RU2401828C2 - N-(1-adamantyl)acetamide synthesis method - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, specifically to a novel method for synthesis of N-(1-adamantyl)acetamide, which can be used in synthesis of scarce adamantane derivatives. The method is realised by reacting adamantane with acetonitrile in bromotrichloromethane in the presence of water under the effect of Mo(CO)₆ at 130-140°C for 2-3 hours, in molar ratio [adamantane] : [CH₃CN] : [CBrCl₃] : [Mo(CO)₆] : [H₂O] = 100 : 100-150 : 100-150 : 1-3 : 1000-2000.

EFFECT: novel N-(1-adamantyl)acetamide synthesis method.

1 cl, 8 ex, 1 tbl

Description

The invention relates to the field of organic chemistry, in particular to a method for producing N- (1-adamantyl) acetamide (1).

N- (1-Adamantyl) acetamide (1-acetamidoadamantane) (1) is used in the synthesis of a number of hard-to-reach derivatives of adamantane. By removing acetyl protection from N- (1-adamantyl) acetamide, 1-aminoadamantane, the active substance of the known drug midantane (1-aminoadamantane), is obtained. Midantan is used to treat viral diseases and Parkinson's disease (E. Bagriy. Adamantany. M: Nauka, 1989, 264 p. [1]; K. Gerson, E. Krumkalns, R. Brindle, F. Marshall, M. Root. J. Med. Chem., V. 6, 760 (1963) [2]; V.Yu. Kovtun, V. M. Plahotnik. Chemical-pharmaceutical journal No. 8, 931-940 (1987) [3] ; M.D. Mashkovsky. Medicines. M: New Wave, 2005, 1200 pp. [4]; S. D. Isaev, A. G. Yurchenko, S. S. Isaev “Physiol. Active substance” ( Kiev) No. 15, 3-15 (1983) [5]).

Most methods for the preparation of the acetyl derivative of 1-aminoadamantane (1) are based on the reaction of halogen derivatives of adamantane with acetonitrile.

Thus, the electroreduction of 1,3-dibromadamantane on the Hg cathode in CH ₃ CN leads to 1,3-dehydroadamantane, which, reacting with H ₂ O and CH ₃ CN, turns into acetamidoadamantane (1) with 70% yield (B.N. .Leibzon, A.S. Mendkovich, T.A. Klimova, M.M. Krajushkin. "Scientific conference on the chemistry of organ. Polyhedranes. Abstract. Volgograd, 1981, 81 [6]).

The electrolysis of adamantane or 1-bromo-adamantane in CH ₃ CN at the Pt anode leads to acetamido adamantane (1) with a yield of 75 and 89%, respectively (VRKoch, LLMiller. Tetrahedron Lett. N 9, 693-696 (1973) [7]).

The disadvantages of the method:

1. The use of inaccessible 1-bromo- or 1,3-dibromadamantanes.

2. The use of expensive electrodes (Pt).

The synthesis of N- (1-adamantyl) acetamide (1) by the reaction of adamantyl halides (AdX, X = Cl, Br, J, F) and adamantyl methyl ether with acetonitrile under the influence of nitronium tetrafluoroborate (NO ₂ BF ₄ ) in a stream of N ₂ for 1-1 is described , 5 hours at ~ 20 ° C followed by treatment with water. The reaction is exothermic, it is carried out with a temperature control of 15 minutes at ° C and then 1-6 hours at 20 ° C (RDBach, JW Holubka, TATaaffee. J. Org. Chem, t. 44, N 10, 1739-1740 (1979) [ 8]; RDBach, TATaaffee. J. Org. Chem, Vol. 45, No. 1, 165-167 (1980) [9]).

Similarly, the reaction of 1-bromadamantane with acetonitrile in the presence of nitrosonium hexafluorophosphate (NOPF ₆ ) followed by hydrolysis (GAOlah, BGGupta, SCNarang. Synthesis, N 4, 274-276 (1979) [10].

