FI61187B - PROCEDURE FOR FRAMSTATION OF ANTITUMO 1,2,5,6-DIANHYDRO-3,4-DI-0-ACYLGALACTTOLDERIVAT - Google Patents

Description

Γ-ιΤτ -'- Ί Γηΐ NOTICE OF PUBLICATION * ΛΛΆΠ «Γφ IBJ (11) UTLAGGNINGSSKRIFT O 1 10 / C (45) Patent extended 10 05 1932 Patent meddelat V 'V (51) Kv.lk.3 / lm.ci.3 C 0? D 303/16 SUOH | _FINLAND (21) P »M« ttlh »k * imi · - ht« MMtknln | 75361) 3 (22) Hikamlsptlvt - Ana (Mcntnpd * c 23 · 12.75 (23) Alkupllvi —GHtl | h «tad« g 23.12.75 (41) Tullut slikutuksi - Bllvlt offtntllg 25.06.76

Pentti, and the registered NlhtMlulp ™ *, |. month * mdd--

Patent- and Register-Register 'Antekan utiagd och uti.tkrifun publicerad 26.02.82

(32) (33) (31) »Baglrd priorttat 2h.12.7U

Hungary-Hungary (HU) MA-263O

(71) Chinoin Pharmaceuticals and Chemicals Gyära RT., To u. 1-5 »Budapest IV, Hungary-Hungary (HU) (72) Läszlö Ötvös, Budapest, Sandor Eckhardt, Budapest, Anna Szabolcs, Budapest, Ilona Elekes, Budapest, Zsuzsa Somfai, Budapest, Jänos Sugär, Budapest, Laszlo Institoris, Budapest , Sändor Viräg, Budapest, Ägoston David, Budapest, Hungary-Hungary (HU) (7I4) Oy Kolster Ab (51)) Method for antitumor 1,2,5,6-dianhydro-3, U-di-O-acyl- for the preparation of galactitol derivatives - Preparation for the preparation of antitumor 1,2-5,6-dianhydro-3,3-di-O-acylgalactitol derivatives

The invention relates to a method for the treatment of 1,2-

For the preparation of 5,6-dianhydro-3,4-di-O-acylgalactitol derivatives of general formula I

1 / ° CH ^ I 0 I "

CH-O-C-R

I I

CH-O-C-R

I; CH>.

I> CH / ί 2 61187 wherein R is alkyl of 1 to 3 carbon atoms which may be substituted by halogen phenyl or methoxycarbonyl? cyclohexyl, phenyl or 2-furyl.

Diepoxide-type dianhydro derivatives of alcohols, such as L1, 2,3,4-diepoxybutanol, especially derivatives of six-atom alcohols, such as 1,2-5,6-dianhydro-D-mannitol and 1,2-5,6-di-anhydro-dulsitol derivatives are well known for their anti-tumor activity. (Jarman, M. Ross, WX j, The formation of epoxides from substituted hexitols, Carbohydrate Research 9 (1969) 139? Jarman, M. Ross W. CJ. Formation of 1,2- 5,6-dianhydro-D-mannitol from 1,6-dibromo- and 1,6-dimethanesulphonoxy-1,6-dideoxy-D-mannitol, Chem. Ind. 42 (1967) 1788? Elson, AL, Jarman, M. Ross WCJ, Toxity, haematological effects and antitumor activity of epoxides derived from disubstituted hexitols, Eurp. J. Cancer 4, (1968) 617. The most effective of these is 1,2-5,6-dianhydro-dulsitol (Nämeth, L., Tnstitöris, L., Somfai, S., Gäl, F., Pälyi, 1., SugSr, J., Csuka, O. Szentirmay, Z., Kellner, B., Pharmacology and antitumor effect of dulcitold diepoxide (1,2-5,6-dianhydro-galactitol , NSC-132 313), Cancer Chemotherapy Rep, T. 56 (1972) 593? InstitÖris, L., NSmeth, L., Somfai, s., BSl, F., Hercsel, I., Zaka, 5., Kellner , B., Investigation into the Correlation of Cytostatic Activity with the In Vitro Diepoxide Formation on Some Terminally Substituted Hexitols, Neiplasma 17 (19 70), 1, 15-24. However, due to free hydroxyl groups and due to intranuclear reactions between epoxy rings, even without a biological medium, changes occur in the compound in a buffered aqueous solution. These reactions form metabolites that are unfavorable or toxic to the cytostatic effect.

to protect the compound from unexpected changes, protecting groups may be added which are removed in the biological environment to form the diepoxy compound as the active metabolite.

