO ₂ silica gel and toluene PhCHg as eluent. 43.68 g (96% yield) of a mixture of 2-sthylantracene-9-carbaldehyde and 3-ethylantracene-9-carbaldehyde was obtained.

Example AA

3,5-diphenyl-7a (7H) -ethoxymethyl-lH, 3H, 5H-oxazole / ^- 3,4-oxazol-A_7.

First, a 60% dispersion of sodium hydride in mineral oil (34.0 grams corresponding to 0.15 moles) was mechanically stirred, then washed with dry hexane to remove the oil, and then suspended in DMF (300 mL). To this mixture was added a solution of 3,5-diphnyl-1H, 3H, 5H-oxazole (3,4-c) oxazol-7a (7H) methanol in an amount of 208.2 grams corresponding to 0.7 mol prepared according to the procedure of 3. Pierce et al., cf. 3ACS 73, 2595, 1951, in dry DMF (300 mL), maintaining the reaction at a temperature between 30 and 35 ° C. The salt suspension was then stirred at ambient temperature for 60 minutes, then diluted with 200 mL DMF dry DMF to facilitate stirring, then cooled and treated with ethyl iodide (in excess) to maintain the reaction temperature at room temperature. range 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 formed was filtered off. The solvent was removed using a rotary evaporator to give 229.5 g of a yellow oil containing both the starting material and the desired product. Then the solution of the above oil in chloroform, mixed with SiO ⁰ weight 200 g, and the solvent odstranšno. The resulting solid was then loaded onto a column packed with SiOg (800 grams). Elution with 1: 3.5 EtOAc / hexane: ethyl acetate / hexane yielded 139.7 g (61.3% yield) of 3,5-diphenyl-7α (7H) -ethoxyraethyl-1H, 3H. 5H-oxazolo (3,4-c) oxazole. An analytical sample was obtained by recrystallization from hexane. The melting point of the product thus obtained was in the range of 83.5 to 85 ° C, the elemental analysis values (C, H, N) corresponding to the compound. All of the material was used without further purification.

2-amino-2-ethoxymethoxy-1,3-propanediol in the form of 1/4 H 2 O hydrochloride.

3,5 diphenyl-7a (7K) -ethoxymethyl-1H, 3H, 5H-oxazolo- (3,4-c) oxazole, 135 grams, equivalent to 0.42 mol, was dissolved. in 6N hydrochloric acid at 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, which was then cooled in an ice bath to facilitate crystallization. The solid was diluted with cold CH 2 CN (8), 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 1/4 HgO hydrochloride. The melting point of the product thus obtained ranged from 78 to 79 ° C, the elemental analysis values (C, H, Cl, N) corresponded to the compound.

Example AB

4-aza-3-hydroxymethyl-3-methyl-1-oxaspiro (4,5) decane.

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

303.4 g (3.0 mol) of cyclohexanone (294.5 g), corresponding to 3.0 mol of toluene PhCH ₃ (400 ml) was heated under reflux for about 2 hours with azeotropic removal of water. Upon cooling, the stage crystallized from toluene, which was then recrystallized twice from hexane to give 444.4 grams of 4-aza-3-hydroxymethyl-3-methyl-1-oxaspiro / 4,5-decane (equivalent to 80% yield). melting at 52-54 ° C; elemental analysis (C, H, N) was consistent with the indicated compound.

4-aza-3-methoxymethyl-3-methyl-1-oxaspiro (4,5) decane.

A 60% dispersion of sodium hydride NaH in mineral oil was first mixed with 75 grams corresponding to 1.9 moles by mechanical means, and the mixture was washed with dry hexane to remove the oil and suspended in dry DMF (200 mL). A solution of 4-aza-3-hydroxymethyl-3-methyl-1-oxaspiro [4,5] decane was added to the mixture in an amount of 27.8 grams, corresponding to 1.5 moles, in DMF dry DMF. 200 ml while maintaining the temperature of the reaction mixture at 30-35 ° C. Then, small amounts of dimethylformamide DMF were added, only necessary to facilitate stirring. The mixture was stirred at ambient temperature for 1.5 hours, then cooled and treated with methyl iodide in an amount

234.2 g, corresponding to 102.7 milliliters, or 1.65 moles, maintaining the reaction 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 (3 L). The reaction mixture was then filtered and the solvent was 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-oxaspiro (4,5) decane as colorless. bp 114 ° C (14 mm; elemental analysis was consistent with the compound).

2-Amino-3-methoxy-2-methyl-1-propanol.

A 4-aza-3-mothoxymethyl-3-methyl-1-oxaspiro (4,5) decane solution of 299 grams corresponding to 1.5 moles and a 6N hydrochloric acid solution of 500 milliliters were heated under heating. reflux condenser for 60 minutes. After cooling, two layers were formed, the top layer containing cyclohexanone and was removed by extraction with Et2O diethyl ether (2 x 400 ml). The lower aqueous layer was concentrated on a rotary evaporator to give a syrupy mass which was then treated with 50% sodium hydroxide, which was used in excess. The resulting slurry was extracted with a 2: 1 mixture of diethyl ether and dichloromethane Et ₂ O / GH ₂ Cl ₂ in an amount of 4 x 500 milliliters. 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 ° C (17 mm; elemental analysis (C, H, N) was consistent with the title compound).

Example AC

3 <£ -2-amino-1,3-cyclohexarodioacetate ·

This compound was prepared according to the method of F. Lichtenthsler (see Ber.

95, 851 (1963), the melting point of the product thus obtained was in the range of 175 to 177 ° C; elemental analysis values (C, H, N) corresponded to the product (m.p. 175-177 ° C in literature), F. Lichtenthaler, Ber. 96,

851 (1963).

Example AD

2-isopropyl-2-nitro-1,3-propanediol.

A solution of 2-methyl-1-nitropropane of 38.7 grams, corresponding to 0.375 mol, prepared according to N, Kornblum, B, Tunbe and H. Ungnad, see 3, Am. Chem. Soc., 1954, 76, 3029, and NEt ₃ in an amount of 3.79 g, corresponding to 0.0375 mol, in 50 ml of methanol, added dropwise to a 37.2% aqueous formaldehyde solution of 76.2 After 72 hours, the solution was concentrated under vacuum and the excess was dissolved in 250 ml of water. The solution was then continuously extracted for 1 hour. 1 hour with dichloromethane CF 3 Cl 2. The dichloromethane solution was dried over MgSO ₄ , filtered and concentrated to give 53.3 g of 2-isopropyl-2-nitro-1,3-propanediol as a waxy white solid (m.p. yield 87%). The melting point of the product thus obtained was in the range of 67-72 ° C (melting point in the literature is in the range of 87-88 ° C, see BM Vanderbilt and HB Haas, Ind. Chem., 32, 34, 1940). In our experience, this procedure 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-propanediol, resulting in 2-amino-2-isopropyl-1 acetate. 3-propanediol, which was obtained with a yield of 98%, the melting point of this product 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, Heterocyclic Chem, 13, 337 (1975), the melting point of which is in the range of 70 to 72 ° C) .