The disadvantages of the method:

1. The use of a large excess of highly reactive, explosive NO ₂ BF ₄ and NOPF ₆ .

2. The inaccessibility of the starting compounds: chloro, bromo and fluoro derivatives of adamantane.

3. The need for a reaction with cooling (0 ° C).

Acetoamidoadamantane can be obtained by the reaction of adamantanol-1 with an excess of acetonitrile in CH ₂ Cl ₂ in the presence of trifluoromethanesulfonic anhydride (CF ₃ CO ₂ ) ₂ O followed by hydrolysis of NaHCO ₃ (yield 98%) (MAGarcia, ARMartinez, VEJeso, FAGarcia, M. Hanck LRSubramanian, Tetrahedron Lett., Vol. 30, No. 5, 581-582 (1989) [11]. Under the conditions of the Ritter reaction, adamantanol-1 and CH ₃ CN in the presence of CF ₃ COOH are converted to N-adamantylacetamide in 85% yield. Along with alcohol (Ad-OH), its trifluoroacetate can be used as a source of the adamantyl cation, but in this case the reaction proceeds much more difficult. When heated CH ₃ CN with Ad-OCOCF ₃ CF ₃ CO ₂ H for 15 hours (1) was isolated in a yield of 38%. It was found that 1-bromoadamantane (Ad-Br) in CF ₃ CO ₂ H with nitriles It does not enter the reaction, however, the addition of boron trifluoride (BF ₃ · Et ₂ O) to the reaction mass, which is known to accelerate the formation of carbonium ions, initiates the process. When using BF ₃ · Et ₂ O as a catalyst, yield (1) is 55%. (Plowman, V.Yu. Kovtun, V.G. Yashunsky. J. Organ. Chemistry, vol. 18, No. 5, 1001-1005 (1982) [12].

The disadvantages of the method:

1. The inaccessibility of the starting compounds (Ad-OH, Ad-OCOCF ₃ , Ad-Br).

2. Use of a large excess of CF ₃ CO ₂ H.

3. Low yield of the target product.

The reaction of adamantanol-1 with acetic acid amide CH ₃ CONH ₂ in trifluoroacetic acid at 90-100 ° С yields (1) with a yield of 63-94% (E. Shokova, T. Mousoulou, Y. Luzikov, V. Kovalev. Synthesis (BRD), N 9, 1034-1040 (1997) [13]. At the same time, the preparation of (1) by reaction of CH ₃ CONH ₂ with 1-bromo or 1-chloradamantanes does not require the presence of CF ₃ CO ₂ H and passes at 170-220 ° С for 15 min (J. Burkhard, J. Janku, L. Vodicka, J. Mostecky. Ac Czechoslovakia 197133, (1982) [14]).

The disadvantages of the method:

1. The inaccessibility of the starting compounds (Ad-OH, Ad-Br, Ad-Cl).

2. Use of a large excess of acetamide.

3. High reaction temperature.

Education (1) of 1-bromoadamantane with CH _z CH catalyzes also concentrated sulfuric acid (H ₂ SO _4). To a solution of 100 g of 1-bromo-adamantane and 750 g of CH ₃ CN are added dropwise in 2.5 hours 270 g of concentrated H ₂ SO ₄ , the mixture is poured into 2.5 l of water and separated (1), the yield of which is 90% (EJ du Pont de Nemours , M.Paulshock, JCWatts. Irl.pat.No. 27380 (1968) [15]; M.Paulshock, JCWatts.US 3310469 (1966) [16]; EJ du Pont de Nemours and Co. Neth. Appl. 6414720 (1964 ) [17]; T. Sasaki, S. Eguchi, T. Toru. Bull. Chem. Soc. Japan, Vol. 41, No. 1, 236-238 (1968) [18]:

The disadvantages of the method:

