Simple Two-step Procedure for the Synthesis of Memantine Hydrochloride from 1,3-Dimethyl-adamantane

Abstract

Memantine hydrochloride is a medicine used for the treatment of Alzheimer’s disease. A number of methods for the preparation of memantine hydrochloride have been reported. These procedures started from 1,3-dimethyl-adamantane by as many as using three or four reaction steps to produce memantine hydrochloride with overall yields ranging from 54 to 77%. In this article, a simple, concise two-step synthesis of memantine hydrochloride from 1,3-dimethyl-adamantane via N-formamido-3,5-dimethyl-adamantane with an improved overall yield of 83% was developed. In step 1, 3,5-dimethyl-adamantane was reacted with formamide and nitric acid to afford 1-formamido-3,5-dimethyl-adamantane in 98% yield, followed by hydrolysis of 1-formamido-3,5-dimethyl-adamantane with aq hydrochloride to give memantine hydrochloride in 85% yield. The procedure can be easily deployed at an industrial scale.

Introduction

Alzheimer’s disease is an irreversible brain disorder that affects memory, thinking, and behavior. The medications are known as galantamine, donepezil, rivastigmine, and memantine hydrochloride reduce and help relieve some behavioral symptoms. Memantine is prescribed to work by regulating glutamate, an essential chemical leading to brain cell death.¹ In 2003, the FDA approved it for the treatment of moderate to severe Alzheimer’s disease.

A number of papers and patents have been reported regarding the synthesis method of memantine and memantine hydrochloride (1) starting from various input materials such as 1,3-dimethyl-adamantane,²⁻¹⁰1-halogeno-3,5-dimethyl-adamantane,¹¹⁻¹⁶ and 1-hydroxy-3,5-dimethyl-adamantane.¹⁷⁻²⁰ Obviously, with the same input materials, different catalysts, types of reactions, or modes of purification could result in different synthesis yields.

Several groups have reported^2,6,7 the synthesis of memantine or memantine hydrochloride (1) from 1,3-dimethyl-adamantane (2) in three or four steps, with an overall low yield, and complicated procedures employing bromination of 2 with liquid bromine at reflux temperature to give 1-bromo-3,5-dimethyl-adamantane (3). N-(3,5-Dimethyl-adamantan-1-yl)-acetamide (4) is prepared via 3 with acetonitrile in sulfuric acid (Ritter-type reaction). Compound 4 is treated with NaOH in diethylene glycol (DEG) at 245–250 °C to give 5, followed by salt formation with anhydrous HCl in ether to produce memantine hydrochloride (1) (Scheme 1).²

Scheme 1. Four-step Synthesis of 1 from 2(2).

Reagents and conditions: (a) Br₂/reflux/6 h; (b) H₂SO₄, CH₃CN, RT °C/15 h; (c) i, NaOH/PEG/ref (245–250 °C/6–10 h) and ii, benzene extraction; and (d) anhydrous HCl, ether.

Their procedure has several disadvantages: First, this procedure has multiple steps (four steps), potentially decreasing the overall yield. Second, bromination of 2, which is conducted in liquid bromine at reflux, can lead to the release of bromine vapor.¹⁷ Third, benzene used in the isolation of 4 is toxic. Fourth, in the deacetylation of 4 into 5, diethylene glycol (DEG), which is used as a solvent, is toxic when heated to 245–250 °C with an alkali base. This can lead to an exothermic decomposition reaction with the release of hydrogen gas and acidic vapor.¹⁷ This procedure is a safety concern for large-scale production and is dangerous for the environment, along with the low reaction efficiency.

Some works of literature have also illustrated the process of preparing 1 from 2 in two steps: via intermediate 4, which was synthesized by the reaction of 2 with acetonitrile⁴ in a mixture of sulfuric acid, nitric acid, and 30% oleum, or via intermediate 6 by the reaction of 2 with formamide⁸⁻¹⁰ in a mixture of sulfuric acid and nitric acid. However, these reagents are either expensive or toxic, rendering the described methods unfavorable for the large-scale production of 1. In this article, we report an improved method for the synthesis of 1 from 2 in two steps: using only nitric acid instead of a mixture of two acids or two acids and 30% oleum, making the experimental manipulation straightforward, and increasing the overall yield to approximately 84% (compared to 36%⁴ or 54–77%⁸⁻¹⁰).