In addition, the protecting groups attached to the hydroxyl groups in many cases advantageously affect the solubility of the highly water-soluble hexitol diepoxide, increasing the cytostatic effect of said compound. Animal experiments with some of these compounds show that they still have some other beneficial effects, e.g. a strong reduction in toxicity, and that these substances can advantageously influence changes in the tumor spectrum. The process according to the invention is directed to the preparation of new compounds which have not been prepared to date. To date, derivatives of 1,2-5,6-dianhydro-D-mannitol and 1,2-5,6-dihydrodulsulitol monoacylated at the 3- or 4-position or diacylated at the 3,4-position are not known in the literature. Diacyl derivatives may have two identical or different acyloxy groups. The process according to the invention is characterized in that 1,2,5,6-dianhydro-galactitol is acylated with an acylating agent of the formula R-CO-X in which R is as defined above, X is halogen or OR 1 in which R 'is alkyl, aryl -, aralkyl or -CO-R group or p-nitrophenyl group, the reaction preferably being carried out in benzene, toluene or dichloroethane, preferably at room temperature to 50 ° C and using anhydrous triethylamine, pyridine or potassium carbonate as acid scavenger , in which case the excess organic base used can also act as a solvent. Using the process of the present invention, the novel compounds having antitumor activity are prepared as follows: 1 mole of 1,2-5,6-dianhydrogalactitol is dissolved in an organic solvent, preferably benzene or a homologue thereof, in a ratio of 40 volume units per weight unit. 2.0 to 3.1 moles of an organic acid-binding base or an inorganic acid-binding agent are then added to the solution. In certain cases, a large excess of an acid scavenger, e.g. triethylamine or pyridine, may be used if the excess acts as a solvent. To the dianhydrogalactitol solution containing the acid scavenger is added about 2 moles of acylating agent in portions as a 0.5 molar solution at such a rate that the temperature remains below the boiling point of the mixture. The preferred temperature is 20-50 ° C. The reaction mixture is then stirred at this temperature for about 10-180 minutes. In some cases, a post-mixing of about 10-24 hours may be necessary. The further treatment depends on the type of acylating agent used.

a) When using an acid halide as an acylating agent, the salts formed are filtered off from the reaction mixture and washed as an anhydrous organic solvent, preferably benzene. The solution is concentrated to a small volume below 50 ° C, then diluted with methanol. or with another solvent, preferably a mixture of ether and methyl acetate or another mixture, and cooled. The formed crystals are filtered off. A second crop of crystalline product can also be formed by concentrating the stock solution or using a precipitating solvent. This is about 10-20% of the original product.

The products - first and second yields - are purified by recrystallization. The second yield most often requires recrystallization.

b) When acid anhydrides or esters are used as the acylating agent, upon completion of the reaction, the reaction mixture is concentrated to about half its original volume and the reaction mixture is added to about 2-3 times the volume with stirring of the ice-water mixture. The aqueous phase is isolated from the organic phase. If the reaction of the aqueous phase is acidic, the organic phase is washed until neutral, preferably extracted with sodium hydrogen carbonate solution (5-10%). After separation of the organic phase from the washing solution, it is concentrated to dryness in vacuo. The residue shall be further processed in accordance with point (a).

1,2-5,6-Dianhydrogalactitol (melting point 98.5 ° C, - + 2 ° in water, c = 1.25) is used as starting material. It is prepared by methods known per se (Jarman, M, Ross, WCJ, Formation of 1,2-5,6-dianhydro-D-mannitol from 1,6-dibromo and 1,6-dimethane-sulphono-1,6 dideoxy-D-mannitol, Chem. Ind. 42 (1967) 1789.

Anhydrous organic solvents which do not chemically affect the reaction components can be used as the medium or solvent. Preferred solvents are homologues of aliphatic, cycloalkyl and aromatic hydrocarbons and hydrocarbon halides. An organic acid-binding base, e.g. triethylamine or pyridine, can also act as a solvent if used in a suitable excess. The salt separated by filtration must be washed with an anhydrous solvent, suitably using the same as before to prevent the formation of solvent mixtures. Such solvent mixtures cause difficulties in preparing the reaction mixture. Tertiary amines, trialkylamines, their homologues and alkali metal carbonates can be used as the acid scavenger. Triethylamine is the preferred acid scavenger because it dissolves 1,2-5,6-dianhydrohexitol well and the precipitated salts can be easily separated.