1. The inaccessibility of 1-bromadamantane.

2. The use of a large excess of concentrated sulfuric acid.

3. A large amount of inorganic waste generated during the neutralization of excess H ₂ SO ₄ .

4. A large amount of wastewater that must be disposed of.

5. Large labor costs.

N- (1-Adamantyl) acetamide (1) is also obtained from 1-chloroadamantane and CH ₃ CN in the presence of H ₂ SO ₄ in methylene chloride (CH ₂ Cl ₂ ). To 243 g of 80% 1-chloradamantane and 296 ml of CH ₃ CN at a temperature of ≤50-55 ° С, 210 g of 95% H ₂ SO ₄ are added in ~ 1 hour, stirred for 1-2 hours (or 24 hours at 25 ° C), 750 ml of CH ₂ Cl _{2 are} added, the suspension is washed at 18-20 ° C with 1.2 L of CH ₂ Cl ₂ and 750 ml of water, the solution (1) in CH ₂ Cl _{2 is} separated. The resulting solution was treated with a 2% Na ₂ CO ₃ solution to a pH of 5-5.5, methylene chloride was distilled off and 250 g of (1) was isolated (impurities -10% adamantane and ~ 10% 1,3-dichloradamantane) (M. Lazarescu, E .Comilescu, M. Jonescu, JCCostea, Pat. CCP 88535, (1986) [19].

The disadvantages of the method:

1. The use of a large excess of H ₂ SO ₄ .

2. A huge consumption of toxic methylene chloride, belonging to hazard class I.

3. The formation of by-products, which creates difficulties in the allocation of the target product.

N (1-Adamantyl) acetamide can be prepared directly from the adamantanol nitro ester. As a catalyst used conc. H ₂ SO ₄ in a 10-40-fold excess with respect to nitrate. The reaction of adamantanol-1 nitrate proceeds with the intermediate formation of an alkyladamantyl cation generated by sulfuric acid. To 0.37 mol of H ₂ SO ₄ (d 1.84 g · cm ^-3 ) at ~ 20 ° C, a solution of 14 mmol of adamantanol-1 nitrate in acetonitrile (0.5 mol) was added dropwise and held for 3 hours. Then the reaction mass was poured onto ice, the precipitate was filtered off washed with water, dried. After recrystallization from hexane with a yield of 76%, (1) was obtained (I.K. Moiseev, E.I. Bagriy, Yu.N. Klimochkin, T.N. Dolgopolova, M.N. Zemtsova, P.L. Trakhtenberg. USSR Academy of Sciences, Ser.Chem. No. 9, 2144-2146 (1985) [20]:

The disadvantages of the method:

1. The inaccessibility of the original adamantanol-1 nitrate.

2. The use of a large excess of concentrated sulfuric acid and the need for its neutralization and disposal of inorganic waste and wastewater.

N- (1-Adamantyl) acetamide (1) is formed by the sequential interaction of adamantane with nitric acid, then with acetamide (6-fold molar excess) at 120 ° C. 6.5 g (0.048 mol) of adamantane was added to 20 ml (0.48 mol) of nitric acid (d = 1.5) at 25 ° С, held for 15 min, and 17 g (0.288 mol) of acetamide was added at a temperature of <30 ° С, kept for 2 h at 120 ° C and poured onto ice. The precipitate was filtered off, washed with water, dried and recrystallized from hexane. Yield (1) 6.7 g (73%) (Yu.N. Klimochkin, EI Bagriy, T.N. Dolgopolova, I.K. Moiseev. Izv. AN SSSR. Ser. Chem. No. 4, 878-880 (1988) [21]):

The disadvantages of the method:

1. The use of a 10-fold excess of concentrated nitric acid and the need for its neutralization and disposal of inorganic waste and wastewater.

A method for producing N- (1-adamantyl) acetamide (1) using a mixture of HNO ₃ , H ₂ SO ₄ and oleum is proposed. A mixture of 5 ml of 50% HNO ₃ , 15 ml of 93-94% H ₂ SO ₄ and 15 ml of 60% oleum is placed in an autoclave, cooled to -5 ° C, 5.06 g of adamantane are gradually added, stirred for 30 minutes , add at a temperature of from -5 ° to 0 ° C in 30 minutes 20 ml of CH ₃ CN and incubated for 1 hour at 0 °. The mixture is poured onto ice, the solution is partially neutralized with 50% alkali, the precipitate is separated, reprecipitated from 30% alkali, dried, recrystallized from 50% AcOH and obtained (1), yield 60% (L.N. Butenko, A.P. Khardin.Aut. St. USSR No. 491616 (1976) [22]:

In 1991, a method for producing (1) by the interaction of adamantane with CH ₃ CN in a sulfuric and nitric acid medium in the presence of CH ₂ Cl ₂ at 15-40 ° C, mol. the ratio of AdH: H ₂ SO ₄ : HNO ₃ : MeCN: CH ₂ Cl ₂ = 1: 10.2-12: 0.9-1.1: 7-8.1: 4-16. (V.V. Pershin, L.N. Butenko, I.A. Novakov. A.S. USSR 1643528 (1991) [23]. The yield of the target product is 86%.

