RU2507191C1 - Method of obtaining 1-hydroxyadamantan-4-one (kemantane) - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining 1-hydroxyadamantan-4-one from adamantanone-2. Adamantanone-2 is brominated by means of CBrCl₃ under action of catalyst Mo(CO)₆, activated with pyridine with molar ratio [Mo]:[Py]:[AdO]:[CBrCl₃]=1-10:200-1000:1000:1000-2500, at temperature 175°C for 6-20 hours with further hydrolysis of formed 1-bromadamantan-4-one.

EFFECT: method makes it possible to carry out the process in absence of aggressive reagents of halogenation and use bromating agent in equimolar amount with respect to adamantanone.

1 tbl, 1 ex

Description

The present invention relates to the field of organic chemistry, in particular to a method for producing 1-hydroxyadamantan-4-one.

1-Hydroxyadamantan-4-one (1) (kemantan) is a broad-spectrum drug, has an immunostimulating effect, and is effective in the treatment of diseases of the vascular system of the extremities, autoimmune genesis. Kemantan is an effective drug for the relief of chronic bronchitis, tuberculosis, infectious-allergic bronchial asthma, chronic stomatitis, herpes, etc. (E.I. Bagriy. Adamantany. M .: Nauka, 1989, 264 p. / 1 /; A.s USSR 1586711, class A61K 31/12 (1990) / 2 /).

From literature there are several known methods for producing 1-hydroxyadamantan-4-one (1). So, it is synthesized by the oxidation of adamantanol-1 (2) using 20% oleum. In this case, a mixture of adamantanediols-1,3 (3), -1,4 (4) and -1,6 (5) is formed, which is then oxidized with chromic acid to give (1) (50% yield) and adamantanedione-2, 6 (6) (JLMA Schlatmann. Angew. Chem, Vol. 83, No. 17-18, 732 (1971) / 3 /).

Another method for producing (1) is based on the oxidation of 2-hydroxyadamantane (7) with 70% sulfuric acid, followed by repeated extraction of the mixture of reaction products with chloroform, the resulting mixture is further oxidized with chromic anhydride to form compound (1) in 25% yield (N.W. Geluk, JLMA Schlatmann. Tetrahedron, Vol.24, No. 15, 5369-5377 (1968) / 4 /).

To obtain (1) directly from adamantane (8), it is oxidized with 20% oleum. In this case, a mixture of 1,3-, 1,4-, 2,6-dioxadamantanes (3-5) is formed, upon addition of chromic anhydride (CrO ₃ ) in 100 ml of water and heating for 0.5 hours at 70 ° C, (1) with a yield of 50%. It should be noted that the reaction is non-selective, at the same time adamantanone-2 (9), adamantandion-2,6 (6) and adamantanol-1 (2) are formed as impurities (H.W. Geluk, JLMA Schlatmann. Rec. Trav. Chim Vol.90, No. 6, 516-520 (1971) / 11 /).

Disadvantages of methods

1. Oxidation is carried out in two stages using strong oxidizing agents.

2. The use of a large number of strong inorganic acids, the need to neutralize them after the reaction, the formation of a significant amount of waste containing H ₂ SO ₄ and chromium compounds, as well as wastewater to be disposed of.

3. Use as an oxidizing agent of stoichiometric amounts of chromic anhydride having carcinogenic properties.

4. Low selectivity of the process, which creates great difficulties in the selection of the target product due to the formation of by-products.

During the oxidation of adamantanone-2 (9) with 100% nitric acid (the reagents are mixed at 13-15 ° C, incubated for 70 hours at 20 ° C, then 1.5-2 hours at 60 ° C along with a small amount of adamantanedione-2,6 (6) formed (1), the yield of which is 77% (H.W. Geluk. Synthesis, No. 7 (1972) / 5 /; AS USSR No. 535085, class A61K 31/035 (1977) / 6 /).

Disadvantages of the method

1. The use of a large excess of oxidizing agent - concentrated nitric acid.

2. The reaction time is 70 hours.

3. The formation of a by-product of adamantandione-2,6 (6) creates problems in the purification and isolation of cemanthan.

4. The explosion hazard of the process due to the use of 100% nitric acid as an oxidizing agent.

5. The need to use corrosion-resistant equipment.

6. The formation of large amounts of waste.

A method for producing 1-hydroxyadamantan-4-one (1) by oxidizing adamantanone-2 (9) with chromium oxide at a temperature of 5-100 ° C in a solution containing one part of compound (9) in 8-40 parts of acetic, propionic or trifluoroacetic acids (Czechoslovak Patent No. 163671, CL C07 49/38 (1976) / 7 /); S Srivastava, W.Ie Noble. Synth. Commun., Vol. 14, No. 1, 65-68 (1984) / 8 /).