Results and Discussion

In this report, 1 was synthesized from 2 only in two steps via intermediate 6. Compound 6 is considered a suitable intermediate to prepare 1, which was prepared from formamide in the presence of nitric acid in one step to afford N-(3,5-dimethyl-adamantyl-1-yl)formamide (6). The reaction is carried out at 85 °C for 2 h. Intermediate 6 was hydrolyzed using a solution of 21% aq HCl to form 1. Conversion of 2 directly into 6 is a key stage in the synthesis of 1 (Scheme 2).

Scheme 2. Simple, Two-step Procedure for the Synthesis of 1 from 2.

Reagents and conditions: (a)/HNO₃, NH₂CHO/85 °C/2 h, 98%; (b) 21% aq HCl/100 °C/1 h, 85%.

The process illustrated in Scheme 2 has advantages, including (a) the key step that employs formamide (instead of acetonitrile), resulting in compound 6 in high yield (98%), which was efficiently hydrolyzed to 1 with 21% aq HCl in very good yield. (b) In the key step for the preparation of 6 from 2, it is not necessary to use large quantities of sulfuric acid, or use benzene as a carcinogenic solvent for the extraction of the intermediate amide, reducing the potential toxicity of the described procedure. (c) the hydrolysis of 6 avoids using NaOH in DEG under reflux conditions for an extended period⁷ (240–250 °C for 10 h). Here, the hydrolysis of 6 with 21% aq hydrochloride under milder conditions at 100 °C for 1 h gave very high yield (85%) of 1, and without the use of anhydrous HCl in ether to form the HCl salt of 1, eliminating the hazardous effect of diethyl ether. (d) The number of steps was reduced to two instead of three, or four, in previous reports; therefore, the overall yield of the procedure for the preparation of 1 from 2 is high (83% versus of 36–77%²⁻¹⁰); the time to complete the whole procedure is very short (5–8 h compared to 35–40 h). In our opinion, this procedure is economically favorable over the earlier literature syntheses because of the high overall yield, fewer steps, and use of inexpensive start materials. The safety studies also illustrated that this procedure was safe and not explosive (see Figures S9–S13) and can be easily upgraded to an industrial scale.

Preparation of N-(3,5-Dimethyl-adamantan-1-yl)-formamide (6)

Compound 6 was synthesized from 2 in one step (Ritter-type reaction). First, nitric acid is an agent in the addition of an amide to the carbonium ion of compound 2, which is treated with water to afford 6. This method bypassed the bromination of 2 (Scheme 1, step a), thus eliminating the need for liquid bromine.² In addition, we examined the effect of reaction temperature, and it is suitable for the reaction temperature to be in the range from 60 to 90 °C. Our study showed that the optimal reaction temperature and the time of this step (Scheme 2, step a) is 85 °C over 2 h, respectively (see Table S1). We also optimized the molar ratio of reagents and saw that the molar ratio of 2/nitric acid/formamide was 1:10:9 (see Tables S2 and S3).

Synthesis of Memantine Hydrochloride (1)

The hydrolysis of 6 to form memantine can be carried out using a base or acid catalysis; however, it is more efficiently performed under acid conditions because, after hydrolysis, the resulting memantine is protonated in situ with HCl to give 1. The reaction parameters of the hydrolysis process, such as solvents, hydrolysis time, the molar ratio between 6 and HCl, and volume of solvent, were optimized (Tables S4–S7). Compound 1 was obtained in optimal yield from a mixture of 6 and 21% hydrochloride in a molar ratio of 8.4:1 at the reflux for 1 h. The yield of 1 is 82–84% compared to a yield of 54% in a previous report.²

In summary, Scheme 2 describes an easily accessible, simple synthesis of compound 1 via two steps in one pot, with an overall yield of 83%. This procedure uses economical and accessible raw materials. Process parameters have also been investigated to optimize the volume of toxic reagents and solvents. Total preparation time was significantly reduced compared to other methods.