The acylation can generally be carried out at a temperature of 20 to 50 ° C, except when using acid halides substituted with large groups at the OC position, in which case the reaction time must be 1 to 3 hours at 50 ° C to obtain a good yield. The temperature must not be higher than the boiling point of the solvent. The temperature is usually controlled by the supply of an acylating agent. External cooling is only necessary if the acylating agent is added at too high a rate.

It is essential that the starting materials, solvents, acid scavengers and acylating agents be completely anhydrous. Before using them, they must be examined and, if necessary, distilled and cleaned. The antitumor activity of the diepoxydiacyl-galactitol derivatives prepared according to the invention was studied using implanted animal tumors. Each compound thus prepared limits the growth of implanted tumors depending on the amount of dosage.

A comparison was made between the toxicological and antitumor effects of 1,2-5,6-dianhydro-3,4-diacetylgalactitol and the original 1,2-5,6-dianhydro-galactitol (DAD) in different experimental systems. Symbols: DAD = 1,2-5,6-dianhydrogalactitol

Diac-DAD = 1,2-5,6-dianhydro-3,4- (diacetyl) -galactitol DS-DAD = 1,2-5,6-dianhydro-3,4-di - (- β-carbomethoxypropio-galactitol FB-DAD = 1,2-5,6-dianhydro-3,4-di (4-phenylbutyryl) -galactitol FP-DAD = 1,2-5,6-dianhydro-3,4-di (β-phenylpropionyl) -galactitol CA-DAD = 1,2-5,6-dianhydro-3,4-di (chloroacetyl) -galactitol Acute toxicity

Acute toxicity was studied in Swiss mice. Deaths were observed after a single dose within 21 days.

Table I.

Acute toxicity

Compound Molecular Weight LD ^ i .p. LD ^ gi.p. LD50P '° "(mg / kg) (m-mol / kg) (mg / kg) DAD 146 15 1.03 18

Diac-DAD 230 34 1.48 50 DS-DAD 347 120 3.20 100 FB-DAD 438 110 2.52 100 FP-DAD 410 160 3.8 not specified 6118 7 6

Toxicity is approximately inversely proportional to the increase in molecular weight. Death occurred under the influence of intraperitoneal as well as oral toxicosis from 5 to 9 p.m. the day after the test compound was administered. This also means that all these compounds can be well absorbed in the gastrointestinal tract as well.

Table II

Accumulation of toxic effects

Compound Dose Mortality Cumulative (mg / kg) (individuals) Residue (%) DAD ixLDgQ 18 9/10 90 1xLD80 / 2 9 0/10 0 2xLDg0 / 2 9 + 9 / 48h 4/10 0 45 2xLDq0 / 2 9 + 9 / 96h 0/10 40 0

Diac-DAD lxLD80 38 5/6 83 1xLDq0 / 2 19 0/6 0 2xLDq0 / 2 19 + 19 / 48h 1/6 17 20 2xLDg0 / 2 l9 + 19 / 96h 0/6 0 0 DS-DAD 1xLD80 L1 ° 5 / 6 83 1xLDq0 ^ 2 56 0/6 0 2xLDq0 / 2 55 + 55 / 40h 0/6 0 0 2.LDq0 / 2 55 + 55 / 96h 1/6 17 20 CA-DAD 1xLD80 5/6 83 lxLDg0 ^ 2 24 0/6 0 2xLDg0 / 2 24 + 24 / 48h 0/6 0 0 2xLD80 / 2 55 + 55 / 96h 1/6 17 20 61187 b) Intramuscular Walker 256 carnosoloma After implantation of 20 million cancer cells, a single treatment followed. The lowest dose that gave a tumor inhibitory effect greater than 90% in the study on day 10 was used to determine the therapeutic index.