Disadvantages of the method

1. The use of a large excess of a toxic oxidizing agent - chromium oxide Cr ₂ O ₃ ([AdO]: [Cr ₂ O ₃ ] = 1: 11).

2. The formation after the reaction of a large amount of waste containing compounds of chromium, sodium, organic acids (60 kg per 1 kg of cemanthan).

When oxidizing adamantanone-2 (9) in the presence of catalysts (manganese and chromium oxides) with a mixture of concentrated nitric and sulfuric acids, 1-hydroxyadamantan-4-one (1) was obtained in 80% yield (RF Patent 2104994, class C07C 049/487 (1998) / 9 /).

Disadvantages of the method

1. The use of a large excess of oxidizing agent, consisting of a mixture of concentrated nitric and sulfuric acids.

2. The explosion hazard of the process due to the use of 100% nitric acid.

3. The need to use anti-corrosion equipment.

4. High consumption of MnO ₂ catalyst and the formation of inorganic waste (~ 180 kg) containing manganese compounds and acids HNO ₃ and H ₂ SO ₄ per 1 kg (1).

During the oxidation of adamantanone-2 (9) using the CBr ₄ -H ₂ O-Mo (CO) ₆ or CBr ₄ -H ₂ OW (CO) 6 system, generating in situ brominated acid, which is the oxidizing agent, was obtained 1- hydroxyadamantan-4-one (1) with a yield of 83-87% (RF Patent 2342358, CL C07C 49/53 (2008) / 10 /).

Disadvantages of the method

1. Difficulties in carrying out the reaction and difficulties in isolating the target product due to the solid state of aggregation of adamantanone-2 (9) and CBr ₄ , which is taken in excess in the reaction.

2. The use of a significant excess of water, which also leads to the loss of cemantan due to its good solubility in water.

It should be noted that an alternative method for the preparation of cemantan is the hydrolysis of 1-chloro- or 1-bromadamantanone-4.

In turn, 1-chloroadamantanon-4 (10) is obtained by chlorination of adamantanone-2 (9) or 1-hydroxyadamantan-4-one (1).

So, one of the methods for the synthesis of 1-chloroadamantanone-4 (10) is the substitution chlorination of 1-hydroxyadamantanone-4 (1). The reaction is carried out under severe conditions: boiling 1-hydroxyadamantanone-4 (1) in a solution of thionyl chloride for 30 hours, while the yield of the target product is 45% (J.Josef, B. Jiri, V. Lidek, Collekt. Czechosl. Chem. Commun., 52, No. 8, 2028-2034 (1987))

Also described in the literature is a method for producing 1-chloroadamantanone-4 (10) from adamantanone-2 (9) using CCl ₄ under the action of manganese catalysts (Mn (acac) ₃ , MnSO ₄ , Mn (OAc) ₂ ) at 200 ° C within 3 hours. The yield of 1-chloramadantanone-4 is 92% (RF Patent 2197468, CL C07C 49/483 (2003), 45/63).

Disadvantages of the method

1. High temperature - 200 ° C.

2. The chlorinating agent CCl ₄ is used in a 5-fold excess with respect to adamantanone-2.

The authors propose a method for producing 1-hydroxyadamantan-4-one (1), which does not have these drawbacks. The essence of the method consists in the synthesis of 1-bromo-adamantanone-4 (11) by bromination of adamantanone-2 (9) with CBrCl ₃ under the influence of the catalyst Mo (CO) ₆ activated with pyridine for 6-20 hours at 175 ° C at a molar ratio [ Mo]: [Py]: [AdO]: [CBrCl ₃ ] = 1-10: 200-1000: 1000: 1000-2500. Under optimal conditions, [Mo]: [Py]: [AdO]: [CBrCl ₃ ] = 1: 200: 1000: 1000, 175 ° C, 9 h, the conversion of adamantanone-2 (9) is 71%, the yield of 1-bromadamantanone- 4 (9) - 50% or 70% per converted (9). Then the reaction mixture containing 1-bromadamantan-4-one (11) is hydrolyzed by a known method to obtain the desired product - 1-hydroxyadamantan-4-one (1) (cemanthane) (Geluk N., Schlatmann J. Hydride Transfer Reactions of the Adamantyl Cation. I. A New and Convinient Synthesis of Adamantanone. Tetrahedron, 1968, 24 (15), 5361-5368 / 12 /).