When processing adamantane Br ₂ in a mixture of CH ₃ CN and conc. H ₂ SO _{4 the} initially formed carbcation reacts with CH ₃ CN, after hydrolysis it turns into (1). To a solution of 0.01 mol of adamantane in a mixture of 30 ml of CH ₃ CN and 7.5 ml of H ₂ SO ₄ at 15-20 ° С add 0.05 mol of Br ₃ ((10 min), mix for ~ 16 hours, pour into ice water, destroy the excess of Br ₃ 2% NaHSO ₄ solution, the precipitate is filtered off and with a yield of 92% receive (1) (M.Ohsugi, Y. Jnamoto, N. Takaishi, Y. Fujikura, K. Aigami. Synthesis, N 9, 632-633 (1977 ) [24]):

The disadvantages of the method:

1. The use of a large excess of concentrated inorganic acids (H ₂ SO ₄ , HNO ₃ ).

2. The use of excess poisonous bromine.

3. The duration of the process (8 days).

When a solution of 1-bromadamantane in liquid bromine with the properties of a Lewis acid is mixed with acetonitrile, after hydrolysis in 90% yield (1) is formed. The reaction is completed in 3 minutes, and in the absence of bromine it does not go at all or goes very slowly (V.F.Baklan, A.N. Khilchevsky, V.P. Kuhar. Zh.org.chemistry, t.20, No. 10, 2238 2239 (1984) [25]).

Adamantane also enters into similar transformations in liquid bromine. Thus, upon the interaction of adamantane with acetonitrile in liquid bromine (solvent), 1-acetamidoadamantane is formed after hydrolysis (1). If 3 minutes is required for the trial reaction of 1-bromadamantane, then complete conversion of adamantane takes from 0.5 to 2 hours. Adamantane is functionalized with acetonitrile without binding of hydrogen bromide, since the resulting target N- (1-adamantyl) acetamide under these conditions is not hydrogen bromide splits (V.F. Baklan, A.N. Khilchevsky, V.P. Kuhar. Zh. org.chemistry, t.23, No. 11, 2381-2384 (1987) [26]). It should be noted that for the reaction to occur in high yield (1), the presence of an oxidizing agent, sodium peroxysulfate Na ₂ S ₂ O _{5, is} necessary.

Based on the similarity in three characteristics (the initial reagents are adamantane, acetonitrile, the formation of N- (1-adamantyl) acetamide as a result of the reaction), the prototype is the method of interaction of adamantane with acetonitrile in liquid bromine [26].

The prototype has the following disadvantages:

1. The use of a large excess of toxic bromine.

2. The formation of an equivalent amount of HBr and inorganic waste (NaBr, Na ₂ SO ₄ ) requiring disposal.

The objective of the present invention is to simplify the technology for producing N- (1-adamantyl) acetamide.

The authors propose a method for producing N- (1-adamantyl) acetamide that does not have these disadvantages inherent in the prototype.

The essence of the method consists in the interaction of adamantane with acetonitrile in bromotrichloromethane in the presence of water under the influence of a catalyst Mo (CO) ₆ at a molar ratio of [adamantane]: [CH ₃ CN]: [CBrCl ₃ ]: [Mo (CO) ₆ ]: [H ₂ O] = 100: 100 ÷ 150: 100 ÷ 150: 1 ÷ 3: 1000 ÷ 2000, at a temperature of 130-140 ° C for 2-3 hours.

Under optimal conditions, the only reaction product is 1-acetaminoadamantane (1), and the conversion of adamantane is 90-95%.

Significant differences of the proposed method from the prototype.