Table IV

Effect on intramuscular Walker 256 carcinoma sarcoma

Compound Dose Tumor inhibition (%) Therapeutic Limit dose (mg / kg index (mg) (ld50 / ed9o>

Diac-DAD 1x5 97 1 x 2.6 94 7.6 1 x 1.75 94 1 x 1.25 4 34 / 1.70 = 10.4 FD-DAD 1 X 30 92 1 x 15 92 22 1 x 10 97 110/10 = 11 22 1 x 7.5 73 1 x 5.0 51 DS-DAD 1 x 30 95 1 x 15 90 120 / 7.5 = 16 19 1 x 7.5 94 1 x 6.0 53 FP-DAD 1 X 30 98 1 x 15 99 1 x 10 100 160 / 7.5 = 21 18 1 x 7.5 90 1x5.0 88 DAD 1 x 40 92 1 x 2.0 98 1 x 1.5 96 1 x 1.25 80 15 / 1.5 = 10 10.3 1 x 1.0 53 1 x 0.75 79 8 61187

Table IV continues

Effect on intramuscular Walker 256 carcinoma sarcoma CA-DAD 1 x 10 98 1x5 91 45 / 2.5 = 18 8.3 1 x 2.5 96 1 x 1.25 4

All the compounds tested were very effective. For Diac-DAD and CA-DAD and unsubstituted DAD, the cut-off dose is 8-10 mm and for DR, FB and FP-DAD double. A significant reduction in the toxicity of diacyl diepoxes was achieved only at the expense of a moderate decrease in antitumor activity.

Effect on Hardlng-Pass subcutaneous melanoma A slow-growing, only slightly sensitive tumor was formed in the mouse by transferring a piece of tumor tissue. Treatment was started 24 hours after transplantation. Results were determined on day 21 of the experiment.

Table V

Effect on Harding-Passey subcutaneous melanoma

Compound Dose Tumor Comparison) Change in Death Study (mg / - weight inhibition weight spleen cases day kg / - (mg) (%) (mg) weight number time) sa (%) DAD 5x2.5 / 72h 181 43 320 - 30 0/6 21 16x2.5 / 24h 73 85 493 -42 0/6 25 12x5 / 96h - 100 493 -30 1/6 20

Diac- 14x8 / 24h 240 90 2 555 -78 2/6 20 DAD 13x6 / 24h 197 76 812 -62 0/6 18 14x4 / 24h 697 73 2 555 -63 0/6 20 13x4 / 24h 278 66 812 -29 0 / 6 18 14x2 / 24h 1 085 58 2 555 -66 0/6 20 CA-DAD 16x8 / 24h 307 28 3 317 -72 0/6 24 15xl0 / 24h 215 86 1 527 -54 2/6 23 FB-DAD 13x20 425 73 1 572 - 6 0/6 18 9 61 1 87

Table V continues

Effect on Hardlng-Passey subcutaneous melanoma DS-DAD 8x30 / 24h 323 90 3 317 -20.0 2/0 24 FP-DAD 16x25 / 24h 430 87 3 317 -60 1/6 24 5x30 / 24h 208 87 1 572 -11 1 / 6 24

The new compounds according to the invention proved to be much more effective against this slow-growing, only weakly sensitive tumor than the original diepoxy compounds with which they have been compared.

Table VI

_Effect on Guär carcinoma__

Compound Dose Tumor Spleen weight Body weight (mg / kg / time) weight inhibition (mg) (% change) (% change) (g) (%)

Diac-DAE 8xu / 24h 4.66 1,087 75.2 +1.8 +25.4 +3.16 +308 8x6 / 24h 6.07 _ 857 -19.8 +23. 67.7 + 15.5> 0 8x4 / 24h 18.0 943 3.0 +7.5 -12.0 +14 +165

Compare 18.7 - 1,068 - +29 +9.4 t355 FD-DAD 14x20 / 24h 4.3 480 89.0 -65.0 +48 +2.8 FP-DAD 14x20 / 24h 1.74 435 96.0 -68, 0 -1.2 t1'1 DS-DAD 14x20 / 24h 2.88 543 93.0 -60 -6.7 +2.6

Compare 39.18 1 370 to +29 +10.1 10 61187

The effect of Diac-DAD is directly proportional to the dosage used. The effect of the other substances is equally advantageous at the same dose level.