Example AE Ethyl M-benzylidene-L-alaninate.

Ethyl N-benzylidene-L-alaninate was prepared according to the general procedure of Method 6, Storka et al., Supra, Org, Chem. 41, 249 (1976), the boiling point of this compound ae being in the range of 98 to 100 ° C (0.4 mm, boiling point in the literature being 100 ° C / 0.3 mm, see A, Calcayai et al. Synthesis 445 (1981).

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

Freshly distilled dihydropyran (59.0 grams, equivalent to 0.7 mole) was added dropwise to a chilled solution of iodoethanol (90 grams, equivalent to 0.57 mole) in Et 1 O diethyl ether, containing 0.1 grams of p-toluenesulfonic acid. The solution was stirred for 1 hour at 5 ° C. To the reaction mixture was added solid potassium carbonate K 2 CO 3 in an amount of 5 grams, and the resulting suspension was stirred for an additional hour at ambient temperature. The reaction mixture was filtered and the collected solids were washed with Et 1 O diethyl ether. The obtained organic solutions were combined and concentrated on a rotary evaporator (in a vessel washed with 1% -nm NEt ₃ in water). The thus obtained crude 2- (2-iodoethoxy) -tetrahydro-2H-pyran in an amount of 100 grams (corresponding to a yield of 68.9%) was used without further purification.

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

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

51.5 g, corresponding to 0.51 mole, in a 700 ml mixture of dry THF of 700 mlCS 273347 Q2 liters and 40 ml of dry HMPA, maintaining the temperature at 30 to 40 ° C. The solution was cooled to -70 ° C and 74.9 g (0.365 mol) of N-benzylidene-L-alaninate was added dropwise to the solution while the reaction mixture was allowed to warm to room temperature. temperature of -20 ° C over a period of several minutes. The red solution was then cooled to -70 ° C,

In a further procedure, 2- (2-iodoethoxy) -tetrahydro-2H-pyran in an amount of 90.1 g, equivalent to 0.330 mole, was added to the solution prepared as described above at a rate such that the temperature in the reaction mixture did not exceed -65 ° C. The solution was allowed to warm slowly to ambient temperature and stirred for 14 hours. The volume of this solution was then reduced to 300 ml with a stream of dry nitrogen over a few additional hours to facilitate the final treatment. The reaction was then quenched by the addition of 800 mL of saturated sodium chloride solution and diluted with 600 mL of EtgO. The diethyl ether was then removed and the aqueous layer was extracted with 500 mL hexane. The thus obtained about diethylotorové hoxanové layers were combined and dried with sodium sulphate Na ₂ S0 _{4 t} the resulting solution was filtered and the solvent removed to afford 124 g of crude red oil. Flask-to-flask distillation (glass flasks were washed with 1% aqueous NEt ₃ solutions) at a bath temperature of 210 ° C and 0.3 mm to give 95 grams of ethyl 2-benzylideneamino-2-methyl-4 - (/ tetrahydro) -2H-pyran-2-yl / oxy) butyrate, which was then homogenized in pc to give acceptable NMR and mass spectra. This product was stored under nitrogen in a freezer and used without further refining.

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 100.0 grams, equivalent to 0.3 mol, in THF tetrahydrofuran was added. 100 milliliters was added slowly to a suspension of t-aluminum aluminum hydride (22.77 grams, corresponding to 0.6 mole) which was rapidly stirred in dry 1 liter tetrahydrofuran at a 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), 15N sodium hydroxide solution (23 ml) and again with water (45 ml). This gave a solid pod 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-benzylidene-amino-2-methyl-4- ((tetrahydro-2H-pyran-2-yl) oxy) butyrate in an amount of 81%. 1 g, which corresponds to a yield of 92.0%, and this product was in the form of a thick oil which was used for further purposes without further purification.

2-benzylamino-2-methyl-1,4-butanediol.

In this embodiment, the crude ethyl 2-benzylidenemino-2-methyl-4- ((tetrahydro-2H-pyran-2-yl) oxy) butyrate 80.1 g, corresponding to 0.273 mol, was dissolved in a 3N solution hydrochloric acid (128 ml).

After 5 minutes, the mixture was washed with Et 2 O diethyl ether (200 mL). The 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 so formed was extracted with Et2O (3.times.200 ml). The combined diethyl ether extracts were combined and concentrated to give 63.6 g of a thick oil. It was distillation. 49.8 g (94% yield) of 2-benzylamino-2-methyl-1,4-butanediol were obtained as a pale yellow oil. The boiling point of the product thus obtained was between 168 and 170 ° C (0.35 mmj elemental analysis (C, H, N) corresponding to the compound).

2-amino-2-methyl-1,4-butanediol in the form of the hydrochloride.

To prepare this compound, 2-benzylamino-2-methyl-1,4-butanediol (31.08 g, equivalent to 0.149 mole) was dissolved in 95% ethanol (240 mL) containing concentrated hydrochloric acid. 21 ml, corresponding to 0.25 mole, and 5% palladium on charcoal 10.0 grams, then reduced in a Parr apparatus at 0.275 MPa for 37 hours at ambient temperature. The catalyst was removed by filtration and the solvent removed on a rotary evaporator (60 ° C bath) to give 20.91 g of 2-amino-2-methyl-1,4-butanediol hydrochloride. (yield 90.2%), and was a clear, thick, colorless oil with acceptable NMR and mass spectrum. 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), however, no values are given for this compound.

Ex. 1 a d AF

10-Chloroanthracene-1-carboxylic acid.

In this example, 1-anthroleic acid, 24 grams corresponding to 0/108 mol, was treated with N-chlorosuccinimide at 24 grams corresponding to 0.18 mol, in N-methylpyrrolidinone, and the mixture was heated under a nitrogen atmosphere at - a temperature of 90 ° C for 1.5 hours. The reaction mixture was diluted with 3.5 liters of water, filtered, dried and the precipitate obtained was recrystallized from ethyl acetate with EtOAc to give 16.41 g (59% yield) of 10-chloroanthracene. The melting point of this product was between 257 and 277 ° C. The elemental analyzes (C, H, Cl) corresponded to the compound.

Ethyl 10-chloroantracene-1-carboxylate.

The above compound was prepared by adding concentrated sulfuric acid (1.0 mL) and absolute ethanol (10 mL) to 10-chloroanthracene-1-carboxylic acid (17.3 g, equivalent to 0.0674 mol). 500 ml, the mixture was heated together under reflux for 3 days using a 4X molecular sieve in a Soxhlet extractor to remove water. The solvent was then removed and partitioned between ethyl acetate and EtOAc and saturated sodium bicarbonate. The solvent was removed from the organic layer to give 14.85 g (77% yield) of ethyl 10-chloroantracene-1-carboxylate, which was used without further purification.

10-chloro-1-anthracenemethanol.