1. To obtain N- (1-adamantyl) acetamide (1) from adamantane, the CBrCl ₃ -H ₂ O-Mo (CO) _{6 system is used} .

Advantages of the proposed method:

1. Availability of starting reagents: adamantane, H ₂ O and CBrCl ₃ .

2. The absence of highly toxic reagents (Br ₂ ) and inorganic waste.

3. Cost reduction and simplification of the technology as a whole by reducing energy and labor costs.

The proposed method is illustrated by examples.

General methodology

0.1–0.3 mmol of Mo (CO) ₆ , 10 mmol of adamantane, 10-15 mmol of CH ₃ CN were placed in a stainless steel micro autoclave (V = 17 ml) or a glass ampoule (V = 20 ml) (the results of parallel experiments) , 10-15 mmol of CBrCl ₃ and 100-200 mmol of water (which plays the role of a reagent and a solvent at the same time), the autoclave was sealed (the ampoule was sealed) and heated at 130-140 ° С for 2-3 hours. After the reaction, the microautoclave (ampoule) was cooled to ~ 20 ° C, opened, the reaction mass was extracted with methylene chloride (5 ml × 3p), the solvent was distilled off, the residue was crystallized from hexane. The yield of N- (1-adamantyl) acetamide is 90-95%.

EXAMPLE 1. 0.3 mmol of Mo (CO) ₆ , 10 mmol of adamantane, 15 mmol of CH ₃ CN, 15 mmol of CBrCl ₃ and 150 mmol of water were placed in a micro autoclave, the autoclave was sealed and heated at 130 ° C for 3 hours. After the reaction, the autoclave was cooled to room temperature, opened, after processing the reaction mass, as indicated above, 1-acetaminoadamantane was isolated in 95% yield.

The obtained N- (1-adamantyl) acetamide (1) had a melting point of 147 ° C (hexane). IR spectrum (ν, cm ^-1 ): 3220 (NH), 1645 (C = O), 1545 (NH). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 51.61 (C ¹ ), 41.50 (C ² , C ⁸ , C ⁹ ), 36.42 (C ³ , C ⁵ , C ⁷ ), 36.42 (C ⁴ , C ⁶ , C ¹⁰ ), 25.40 (CH ₃ ), 160.86 (C = O). Mass spectrum, m / z (J _rel. ,%): 193 [M] ⁺ (43), 192 (9), 150 (7), 137 (8), 136 (100), 135 (24), 134 (25), 100 (8), 94 (45), 93 (18), 92 (16), 91 (17), 79 (15), 77 (14), 58 (8), 55 (7), 43 (31), 42 (12), 41 (21), 39 (14). Found,%: C 74.61; H 9.88; N 7.19. C ₁₂ H ₁₉ NO. Calculated,%: C 74.56; H 9.91; N, 7.25.

Other examples confirming the method are given in table 1.

Table 1
The results of experiments on the synthesis of N- (1-adamantyl) acetamide by the reaction of adamantane with the CBrCl ₃ -H ₂ O-CH ₃ CN system under the influence of Mo (CO) ₆ No. p / p The molar ratio [Mo]: [AdH]: [CH ₃ CN]: [CBrCl ₃ ]: [H ₂ O] Temperature ° C Reaction time, h The yield of N- (1-adamantyl) acetamide,% one 2 3 four 5 one. 1: 100: 100: 100: 1000 130 3 61 2. 1: 100: 150: 100: 1000 130 3 66 3. 1: 100: 150: 150: 1000 130 3 73 four. 1: 100: 150: 150: 1000 140 2 78 5. 2: 100: 150: 150: 1000 130 3 89 6. 3: 100: 150: 150: 1000 130 3 90 7. 3: 100: 150: 150: 1500 130 2 95 8. 3: 100: 150: 150: 2000 130 3 91

Claims (1)

The method of obtaining N- (1-adamantyl) acetamide of the formula (1)

the interaction of adamantane with acetonitrile, characterized in that the reaction is carried out in the presence of bromotrichloromethane, water and a catalyst Mo (CO) ₆ with a molar ratio of [adamantane]: [CH ₃ CN]: [CBrCl ₃ ]: [Mo (CO) ₆ ]: [ H ₂ O] = 100: 100 ÷ 150: 100 ÷ 150: 1 ÷ 3: 1000 ÷ 2000, at a temperature of 130-140 ° C for 2-3 hours