Conclusions

An enhanced process for the synthesis of memantine hydrochloride (1) has been published, with an overall yield of 83% via two steps in one pot and a purity of 99.39% via gas chromatography–mass spectrometry (GC–MS). The preparation of 6 from 2 is carried out at 85 °C for 2 h in a Ritter-type reaction. The subsequent conversion of 6 to 1 was performed in 21% HCl aq solution at reflux for over 1 h. These improvements facilitate the effective and economic production of memantine hydrochloride, which can be upgraded conveniently to a large scale.

Experimental Section

General Procedure

The reagents and solvents were used without further purification. Thin-layer chromatography was performed on a Kieselgel 60F-254 plate. The melting points were measured on an SMP-10 (Stuart). The IR spectra data were identified in the solid-state (potassium bromide dispersion) using a GX-Perkin Elmer 1650 FT-IR spectrophotometer. The mass spectrum (70 eV) was recorded on an AutoSpec Primer spectrometer. The ¹H NMR and ¹³C NMR spectra were measured in CDCl₃ on a Bruker-AV 500 spectrometer; the chemical shifts were calculated in ppm relative to tetramethylsilane (TMS).

Synthesis of N-Formyl-1-amino-3,5-dimethyl-adamantane (6) from 1,3-Dimethyl-adamantane (2)

In a round-bottom flask, at 20–25 °C, 1,3-dimethyl-adamantane (11.13 mL, 9.86 g, 0.06 mol) was slowly added to nitric acid (25.25 mL, 0.6 mol) over 20 min with stirring at this temperature for 1 h and then formamide (22.5 mL, 0.54 mol) was added within 0.5 h, followed by heating the mixture to 85 °C for 2 h. After the reaction was complete, the solution was cooled to 5–10 °C and added to an ice-cold water (120 mL); then, the reaction mixture was extracted with dichloromethane (150 mL). The separated organic layer was adjusted to pH 8–9 with 10% NaOH solution and then washed with chilled water; then, organic layer was dried over Na₂SO₄, and the solvent was evaporated to dryness in a vacuum to give N-formyl-1-amino-3,5-dimethyl-adamantane (12.18 g, 97.91%) as an oil, which crystallized into white solid at 10–15 °C, m.p. 60–64 °C. IR (KBr), (cm^–1): 3450–3199 (N–H); 2947–2847 (C–H); 1693,50 (C=O). MS (m/z): 208.16[M + 1]⁺. ¹H NMR (500 MHz, CDCl₃), δ (ppm): 8.23 (d, J = 12.5 Hz, 1H, NH) 7.99 (s, 1H, CHO); 6.23 and 5.25 (br, s, 1H); 2.12–2.17 (m, 1H); 1.83 (s, 1H); 1.67–1.61 (m, 2H); 1.48–1.40 (m, 2H); 1.37–1.25 (m, 4H); 1.17–1.12 (m, 2H); 0.85–0.83 (m, 6H, 2CH₃). ¹³C NMR (125 MHz, CDCl₃), δ (ppm): 162.3/160.3 (CHO); 53.7/52.3 (C₁) 50.5–50,3 (2C, C₂, and C₉); 47.8 (C₄); 42.7/42.5 (C₆); 42.2 (C₁₀); 40.4 (C₇); 32.5–32.4 (2C, C₃, and C₅); 30.1/30.0 (C₈); 29.9 (C₁₁); 29.8 (C₁₂) (see Figures S1–S4).