In summary, the toxicity of the diepoxygalactol compounds studied proved to be lower than that of the original epoxides. The antitumor effect of these substances can be demonstrated by a number of transplantable tumors (Ehrlich / asklites, Walker carcinoma, Harding-Passey melanoma, Buerin carcinoma) and in some cases their effect was greater than the initial t | compound. Therapeutic indices were calculated based on the effect of different compounds on Walker carcinoma sarcoma. Therapeutic agents were well absorbed in the gastrointestinal tract. The novel acyl derivatives of 1,2-5,6-dianhydrogalactitol having antitumor activity can be used therapeutically in various ways. For oral administration, the active ingredient or a mixture thereof with commonly used excipients such as lactose, starch and talc is used, for example, as tablets and for intravenous administration as a solution or suspension.

For intraperitoneal or intrasevital administration, a solution or suspension is used.

When applied topically, the compound is applied to the skin or other treatment site as such or in combination with conventional anti-bacterial and wound healing agents (sulfonamides, corticoids, vitamins).

The concentration of the compound in the various preparations is as follows: 1-10% in solutions, 1-70% in suspensions and 20-90% in tablets.

The following examples illustrate the preparation method.

Example 1 Preparation of 1,2-5,6-dianhydro-3,4-diacetylgalactitol using acetyl bromide as acylating agent Dianhydrogalactitol (1.46 g, 10 mmol) in absolute benzene (60 mL) was stirred at room temperature for 10 minutes in a three-necked 100 mL flask which was equipped with a stirrer, condenser, and dropping funnel. Absolute triethylamine (2.8 mL, 20 mmol) or anhydrous potassium carbonate (1.4 g, 20 mmol) and acetyl bromide (2.46 g, 20 mmol) were then added to the above solution and stirring was continued at room temperature for an additional 20 minutes. The crystalline triethylamine was then filtered off using a G3 glass filter and washed thoroughly with absolute benzene. The combined filtrates were concentrated in vacuo and absolute methanol (5 mL) and absolute ether (15 mL) were added to the resulting syrupy substance. The reaction mixture was then cooled, whereupon crystallization occurred immediately. The solution was kept in the refrigerator overnight, and the formed crystals were filtered off and recrystallized from methanol. The title compound crystallized as white needles. The yield was 1.65 g (71.7%), melting point 91 ° C. Rf = 0.63 (determined from benzene / methanol solution, 90:15 ratio)

Analyzes: C calculated = 67.79%, C measured = 67.75% H "= 5.0%, H" = 5.3%.

Example 2 Preparation of 1,2-5,6-dianhydro-3,4-diacetylgalactitol using acetic anhydride as acylating agent Dianhydrogalactitol (1.46 g, 10 mmol) in absolute benzene (60 mL) or anhydrous toluene was stirred at room temperature for 10 minutes in a three-necked, 100 mL In a flask equipped with a stirrer, condenser and dropping funnel, absolute triethylamine (2.8 mL, 20 mmol) and a freshly distilled solution of acetic anhydride (2.4 g, 2 mL, 20 mmol) in benzene (5 mL) were then added to this solution and stirred. at room temperature for one hour and at 50 ° C for a further two hours. The solution was concentrated to dryness in vacuo, dissolved in water (20 mL) and extracted with benzene (30 mL). The benzene phase was washed with NaHCO 3 solution (10%), dried over MgSO 4, filtered and concentrated. To the resulting syrupy substance were added absolute ether (15 ml) and absolute methanol (10 ml).

The mixture was then cooled, whereupon crystallization occurred immediately. The solution was kept in the refrigerator overnight, and the formed crystals were filtered off and recrystallized from methanol. The title compound crystallized as white needles.

Yield: 1.65 g (71.7%), melting point = 91 ° C Rf = 0.63 (benzene: methanol = 90:15).

611 87 12

Example 3 Preparation of 1,2-5,6-dianhydro-3,4-diacetylgalactltol using p-nitrophenylacetate as acylate Dianhydrogalactitol (1.46 g, 10 mmol) in absolute benzene (80 ml) or anhydrous trichloroethane (60 ml) was stirred at room temperature for 10 minutes over three minutes. In a 10 ml flask equipped with a condenser, dropping funnel and stirrer. Absolute triethylamine (2.8 mL, 20 mmol) and p-nitrophenyl acetate (g, 20 mmol) were then added to the solution and stirred together at 50 ° C for 6 hours. The solution was then kept at room temperature overnight. The solution was extracted with water (20 mL) and dried over MgSO 4. To the resulting syrupy substance was added absolute ether (15 ml), and the mixture was cooled. It was kept in the refrigerator overnight, and the formed crystals were filtered off using a G3 glass filter. The weight of the product was 2.5 g. The melting point was 72-78 ° C. The obtained yellow crystals were purified as follows: Benzene (20 ml) and diethylaminopropylamine were added to the crystals. After 1 hour, the solution was extracted with water (10 ml), and after removing the aqueous phase, the extract was repeated. The benzene phase was dried over MgSO 4 and concentrated. To the resulting syrup were added absolute ether (15 ml) and absolute methanol (5 ml). The solution was kept in the refrigerator overnight and then filtered. Weight: 1.58 g (69%), melting point = 90 ° C.