To prepare the title compound, starting from ethyl acetate 10-chloroantracene-1-carboxylate (14.85 g, 0.052 mol) in THF (300 mL) was treated with LiBH4 (1.14). gram, corresponding to 0.052 mole, and was then heated under reflux for 16 hours. The reaction mixture was then poured into ice water and acidified to pH 6 with hydrochloric acid. The solid was filtered, washed with water (500 ml), dried and finally chromatographed on silica gel (SiOg) at 500 grams using ethyl acetate EtOAc as eluent. The solvent was removed on a rotary evaporator to give a solid 24.

This material was crystallized from carbon tetrachloride G & ₄ , yielding 10.3 grams (corresponding to B1% yield) of 10-chloro-1-anthracenemethanol having a melting point of 133-140. ° C i values for elemental analysis (C, H, Cl) corresponded to the indicated compound.

10-chlorantracan-1-carbaldehyde ·

10-Chloro-1-anthracenemethanol (8.8 g, 0.036 mole) was dissolved in CH 2 Cl 2 diethyl ether (200 mL) and treated with BaMnO 2 (15 grams, 0.059 mole). the treatment was carried out for 3 days and then the mixture was rapidly refluxed. The reaction mixture was filtered and the filtrate was worked up to dryness. The residue was chromatographed using high pressure preparative liquid chromatography using toluene PhCH ₃ as eluent to give 6.0 g (69% yield) of slightly contaminated 10- chlorantracene-1-carboxaldshyde, which was then used for further purposes without over-conversion,

Example AG 3-nitro-2,4-pentanediol.

73.3 g (1.2 mole) and acetaldehyde (158.6 g, 3.6 mole) were cooled in an ice bath. Water was added to the flask. 80 ml and calcium hydroxide at 0.40 grams. The resulting mixture was then stirred under nitrogen for 8 hours, then neutralized with carbon dioxide and filtered. The filtrate was extracted continuously with CH 2 Cl 2 dichloromethane for one hour. The dichloromethane extract was concentrated in vacuo to give 114.6 g (77% yield) of crude 3-nitro-2,4-pentaridiol 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. Ecketein and T. Urbanski, see, Roczniki Chem * 26, 571 (1952).

(2 6 6,4 4 5 C C 6 6 £) -4,6 dimethyl dimethyl-5-nitro-2-phenyl-1,3-dloxane *

In this embodiment, the solution of crude 3-nitro-2,4-pentanedioles was 115 grams, corresponding to 0.77 moles prepared as described above, and longer to 81.7 grams of benzaldehyde corresponding to 0 grams. 77 moles and 1.28 g of p-toluenesulfonic acid in 400 ml of benzene were heated under reflux (1.5 hours with azeotropic removal of water). After removal of the solvent under vacuum, the crude product (i.e. The mixture was dissolved in absolute ethanol (150 ml), and after 36 hours at room temperature, the crystals were collected and dried to give 25.8 g of the mixture as a white solid. The ratio of 5 t 1 (determined by NMR) of the desired product and further isomeric elemental analysis (C, H, N) was consistent with theory.

Pure 2 Z, 4 ', 6', 5', 6'C'-4,6-dimethyl-5-nitro-2-phenyl-1,3-dioxane was obtained after crystallization from absolute ethanol, the melting point of the product thus obtained being ranging from 117.5 to 118 ° C, the elemental analysis values (C, 1 H, N) corresponded to the compound.

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

The preparation of this compound was carried out from (2Z, 4 < 0.5 &gt; 6Z) -4,6-dimethyl-5-nitro-2-phenyl-1,3-dioxane in the same manner as in Example AM, with the difference using a temperature of 50 ° C and recrystallizing from 95% ethanol to give meso-3-amino-2,4-pentondiol acetate with a melting point of 108.5 to 100, 5 θθ; elemental analysis values (C, H, N) corresponded to the indicated compound.

Example AH

12-ethyl-G-chrysencarbaldshyd.

60 grams (0.234 mole) of 6-ethylchrysene was formulated as in Example A except that CH 2 Cl 2 was used as the reaction solvent for 1000 mL. The crude material was chromatographed on a 1 kg silica gel SiO ₂ cartridge eluting with toluene PhCH _{3 to give} 50.38 g (76% yield) of 12-ethyl- The melting point of this product ranged from 138 DEG to 139 DEG C. The elemental analysis (C, H) corresponded to the compound.

Example A1 10- (imidazol-1-yl) -9-anthracenecarbaldehyde.

Thiadiazole A solution of l0-chloro-9-e ^nt hraldehyduv 15 g, corresponding to 0.062 mol, as imidazole in an amount of 10.2 g, 0.15 mol, and DMF in an amount of 300 ml, at 55 ° C processed target. with potassium butylate KOtBu ^{in an} amount of 7.9 grams corresponding to 0.07 mol, and the mixture was stirred for 30 minutes. The reaction mixture was then poured into 0.1 H NaOH (1.5 L). The precipitate was collected by filtration and chromatographed on SiO ₂ silica gel (500 g), eluting with CH ₂ Cl ₂ (3 L) to remove the starting material and by-products. The yellow product layer was eluted with EtOAc (2 L) to remove 12.29 g (73% yield) of 10- (imidazol-1-yl) -9-anthracenecarbaldehyde after removal of the solvent and drying. a melting point ranging from 194 to 196 ° C; EtOAc system; elemental analysis (C, H, N) was consistent with the compound.

Example AO 12-ethoxychrysen-S-corbaldohyd.

6-Ethoxychrysen (48 grams, equivalent to 0.176 mole) was formulated using the same procedure as in Example A except that the reaction solvent used was CH 2 Cl 2 dichloromethane (1000 mL). After separation of the crude material was chromatographed on silica gel packed _SiO2 weighing 500 g, using dichloromethane as .elučního agent, and after solvent removal and drying was obtained 33.7 grams (64% yield) of 12-ethoxyohrysen-6 -carbaldehyde, m.p. 173.5-176 ° C; elemental analysis (C, H) values were consistent with the indicated compound.

Example AK

4-chloro-10- (2-hydroxyethoxy) -9-anthracenecarbaldehyde.

According to this example, the isomeric mixture of 1-chloro-9-anthraldehyde and 4-chloro-9-anthraldehyde was in an amount. 36.8 g, 0.133 mol, in ethylonglycol (1000 ml), and tetrahydrofuran THF (200 ml), treated with the target. 12.5 g of KOtBu butylate, equivalent to 0.11 mol, was then heated to 80 DEG C. and heated at that temperature for 14 hours. The reaction mixture was poured into water (2 L). The precipitate obtained was filtered, washed with water (500 ml), sucked dry and then chromatographed on a 500 g SiOg silica gel, eluting with a solvent.

Dichloromethane CH 2 Cl 2 was used for the initial phase to remove starting material and by-products. The desired product was then eluted with EtOAc ethyleaterem acetic acid, after removal of the solvent and recrystallization from EtOAc to give 3 g are obtained (corresponding to a yield 7.5%) of 4-chloro-l0- (2-hydroxyethyl _xy) _g_ _an t _rQCOn carbaldohydd, melting at 141-145 ° C; elemental analysis values (0.11.01) corresponded to the fragrant compound.