Advantages of the proposed method

1. The brominating agent CBrCl _{3 is} used in an equimolar amount with respect to adamantanone.

2. The absence of aggressive halogenation reagents.

3. The scaling of the reaction does not affect the output of 1-bromadamantan-4-one (11) and cemantan (1).

The method is illustrated by an example.

Example

Stage 1

In a glass ampoule (V = 10 ml) was placed 0.001 mmol (0.003 g) of Mo (CO) ₆ , 0.2 mmol (0.1 ml) of pyridine, 1 mmol (1 g) of adamantanone-2 (9), 1 mmol ( 0.66 ml) of bromotrichloromethane (CBrCl ₃ ). The ampoule was sealed and placed in a steel micro autoclave, which was hermetically sealed, the reaction mixture was heated at 175 ° C for 9 hours.

After the reaction, the autoclave was cooled to room temperature, the ampoule was opened. The reaction mixture was extracted with chloroform or methylene chloride (5 ml × 3p.), The solvent was distilled off. The yield of 1-bromadamantan-4-one (11) is 50%. Mass spectrum, m / z (J _rel (%)): 229 [M] ⁺ (15), 55 (15), 67 (15), 79 (37.5), 93 (50), 121 (25) , 149 (100), 228 (15).

Other examples confirming the method for producing 1-bromadamantan-4-one (11) are shown in table 1.

Stage 2

For the synthesis of cemantan (1), the resulting reaction mass was boiled in 500 ml of 0.1 N. NaOH solution with a reflux condenser equipped with a glass nozzle for 5-6 hours. Unreacted adamantanone-2 (9) sublimates and settles on the nozzle and it can be returned to the reaction. Residues of adamantanone-2 (9) from an aqueous solution (with NaOH) after hydrolysis were extracted with hexane. Target cemantan (1) was extracted with methylene chloride. After distillation of CH ₂ Cl ₂ on a rotary evaporator, a dark solid precipitate remained in the flask, which was purified by boiling in activated carbon ethyl acetate for 20 min, then it was filtered off and the solvent was distilled off. The residue was recrystallized in hexane.

Isolated in the form of white crystals of 1-hydroxyadamantan-4-one (1) (kemantan) had the following constants: so pl. 320-321 ° C. IR spectrum (ν, cm ^-1 ): 1725 (С = O), 3400-3600 (OH). ¹³ C NMR spectrum (CDCl ₃ , δ, ppm): 45.01 (C-2, C-6), 38.16 (C-7, C-10), 46.97 (C-5, C-3), 216.68 (C-4), 67.18 (C-1), 44.14 (C-9), 29.82 (C-8). Mass spectrum, m / z (J _rel (%)): 166 [M] ⁺ (43), 53 (5), 67 (10), 77 (8), 79 (11), 80 (8), 94 (12), 55 (15), 148 (15), 95 (100), 96 (20), 97 (10), 106 (8), 107 (7), 108 (23), 109 (7). Found (%): C 72.48; H 8.46. C ₁₀ H ₁₄ O ₂ . Calculated (%): C 72.25; H 8.49.

Table 1 The results of experiments on the synthesis of 1-bromadamantan-4-one (11) by the reaction of adamantanone-2 (9) with Mo (CO) ₆ -Py-CBrCl ₃ No. p / p The molar ratio of reagents T, ° C τ, h Conversion% Yield, 1-bromadamantan-4-one,% Ado CBrCl ₃ Mo (CO) ₆ Py one 1000 2000 one 200 175 12 65 39 2 1000 2000 one 400 175 12 21 8.5 3 1000 2000 one 1000 175 12 twenty 7.8 four 1000 1000 one 200 175 9 70 42 5 1000 1500 one 200 175 9 68 44 6 1000 2500 one 200 175 9 71 48 7 1000 2500 200 175 9 48 31 8 1000 2500 10 200 175 9 49 32 9 1000 2500 one 200 175 6 40 25 10 1000 2500 one 200 175 8 37 17.5 eleven 1000 2500 one 200 175 10 65 36 12 1000 2500 one 200 175 12 79 47 13 1000 2500 one 200 175 twenty 88 47

Claims (1)

The method of obtaining 1-hydroxyadamantan-4-one of the formula (1)

from adamantanone-2, characterized in that adamantanone-2 is brominated with CBrCl ₃ under the action of a Mo (CO) ₆ catalyst activated with pyridine in a molar ratio of [Mo]: [Py]: [AdO]: [CBrCl ₃ ] = 1- 10: 200-1000: 1000: 1000-2500, at a temperature of 175 ° C for 6-20 hours, followed by hydrolysis of the resulting 1-bromadamantan-4-one.