Rf = 0.63 (benzene-methanol = 90:15)

Analysis: C calculated 67.79%, C measured 67.75% H "5.0%, H" 5.3%.

Example 4 Preparation of 1,2-5,6-dianhydro-3,4-dichloroacetylgalactitol Dianhydrogalactitol (5 g, 34 ml) in absolute benzene (150 ml) was stirred for 4 hours in a three-necked 100 ml flask equipped with a condenser, dropping funnel and stirrer. Absolute pyridine (5.7 ml) was then added to the mixture, and a solution of 6 ml of freshly distilled chloroacetyl chloride in absolute benzene (6 ml) was added dropwise over 5 minutes. The solution was stirred at room temperature for 30 minutes and the triethylamine hydrochloride was filtered off using a G3 glass filter and washed thoroughly with benzene. The combined filtrates were concentrated in vacuo and to the resulting syrup were added 13,61187 absolute ether (15 mL) and absolute methanol (5 mL). The reaction mixture was then cooled, whereupon crystallization occurred immediately. The solution was kept in the refrigerator overnight, and the formed crystals were filtered off and recrystallized from methanol. The title compound crystallized as white needles. Weight = 4.4 g (43%), melting point = 102 ° C.

Analysis: C calculated = 40.0%, C measured = 40.0% H "= 4.0% H" = 4.4%

Example 5 1,2-5,6-Dianhydro-3,4-dibenzoylgalactitol

Dianhydrogalactitol (1.46 g, 10 mmol) in absolute benzene (60 mL) or anhydrous triethylamine (60 mL) was stirred at room temperature for 10 minutes in a three-necked 200 mL flask equipped with a stirrer, condenser and dropping funnel. Absolute triethylamine (2.8 mL, 20 mmol) was then added followed by a dropwise addition of a 5 mL solution of freshly distilled benzoyl chloride (2.8 g, 20 mmol, 2.32 mL) in absolute benzene over 10 minutes. The mixture was stirred at room temperature for 1 hour and then at 50 ° C for 1 hour and kept at room temperature overnight. The formed triethylamine hydrochloride crystals were filtered off using a G3 glass filter and washed thoroughly with benzene. The combined filtrates were concentrated in vacuo and absolute methanol (10 mL) was added to the resulting syrup. The reaction mixture was then cooled and the formed crystals were filtered off and recrystallized from benzene: petroleum ether.

Weight: 2.7 g (76.2%), melting point = 171 ° C.

Analysis: C calculated = 67.79%, C measured = 67.9% H "= 5.0%, H" = 5.2%

Rf = 0.75 (benzene: methanol = 90:15).

Examples 6-13

The following Examples 6-13 are tabulated for clarity, with all final products prepared according to the above examples. All characteristic features can be found in the following tables.

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Claims (1)

A process for the preparation of 1,2-5,6-dianhydro-3,4-di-O-acylgalactitol derivatives of the general formula I ch2 CH '/ ^ 0 CH-OCR CH-OCR I CH 0 \ O CH2 wherein R is alkyl of 1 to 3 carbon atoms which may be substituted by halogen, phenyl or methoxycarbonyl; cyclohexyl, phenyl or 2-furyl, characterized in that 1,2-5,6-dianhydrogalactitol is acylated with an acylating agent of the formula R-CO-X in which R is as defined above, X is halogen or OR1 in which R ' is an alkyl, aryl, aralkyl or -CO-R group or a p-nitrophenyl group, the reaction preferably being carried out in benzene, toluene or dichloroethane, preferably at room temperature to 50 ° C and using anhydrous triethylamine as an acid scavenger, dine or potassium carbonate, in which case the excess organic base may also act as a solvent.