Example AL

Formylation of 3-ethylfluoranthe.nu,

Accordingly, 3-ethylfluoranthene (70 grams, equivalent to 0.304 moles) was 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. Chromatography of the product on a 1 kg SiO ₂ cartridge yielded 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 follows:

a) 3-ethylfluoranthen-7-carbaldehyde and 4-ethylfluoranthen-7-carbaldehyde, as obtained in an amount of 5.0 g (yield 6%) _(Rf »0.55, Si0 _2, PhCHg); elemental analysis values (C, H) corresponding to the product obtained,

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

4.7 g (yield 6%}, R _£ = 0.49, Si0 _2, PhCH _3; Elemental analysis / C, H / corresponds to said product;

c) 3-ethylfluoranthene-8-carbaldehyde and 4-ethylfluoranthene-8-carbaldehyde, ziacano in amounts

47.3 g (60% yield), ( _Rf = 0.38, SiO2, PhCH3); elemental analysis values (C, H) correspond to said product;

d) 4-ethylfluoranthene-3-carbaldehyde.

The above mixture (b) at 4.7 g was recrystallized twice from CH ₂ Cl ₂ / hexane to give 1.83 g (2% yield of 3-ethylfluoranthene) 4-ethylfluoranthene -3-carbaldehyde, mp 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 (286 mg, 7.15 mmol) was added to a solution of 3-nitro-2-butanol (59.6 g, 0.50 mol) and acetaldehyde in 132 g, corresponding to 1.50 moles, in anhydrous DMSO at 100 ml. The reaction was then carried out with stirring the reaction mixture under a 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 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 sequentially with water (50 mL) and brine (50 mL), followed by drying over magnesium sulfate and finally filtration. The volatile components 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 (64% yield). This liquid was mixed with EtOAc / hexane (1: 1, 1: 1, 50 mL) and subjected to 1.5 kg SiO ₂ flash chromatography (silica gel 60, 230-400 mesh), eluting with ethyl acetate / hexane 1: 1 EtOAc / hexane to separate 50 .mu.l fractions. The corresponding formulations were combined and the solvent removed on a rotary evaporator to give 43.5 g (53% yield) of the diastereomeric mixture of 3-methyl-3-nitro-2,4-pentanedioles (two meso forms) as described above. ad, 1-pair, easily distinguishable by NMR method in DMSO-d ⁶ ).

(+ -) - (2R ⁺ , 3RS, 4R ⁺ ) -3-nitro-3-methyl-2,4-pentanediol and meso-3-nitro-3-methyl-2,4-pentanediol.

Chromatographic separation of the above diastereoisomers was achieved. From an initial 500 ml fraction, 13.1 grams of one of the meso-3-nitro-3-methyl-2,4-pentanedioles were obtained as a colorless solid having a melting point of 60 to 61 ° C, elemental analysis (C, H, N) was consistent with the compound. The remaining fractions were combined to give 38.3 g of an isomeric mixture containing both the meso- and id-1-compounds. Recrystallization from EtOAc / hexane (EtOAc / hexane, 2: 1, 300 mL) yielded 27.8 g of (+ -) - (2R *, 3RS, 4R ⁺ ) -3-nitro- 3-methyl-2,4-pentanediol and other intermediate 3-nitro-3-methyl-2,4-pentanediol in a ratio of 4: 1, the melting point of this product being in the range of 79 to 86 ° C. C, H, N / were consistent with theory.

The above two substances were then used in the next procedure without further purification.

(+ -) - (2R ⁺ , 3RS, 4R ⁺ ) -3-amino-3-methyl-2,4-pentanedol as acetate.

To prepare this compound, a solution of 3-methyl-3-nitro-2,4-pentanediol in an amount of 16.3 grams, corresponding to 0.1 mole, was a mixture of d, l-pair and one. the meso form shown above, in a 4: 1 ratio, in 95% ethanol at 150 ml, added acetic acid at 19 ml, followed by 10% palladium on Pd / C activated carbon 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 eye temperature for 2 days. The thus obtained colorless ^- albeit viscous syrup was dissolved in absolute ethanol in the amount 3u ml, and the solution was heated and, after addition of dry Et ^ O diethyletoru 100 mL turned 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. Yield of pure (+ -) - (2R ⁺ , 3RS, 4R ⁺ ) -3-amino-3-methyl acetate

2.4 Pentanediol (which was confirmed by NMR method in DMSO-d) was due to this incorporation

12.8 g, ^- wherein the melting point of the product ranged from 110.5 to 112 ° C Elemental analysis / C, H, N / of the product was consistent with the assigned structure, USSR patent no. 521 272 (see. CA 85 177498) discloses 3-amino-3-methyl-2,4-pentanediol as an intermediate, however, 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-methyl-3-nitro-2,4-pentanediol (not analyzed) to give meso-3-amino-3-methyl acetate. -2,4-pentanediol (53% yield), mp 137-138 ° C; elemental analysis (C, H, N) confirmed the compound.

Example A. (+ -) (2R ⁺ , 3S ⁺ ) -2-methyl-2-nitro-1,3'-butanediol (A) and (+ -) (2R ⁺ , 3R ⁺ ) -2-methyl-2 -nitro-1,3-butanediol (B).

According to this example, to the 2-nitro-propanol mixture of 63.0 grams corresponding to 0.60 moles and acetaldehyde in an amount of

39.6 grams, corresponding to 0.90 moles, which were 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 60 hours. The resulting solution was then neutralized with excess carbon dioxide. The resulting mixture was stirred for iodine hour and then filtered using a Millipore filter (TM). The filtrate was concentrated under vacuum at 35 ° C to give a viscous syrup residue which partially crystallized upon drying under vacuum (0.1 mm, ambient temperature, 48 hours) and then the mixture was triturated cold Et2O diethyl ether (35 ml). White solid crystals were formed, which were collected by filtration, then washed with cold EtgO (3 x 15 ml) and dried under vacuum at 0.1 mm and ambient temperature to give 34 g. 1 g of material, which was analyzed by NMR method 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 of 78 ° C in the literature, cf. Beil 1, 482 in Henry). Bull. Soc. Chim. Fr, (3) 15, 1244), the values for elemental analysis (C, H, N) corresponded to theory.