Synthesis of Memantine Hydrochloride (1) from N-Formyl-1-amino-3,5-dimethyl-adamantane (6)

In a round-bottom flask, a mixture of water (36 mL), solution of 36% hydrochloride (45 mL, 0.51 mol), and N-formyl-1-amino-3,5-dimethyl-adamantane (12.44 g, 0.06 mol) was stirred for 10 min, followed by heating to reflux for 1 h. The reaction mixture was concentrated to half the volume of the solvent under vacuum. To this solution, n-hexane (20 mL) was added, and the reaction mixture was heated to reflux for 0.5 h. The reaction was cooled to 5–10 °C for 1 h, when a white solid was separated. The solid was filtered and washed with cooled ethyl acetate to obtain a white solid, which was further recrystallized from a mixture of ethanol and ethyl acetate (5:4, v/v) and dried under a vacuum to give memantine hydrochloride (1) (10.97 g, 84.74%), which was melted at 290 °C and sublimated at 300 °C (literature¹⁷ m.p. 290–295 °C). IR (KBr), (cm^–1): 3441 (N–H); 2943, 2901 (CH); 1364 (C-N); MS, m/z: 180.17 [M–HCl + 1]⁺. ¹H NMR (500 MHz, CDCI₃), δ (ppm): 8.34 (s, 3H, NH₂.HCl); 2.20 (m, 1H); 1.89 (s, 2H); 1.74 (d, J = 11.5, 2H); 1.68 (d, J = 11.5, 2H); 1.42 (d, J = 12.5, 2H); 1.31 (d, J = 12.5 2H); 1.22 (d, J = 12.5 Hz, IH); 1.16 (d, J = 12.5 Hz, IH); 0.86 (s, 6H, 2CH₃). ¹³C NMR (125 MHz, CDCl₃), δ (ppm): 54.4 (C₁); 49.8 (2C, C₂, and C₉); 46.4 (C₄); 41.8 (2C, C₆, and C₁₀); 39.2 (C₇); 32.6 (C₃ and C₅); 29.8 (C₈); 29.6 (2C, C₁₁, and C₁₂) (see Figures S5–S8).

One-pot Synthesis of Memantine Hydrochloride (1) from 1,3-Dimethyl-adamantane (2)

1,3-Dimethyl-adamantane (222.5 mL, 197.1 g, 1.2 mol) was slowly added to nitric acid (505 mL, 12.0 mol) at 20–25 °C over 30 min with stirring for 1 h; then, formamide (440 mL, 10.8 mol) was added within 0.5 h. After that, the mixture was heated to 85 °C over 2 h. After the reaction was completed, the reaction was cooled to 5–10 °C and added to ice-cold water (2000 mL); then, the reaction mixture was extracted with dichloromethane (2400 mL). The separated organic layer was adjusted to pH 8–9 with NaOH 10% solution and then washed with cooled water; the organic layer was then dried over Na₂SO₄ and the solvent was evaporated to dryness in a vacuum to give N-formyl-1-amino-3,5-dimethyl-adamantane as an oil. To this oil, a mixture of a solution of 36% hydrochloride (840 mL, 10.08 mol) and water (720 mL) was added, stirred over 20 min, and heated to reflux for 1 h. The reaction mixture was concentrated to a half volume of solvent; to this reaction mass, n-hexane (300 mL) was added, and the reaction mixture was heated to reflux for 0.5 h. The reaction was cooled to 5–10 °C for 1 h, when a white solid was separated. The solid was filtered and washed with cooled ethyl acetate and dried under a vacuum to give memantine hydrochloride (1) (215.3 g; 83.16%), which was melted at 290 °C and sublimated at 300 °C. Purity (GC–MS) is 99.93% according to USP 38.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c01589.

• General procedure of the synthesis of N-formyl-1-amino-3,5-dimethyl-adamantane (6); investigation of the effect of reaction parameters on the yield of N-formyl-1-amino-3,5-dimethyl-adamantane (6); experimental section; analytical data (IR, MS, NMR) of N-formyl-1-amino-3,5-dimethyl-adamantane (6); synthesis of memantine hydrochloride (1); effect of reaction parameters on the synthesis of memantine hydrochloride (1) from N-formyl-1-amino-3,5-dimethyl-adamantane (6); and analytical data (IR, MS, NMR) of memantine hydrochloride (PDF)

The authors declare no competing financial interest.