Thereafter, the original filtrate (including the wash) was concentrated under vacuum to give a pale yellow liquid, which was subjected to flash chromatography as follows. The sample was mixed with 1: 2 hexane: ethyl acetate / hexane (1: 2) at 100 mL and loaded onto a silica gel 60 column at 1500 grams (230-400 meeh). The column was then eluted with a mixture of hexane and ethyl acetate, with a hexane / EtOAc ratio of 2; 1, 12 L, followed by hexane / EtOAc 1: 1, 6 L, collecting 500 mL fractions. The appropriate fractions were combined. The pure product was obtained from the last 8 liters. The yield was 38.7 g, the resulting material being a viscous syrup and analyzed by NMR as mixture 1; 1 of said two racemic diastereoisomers A and B; elemental analysis (C, H, N) was consistent with theory. ·

The 1: 1 diastereoisomeric mixture (prepared as described above) was combined and combined to give a total weight of 67 grams, then subjected to a sequential liquid-liquid partition between water and ethyl acetate EtOAc and pure A was obtained by the above procedure (99% purity determined by NMR method using preparative liquid chromatography under high pressure using 3.5% aqueous acetonitrile as the mobile phase), the yield of this product was 24.9 grams (k '= 4.3; elemental analysis (C, H, N) corresponded to the compound), and B at 15.8 grams (k' and 2.1; elemental analysis values) (C ', H, N) corresponded 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 8) was determined by comparison of NMR analysis with the corresponding acetals derived from bonzaldehyde. In this way, product A of 1.49 grams corresponding to 0.01 mole and benzaldehyde of 1.06 grams corresponding to 0.01 mole were condensed in benzene in the presence of a catalytic amount of p-toluenesulfonic acid with azeotropic separation of water (see the method of H. Piotrowska, B. Serafin and T. Urbanski, Tetrahedon 109, 379, 1963). The mixture was washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and benzene was removed on a rotary evaporator to give a light yellow solid. Dissolution of this product in ethanol at 0 ° C attracted an oil which was isolated by decanting the mother liquor and drying under vacuum (0.1 mm, ambient temperature). 1.48 g (corresponding to 62% yield) of (+ -) (2R ⁺ , 4S ⁺ , 5R ⁺ ) -4,5-dimethyl-5-nitro-2-phenyl-1,3- was obtained. dioxane; elemental analysis of this product (C, H, N) was consistent with the indicated compound.

In a similar manner (+ -) (2R ⁺ , 4S, 5S) -4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane was prepared from product B and benzaldehyde in 74% yield. , H, N] corresponds to said compound

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

This compound was prepared from (+ -) (2R ⁺ , 3R ⁺ ) -2-methyl-2-nitro-1,3-butanediol using the same procedure as in Example AM, and the compound was obtained in yield. 97% J elemental analysis (C, H, N) was consistent with the title compound, melting at 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 and obtained in 93% yield. ; elemental analysis (C, H, N) was consistent with the compound, m.p. 163-165 ° C.

(+ -) (2R ⁺ , 3R ⁺ ) -2-amino-2-methyl-1,3-butanediol in the form of acetate.

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, mp 117-121 ° C.

(+ -) (2R ⁺ , 3S ⁺ ) -2-amino-2-methyl-1,3-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, the melting point of the product being between 1S3 and 165 ° C.

In the following, the following examples are given for illustrative purposes only, and are not intended to limit the invention in any way.

He did

Alkylaco of 6-chloromethylchrysene to give 2 - ((6-chrysenylmethyl) amino) -2-methyl-1,3-propanediol as the methanesulfonate.

A. Preparation of 6-hydroxymethylchrysene.

In a round-bottomed flask equipped with a condenser, nitrogen bubbler and magnetic stir bar was added 25.0 grams of chrysene-S-carbaldehyde (corresponding to 0.975 mol) in dry tetrahydrofuran (500 mL). 1.85 g of solid sodium borohydride NaBH4 (corresponding to 0.488 moles) was then added to the reaction mixture as a single portion. The solution was stirred overnight at ambient temperature. The mixture was then poured into a mixture of ice □ 0.1 M hydrochloric acid (1500 ml). This gave a solid which was collected by filtration and washed with water (3 x χ ·

This solid was then dissolved in a hot mixture of dichloromethane and tetrahydrofuran CH 2 Cl 2 / HF in a ratio of Ί1 and 1500 ml, then was treated with sodium sulphate Na ₂ SO ₄ , filtered and concentrated to a volume of 200 ml on a rotary evaporator. The solution was diluted with hexane (800 mL) and the resulting solid was removed by filtration and dried in a vacuum oven at 80 ° C overnight. A total of 23.4 grams (equivalent to yield) was attracted

92.9%) of 6-hydroxymethylchryaene, the melting point of the product thus obtained aa being in the range of 208 to 207 ° C;

Analysis »· *

H, 5.46

Found t C 88.32 H 5.47,

B, Preparation of 6-chloromethylchryean.

According to this embodiment, it was. 10.7 grams of 6-hydroxymethylchryaen (compound of Embodiment A, 0.0414 moles) was added to a round-bottomed flask equipped with a condenser, a nitrogen bubbler and a magnetic stir bar, followed by 16.54 grams of thionyl chloride SO _2. (corresponding to 0.139 mole, or 10 ml) and 700 ml of toluene PhCHg. The solution was then slowly heated for 1 hour and then heated at reflux for 1 hour. The solvent was then removed on a rotary evaporator. The last traces of thionyl chloride SOClg and HCl were removed by addition of toluene PhCHg (4 x 100 mL) and this solvent was removed by rotary evaporation. The crude material (pale yellow solid 17.0 g) was used without further purification .

C. Preparation of 2 - ((6-chrysenylmethyl) amino) -2-methyl-1,3-propanediol methanesulfonate.

According to this embodiment, 13.3 grams were added to a round-bottomed vessel equipped with a condenser, a nitrogen bubbler and a magnetic stir bar.

S-chloromethylchryeen (compound obtained according to Embodiment B4 amounting to 48 mmol) gave 10.5 grams of 2-amino-2-methyl-1,3-propanediol (corresponding to 0.1 mole) followed by 13.8 grams of carbonate potassium KgCO3 (corresponding to 0.1 mol) and absolute ethanol (500 ml). The thus prepared mixture was heated at reflux for 6 hours, then cooled, filtered and concentrated to give a white solid. The solid was shaken in hot water (500 mL) and filtered. The solid obtained was washed again with hot water (2 x 500 ml) and then aspirated to semi-dry on a filter. The solid obtained was dissolved in a mixture of absolute EtOH (400 mL) and CH3SQgH (4 mL), then filtered through a medium, porous glass frit and diluted to 2 liters of EtgO disthy. then dissolved in absolute EtOH (400 mL), filtered again and diluted to a volume of 2 L with Et 2 O diethyl ether. The resulting solid was then recrystallized twice from absolute ethanol in the mixture and EtOH / Et 2 O 1 → 1, then The mixture was filtered and placed in a vacuum oven overnight. The yield of 2 - ((6-chryaenylmethyl) amino) -2-methyl-1,3-propanediol mesylate was 6.87 grams (corresponding to a yield of 32.4%). The melting point of this product aa ranged from 226 to 227 ° C (with decomposition). Analysis t · *

Calculated »C - 65.29 H - 6.16 From N - 3.17 S - 7, -26 Found» C - 65/09 H - 6.23 N> 3.12 S 7/20.

£ S 273347 B2

Example?

Alkylation of 3-chloromethylfluoranthene to prepare 2 - ((3-fluoroanthenylmethyl) amino) -2-methyl-1,3-propanediol hydrochloride 0.4 HgO,

A. Preparation of 3-dihydroxymethylfluoranthene 0.1 HgO.

According to this embodiment, 20.0 grams of fluoroanthan-3-kerbehehyde (corresponding to 0.0660 mfilq) in dry tetrahydrofuran (in an amount of? 0.0660 mfilq) was charged into a round-bottomed vessel equipped with a condenser, a due dilution bubbler, and a magnetic stick. 00 milliliters). Then ¹ to this would eměei Sftdný added solid sodium borohydride in an amount of 1.64 grams (0.0434 mole) in one portion forp. The solution was stirred for a warm time. This was then poured into ice and 0.1 M HCl (1500 mL). The solid was collected by filtration and washed with water (3 x 500 ml). The solid was dissolved in hot CH ₂ Cl ₂ (2 L) and dried. Na ₂ SO ₄ filtered and concentrated to a volume of one liter on a rotary evaporator. This solution was then diluted with hexane (1 L) and the resulting solid was filtered off and dried in a vacuum oven at * 80 ° C overnight. In total, 16.21 grams of 3-hydroxyethyl ethylfluoranthene 0.1 HgO (corresponding to a yield of 89.4%) was attracted, with the melting point of the product being within the range of &lt; tb &gt; from 137 to 138 ° C,

Analysis t

H, 5.25

Found: J O m 87, -14 H · 5.31.

Příprava »Preparation of 3-chlorosiephylfluoroanthene,

According to this embodiment, 14 grams of 3-hydroxyraethylfluoranthene 0.1 (µM, corresponding to 0.05 moles) was charged to a round-bottomed flask equipped with a condenser, a due dilution bubbler, and a magnetic stir bar. , 41 g of SOC1 ₂ thicnylchloridu (corresponding 0,18.molu, ie 13 ml) and toluene (800 ml). the mixture was heated under reflux at the boiling point of the solvent-gentle manner for one hour | Py byle then refluxed vigorously well for one hour, ¹ .Analýzou thus obtained reaction mixture, 'which was carried chrome »metodou'V chromatography the TLC, it was found that the dad eměei no starting material. From TetP The solvent was then removed and toluene phCHg (100 ml) was added again and the toluene was removed by rotary evaporation over The solid obtained was dried under vacuum overnight to give 14.4 grams of 3-chloromethylfluorophene (corresponding to 95.4% yield), which was used for the next step without further purification. »»

C. Preparation of 2 - ((3-fluoranthpnylmethyl) amino) -2-methyl-l, 3-pfňpendiolu as hydfockloridu 0.4 H ₂ 0, _n

According Into a round bottom flask » 'which was equipped kondanzátorem,' nitrogen bubbler and a magnetic stirring bar, was charged 14.3 g of 3-chlormethylfluoranthenu (compound of embodiment ^B! And the amount corresponding to 0.1057 mol) 'furthermore 10.5 grams of 2-amino-2-methyl-1,3-propanediol (corresponding to Ο, Ί mol) # followed by 15.61 grams of potassium carbonate KgCOg (corresponding to 0.13 moles), followed by a toluene mixture and absolute ethanol in a PhCHg / EtQH ratio of 1 µl (γ total amount of 100 mil milliliters) and a catalytic amount of potassium iodide množství (amount of 100 milligrams). The mixture was refluxed overnight, then cooled, filtered and concentrated to give a yellow solid. The solid was shaken with hot water (1 L) and filtered, The solid thus obtained was further washed with hot water (2 x 500 ml), sieved to semi-dry on a frit. and then dried overnight in a vacuum oven at 60 ° C. The solid was dissolved in a mixture of absolute EtOH (400 mL) and hydrogen chloride gas in absolute EtOH (4 mL, approximately 10 M concentration) ^; then filtered through a medium porous glass frit and diluted to a volume of 2 liters with EtgO, followed by the addition of hexane to a final volume of 4 liters. The white solid (11.5 grams) was dissolved in absolute ethanol. 300 ml, 'filtered and diluted to 1.5 liters diethyl ether Et ₂ 0. thus ziekaná solid (množetvi 2.5 g) was further recrystallized from absolute ethanol and diethyl ether in a ratio EtOH / i EtgO 1 1, further being The mixture was filtered and placed in a vacuum oven where it was left overnight. A total of 1.31 grams of 2 - ((3-fluoranthenylmethyl) amino) -2-methyl-1,3-propanediol HCl was obtained, 0/5 HgO (corresponding to a yield of 6.45%). The melting point of this product was between 253 and 254 ° C (dec.).

Analysis i .......

Calculated: C - 69.13 H - 6.35 N - 3.83 Cl · 9.71

Found t C - 69.32 H - 6.32 N - 3.81 Cl - 9.71.

Example 3

Alkylation of 9-chloromethyl-10- [2- (diphenyl-t-butyliloxy) ethoxy] entracene to prepare 2 - (((10- (2-hydroxyethoxy) -9-anthracenyl) methyl) amino) -2-methyl- 1,3-propanediol.

A. Preparation of 10- (2- (diphenyl-t-butyl8-oxy) ethoxy) anthracene-9-carbaldehyde.

According to this embodiment, 20 grams of 10 (2-hydroxysthoxy) anthracin-9-carbaldshyde (equivalent to 0.75 mol), imidazole (in an amount of 20-50 ml) were charged to a round-bottomed flask equipped with a condenser, nitrogen bubbler and magnetic stir bar. 11.24 g, corresponding to 0.165 mol) and dimethylfuran DMF (dried over active 4 &apos; molecular sieve, 130 ml). The solution was then cooled to 5 ° C in an ice bath and t-butyl chlorodiphenylellan (22.7 g, 0.0826 mol and 21.5 ml) was added in one portion to the flask. The mixture was then stirred at ambient temperature for 3.5 hours and then poured into a mixture of Et _{&lt; 2 &gt;} O diethyl ether (1 liter) and water (1 liter). The diethyl ether layer was then removed and the aqueous return was removed. extracted with an additional portion of Et 2 O diethyl ether (1 liter), the diethyl ether layers were combined and washed successively with water (10 χ 1 liter) and saturated sodium chloride solution (2 x 1 liter), then dried (sodium sulphate) Na ₂ SO ₄ ) was filtered and concentrated to a volume of 100 ml by rotary evaporation. The mixture (which now contained crystals) was then diluted with hexane (1 L). The solid thus obtained was filtered and dried overnight in a vacuum oven at 60 ° C to give 32.48 g of 10- [2- (diphenyl-t-butylailoxy) ethoxy] anthracene-9-carbaldehyde ( corresponding to a yield of 85/6%) which was used for the next step without further purification. An analytical sample was prepared by crystallizing 2.48 grams of this material from hexane, after drying overnight in a vacuum oven at 60 ° C. was obtained

2.1 grams of a light yellow solid, the Toplots melting of this product ranged from 109 to 111 ° C.

Analysis i

C, 78.53; H, 6.39. Found: C, 78.54; H, 5.49.

8, Preparation of 10- [2- (diphenyl-t-butylsiloxy) ethoxy] -9-hydroxymethylanthracene *

To a round bottom flask equipped with a condenser, a nitrogen bubbler, and a magnetic stir bar was added tetrahydrofuran in an amount of 200 mL and crude 10- (2- (diphenyl-t-butylslloxy) -ethoxy) -anthracene-9- carbaldehyde in an amount of 30 grams corresponding to 0.0559 moles. To this reaction mixture was added 2/25 grams of solid sodium borohydride NaBH _4, corresponding to 0.0559 moles, as a single portion. The solution was stirred overnight at ambient temperature. The mixture was then poured into water (1 L) and extracted with Et 2 O diethyl ether (2 x 700 mL). The diethyl ether extracts were then combined β washed successively with water (5 x 500 ml) and saturated sodium chloride solution (2 x 500 ml), dried (Na ₂ SO ₄ ) / filtration and the solvent removed rotary evaporation to give an oil which solidified upon cooling. After drying overnight at 13/3 Pa, a total of 30.0 grams of crude 10- [2- (diphnyl-t-butylsiloxy) ethoxy] -9-hydroxymethylantracene (corresponding to a yield of 99%) was obtained. ), which was used for the next step without further purification. A sample of 14/1 grams of this material was purified by flash chromatography on silica gel S10 ₂ using toluene PhCHg (3 L) followed by CH ₂ Cl ₂ (4 L) as eluents ( 500 ml fractions). Fractions 8-13 were combined and CH 2 Cl 2 was removed by rotary evaporation to give 11.25 grams of pure 10- [2- (diphenyl-t-butylsiloxy) ethoxy] -9-hydroxymethylantracene (corresponding to a yield of 79.8). The melting point of this product was between 115 and 117 ° C.

Calcd: C, 78.22; H, 6/76

Found: C 78.30 H - 6.80.

C. Preparation of 9-chloroethyl-10- [2- (diphenyl-t-butyliloxy) ethoxy] anthracene,

According to this embodiment, 15.9 grams of crude 10- [2- (diphenyl-t-butylsiloxy) ethoxy] -9-hydroxymethylanthracene (which corresponds to 11/36 grams of thionyl chloride SOCl ₂ (corresponding to 0.0954 mol, or 7 milliliters) and toluene PhK (450 milliliters). The mixture was heated under reflux at a gentle rate for 1 hour and then heated at reflux for a further 1 hour. Analysis of the reaction mixture by thin layer chromatography showed no starting compound. The solvent was removed from the reaction mixture and then longer PhH (3 x 100 ml) was added and the solvent was removed by rotary evaporation (four times) to give 16.0 grams of 9-chloromethyl-10- (24 (diphenyl-t-butylsiloxy) ethoxy) anthracene (corresponding to a yield of 95.4%), which material was used immediately without further purification for the next step,

D. Preparation of 2 - (((10- / 2- (diphenyl-t-butylsiloxy) ethoxy) -9-anthracenyl) methyl) amino) -2-methyl-1,3-propanediol 1,13 HCl,

According to this embodiment, 16/0 grams of 9-chloromethyl-10- [2- (diphenyl-t-butyl8iloxy) ethoxy] anthracene (product) was charged into a round bottom vessel (equipped with a condenser, a nitrogen bubbler and a magnetic stir bar). according to step 0 (the amount corresponds to 0.04304 mol)) further 6/47 grams of 2-amino-2-methyl-1,3-propanediol (corresponding to 0.0616 mol) / further 8/51 grams of potassium carbonate KgCOg (which corresponds to 0.0616 moles), β-beta toluene and absolute ethanol in a ratio of PhCHg / abs · ethanol 1: 1 (600 ml) and a catalytic amount of potassium iodide (100 mg). The mixture was refluxed overnight, cooled, filtered and the solvent removed to give a brown residue. This material was then shaken with hot water (800 mL) and extracted with EtOAc (3/400 mL). The combined ethyl acetate extracts were then combined and washed with water (2 x 500 mL) / dried (Na ₂ SO ₄ ) and the solvent removed to give 15.9 g of a brown oil. was then treated with an excess of hydrogen chloride gas in absolute ethanol HCl in EtOH (25 mL). The solvent was then removed to give a brown gum. This solid was washed with hot toluene FbCHg (3 x 300 mL) and the remaining solid was crystallized from isopropanol i-PrOH and Et ₂ O in i-PrOH / Et ₂ O 1: 10 to give a solid. filtered, washed with Et ₂ O diethyl ether (2 x ZOO milliliters) and stored at 60 ° C in a vacuum oven overnight to lure 0.424 grams of 2 - (( (10- / 2- (diphenyl-t-butylsiloxy) -athoxy / 9antracenyl) mothyl) amino) -2-methyl-l, 3-propanediol 1.13 HCl, ¹ which corresponds to a yield of 2.2%. The melting point of this product aa was between 185 and 186 ° C (with decomposition). Product analysis:

Calculated: C, 70,? 0? 7, 100 N 2, 20 Cl, 6.28

Found: C 69.80 H 7, ,1 N 2/47 Cl 6.16

E. Preparation of 2 - (((10- (2-hydroxyethoxy) -9-anthracenyl) methyl) amino) -2-methyl-1,3-propanediol HCl.

According to this embodiment, the vessel was round bottom. which was equipped with a condenser, rainbow bubblers and a magnetic stir bar charged with 0.30 grams of 2 - (((10- / 2-diphenyl-t-butylsiloxy) ethoxy / -9-anthraconyl) methyl) amino) -2-methyl-1 1,3-propanediol 1,13 HCl (compound of step 0, equivalent to 0,0005 mol), yielded 0.69 grams of anhydrous potassium carbonate 1 CO 2 (corresponding to 0.0005 mol), followed by dry methyl cyanide CH 3 CN ( 5 ml) and NEt.F. hydrate in an amount of 0.098 g, corresponding to 0.100066 mol. The mixture was stirred at ambient temperature for one hour.

The reaction mixture still contained some amounts of starting material. Oo reaction vessel was then added an additional amount of NEt ^ F hydrate (in an amount of 0.196 g, ¹ equivalent 0: 00013 mole) and methyl cyanide CHgCN. (Volume 10 ml) and the mixture was stirred until no starting material (which took 3 hours). The mixture was filtered and the solvent was removed to give a solid which was partitioned between EtOAc (200 mL) and water (200 mL). The ethyl acetate layer was washed successively with water (2 x 100 mL) and saturated sodium chloride solution (2 x 100 mL), then dried (Na ₂ SO 4) and the solvent was removed to give crude crude. yellow solid. This material was dissolved in an excess of hydrogen chloride gas in absolute EtOH (5 mL), filtered and diluted to 500 mL with Et2O diethyl ether. The precipitated solid was removed by filtration and crystallized with 1: 4 ethanol / diethyl ether EtOH / EtgO 1 / filtered, washed with EtgO diethyl ether and dried in a vacuum oven at 60 ° C to yield 0. 0 g 2 - (((10- (2-hydroxyethoxy) -9-anthracenyl) methyl) amino) -2-methyl

1,3-propanediol HCl (corresponding to a yield of 51.3%). The melting point of the product thus obtained was within the range of &lt; from 174 to 176 ° C. .....

Analysis:

Calcd: C - 64, -36 Η> 6, 69 N · 3 * 57 Cl 9.05

Found j C 64.43 6 e 6.70 No 3.52 Cl 9.12 »

Example 4

Examples of pharmaceutical compositions.

A. Tablet

A compound of formula I (as hydrochloride) 500 mg of the previously -0 želatizinovený Corn starch 60 mg O ate sodium starch glycolate, 36 'O _r g Magnesium stearate 4 _{f. o} . _{n &}

The compound of formula (I) is finely divided and completely mixed with 8 powdered excipients, 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 mixture is then compressed to form tablets. Their weight is approximately 600 milligrams.

B. Tablet

Compound of Formula I 500.0 mg cornstarch 70/0 mg lactose 83.8 mg magnesium stearate 4/2 mg polyvinylpyrrolidone 14, Ό mg stearic acid 28/0 mg.

The compound of formula (1) is finely divided and thoroughly mixed with the powdered excipient (which is corn starch and lactose). 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 β mixed with stearic acid powder and magnesium stearate. The mixture is then compressed to form tablets weighing approximately 700 milligrams.

C. Capsules

Compound of Formula I 500.0 mg corn starch 50.0 mg

Magnesium 8-tearet 3.0 mg.

The compound of formula (I) is finely divided and then mixed with corn starch powder and moistened with denatured alcohol to concentrate the powder. The dried powder is then mixed with stearic acid and filled into hard shell gelatin capsules.

D. Syrup

Compound of Formula I - 250.0 mg ethanol 250/0 mg glycerine 500.0 mg sucrose 3500/0 mg flavoring agent - q.e ’. coloring agent q.8. protective agent 0/1% clean water Supplement to 5.0 milliliters.

The compound of formula (1) is dissolved in ethanol, glycerin and a portion of pure water. The sucrose and the preservative are dissolved in a second portion of hot pure water, and then a coloring agent is added to dissolve. The two solutions are then mixed and cooled, followed by the addition of a flavoring agent. The rest of the pure water is then added to the total volume required. The resulting syrup is then mixed properly.

E. Injection

Compound of Formula (I) 50 mg glycerin addition to achieve isotonicity (desired) preservative 0.1% hydrochloric acid or sodium hydroxide as needed to adjust the pH of water for injection supplement to 1 ml.

The compound of formula (I) and the preservative (aa) are added to glycerin and part of the water for injection. The pH is then adjusted with hydrochloric acid or sodium hydroxide. Water for injection is then added to the total volume of ee and the solution ee is completed by thorough mixing. This solution is then sterilized by β filtration using a 0.22 micron filter membrane and aseptically filled into sterile 10 ml ampoules or vials.

Claims (5)

A process for the preparation of polycyclic aromatic alkanol derivatives of the general formula 1 ArCH.NH-c-R. . I · R ⁴ C - R ³ '(I) OH or a monomethyl or monoethyl left derivative of the compound, including ethers of the compound of formula (I) containing a total of at most 2Θ carbon atoms, esters of the β salt of the compound, wherein Ar represents a radical selected from the group consisting of Said radicals being optionally substituted by one or two substituents together comprising a total of up to four carbon atoms, which are the same or different, selected from the group consisting of halogen, cyano, (C 1 -C 3) alkyl, or an alkoxy group having 1 to 3 carbon atoms, each of which is optionally substituted with a hydroxy group or an alkoxy group having 1 to 2 carbon atoms, providing a halogen substituted alkyl group having 1 or 2 carbon atoms or an alkoxy group containing 1 to 2 carbon atoms; 1 or 2 carbon atoms, furthermore a S (O) _n R ^{5 group} in which n is an integer of 0/1 or 2 and R ⁵ represents an alkyl group containing 1 or 2 carbon atoms optionally substituted by hydroxy or alkoxy alkoxy group containing 1 or 2 carbon atoms (or the Ar moiety optionally substituted by NR ^S R ⁷ (which contains a maximum of 5 carbon atoms) and R ⁷ and R ⁷ are the same or different substituents, each of which is an alkyl group containing 1 up to 3 carbon atoms or NR ⁶ R ⁷ form a five-membered or six-membered heterocyclic ring (which optionally contains one or two additional heteroatoms) R 1 is an alkyl group having 1 to 3 carbon atoms substituted with a hydroxy group; R is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a hydroxymethyl group; 3 4 R and R are the same or different substituents (each of which is hydrogen); methyl or ethyl, 1 2 3 4 R, R, R and R contain a maximum of five carbon atoms in total! or group: in which - C - C - is a 5- or 6-membered saturated carbocyclic ring, * which contains two or three hydroxy groups (r8 is hydrogen, *, methyl or hydroxymethyl) ^R and R ^and are identical or different substituents, · and each represents a hydrogen atom or a methyl group » R is a hydrogen atom, a hydroxy group (a methyl group or a hydroxymethyl group) S 9 XO XX R «R,, R rR a and the —C-C- ring together contain less than eight carbon atoms in total *, characterized in that a compound of the general formula (I) is reacted ArCH ₂ L in which Ar is as defined above and L represents a leaving group (IV) OH (IV) in which the substituents R ¹ to R ⁴ have the meanings given above. 2. A method according to claim 1, wherein:. The process according to claim 1, wherein the corresponding starting materials are used to give compounds of formula I wherein Ar is S-chrysenyl / 7-fluoranthenyl or substituted 1-anthracenyl or 9-anthracenyl and the other subetituents are as defined above. 3. A process according to claim 1 or 2, wherein the corresponding starting materials are used to form compounds of formula I wherein Ar is substituted by C1-C2 alkyl or C1-C2 alkoxy. are optionally substituted with chloro, hydroxy, or methoxy, or S (O) _n R ⁵ or chloro / imidazolyl, morpholino, cyano or bromo, with preferred substituents being chloro, 2-chloroethyl or OCH, CH CHR ¹² , 12-- £. wherein R is hydrogen / hydroxy or methoxy or S (O) _n CH ₃ , wherein n is an integer of 0/1 or 2 and the other substituents are as defined above, 4. A process according to any one of Claims 1 to 3, characterized in that the corresponding starting materials are used (to form compounds of the general formula 1) wherein a group of 13 - C - R 'or - C - R' is a group CH-R 11 wherein -R ^A is CH-OH, CH (CH 2) OH or CH-CH-OH, 14 ^J 22 or CH 9 OH / a R is a hydrogen atom / an alkyl group having 1 to 3 carbon atoms R is hydrogen or methyl. 5. A process according to any one of Claims 1 to 4 (characterized in that the corresponding starting materials are used to produce compounds of the general formula 1) wherein the group - C - R ² Q _w gl ^{2 R} @ 3 -R @ 1 -R @ 3 is a group H - C - R @ ¹⁵ 15 ° ^H ° ^H wherein R is hydrogen or methyl R is hydrogen / methyl or ethyl.