Green synthesis of methadone in eutectic solvent

Abstract

Eutectic solvents (DES), have attracted much attention in the last decade. With the advantages of nonflammability, thermal and chemical stability, high solubility and partial vapor pressure, non-toxicity and reasonable prices, these solvents are suggested as useful solvents. On the other hand, the eutectic solvents developed by Abbott are the new generation of ionic liquids. The mixture of eutectics is from an ammonium salt and a hydrogen bonding compound such as urea, acid, amine, and non-toxic amines. Choline chloride and urea, are quite environmentally friendly and are known practically as green solvents. The purpose of the present research is to present the synthesis of diphenyl acetonitrile with 1-dimethylamino-2-chloropropane by a eutectic’s solvent. In addition, methadone is synthesized from the reaction of 2,2-Diphenyl-4-dimethylaminovaleronitrile with ethyl magnesium bromide in the presence of solvent eutectic, which is in optimal and environmentally compatible conditions and by principles of green chemistry.

Keywords

Methadone solvent eutectic system green synthesis pain medicine opioids

1 Introduction

The chemical structures of alkaloids are extremely variable. Generally, an alkaloid contains at least one nitrogen atom in an amine-type structure—i.e., one derived from ammonia by replacing hydrogen atoms with hydrogen-carbon groups called hydrocarbons [1 –3]. This or another nitrogen atom can be active as a base in acid-base reactions. The name alkaloid (“alkali-like”) was originally applied to the substances because, like the inorganic alkalis, they react with acids to form salts. Most alkaloids have one or more of their nitrogen atoms as part of a ring of atoms, frequently called a cyclic system [4]. Alkaloid names generally end in the suffix -ine, a reference to their chemical classification as amines. In their pure form most alkaloids are colourless, nonvolatile, crystalline solids. They also tend to have a bitter taste. Alkaloid, any of a class of naturally occurring organic nitrogen-containing bases. Alkaloids have diverse and important physiological effects on humans and other animals. Example of natural alkaloids are morphine and codeine. Also, some synthetic alkaloids are available such as methadone, heroine, tramadol and others [5 –7].

Methadone belongs to a group of substances called quasi-opioids [8]. Opioids have structural and functional properties similar to morphine (natural and synthetic), one of the opiate-like subgroups is the opiate family, which classified as central nervous system pain relief medications [9]. During the Second World War, it produced by German chemists and Bockmuhl and Erhart [10]. Methadone is an artificial opioid agonist produced by the laboratory and used as a type of treatment for opiate dependence. People with opioid dependence may be dependent on oral or injectable drug use [11]. Other uses of methadone are in severe pain and cough resistant to treatment in lung cancers [12]. Methadone is a longer-lasting drug than other opiates (such as heroin); its oral dose prevents the onset of opiate withdrawal symptoms for 24 hours or more, symptoms include anxiety, restlessness, runny nose, nausea, and vomiting [13] (Fig. 1).

Fig. 1

Structure of some opiate’s drugs.

Many heterocyclic compounds can be considered as beneficial structures. Most frequently, nitrogen heterocycles in five- or six-membered rings can be used. According to records, more than 85%of all biologically-active chemical compounds contain a heterocycle. This fact shows that the main role of heterocycles in modern drug design [14]. The application of heterocycles provides a useful tool for modification of solubility, lipophilicity, polarity, and hydrogen bonding capacity of biologically active agents, which results in the optimization of the drug candidates [15]. The increasing usage of various heterocycles in drugs is arisen from advances in synthetic methodologies, such as metal-catalyzed cross-coupling and hetero-coupling reactions, that allow rapid access to a wide variety of functionalized heterocycles. On the other hand, many heterocyclic lead compounds were synthesized from natural resources, and their structures were subsequently modified by medicinal chemists. Thus, heterocycles have critical importance for medicinal chemists, because using them, it is possible to expand the available drug-like chemical space and drive more effective drug discovery programs [16 –18].

In 1998, Anastas and Warner defined the term “green chemistry” as “developing environmentally compatible processes and products and reducing the negative effects on human health and the environment”[19]. Since the goal of green chemistry is to minimize the use and production of hazardous substances and reduce pollution, many chemists welcomed green chemistry, and since the adoption of this definition, it is is rapidly developing. With the advent of green chemistry, many early efforts by many researchers focus on the development of green solvents [20].

Deep eutectic solvents generally consist of two or three inexpensive and non-hazardous components that can communicate with each other to form a eutectic mixture through hydrogen bonding [21]. Note that most of them are between room temperature and 70⁰C fluid, in most cases, a DES is obtained by a combination of four-part ammonium salts with metal salts or hydrogen bonded zinc (HBD) that can be obtained by Anion-halide forms involving quaternary ammonium salts [22] (Fig. 2).

Fig. 2

Sample structures of halide salts and hydrogen bonding agents used for DES synthesis.

Due to the low vapor pressure and high boiling point that facilitates the recycling of ionic liquids, ionic liquids have been defined as green solvents, but many reports show that most ionic liquids are toxic [23]. To overcome the high price and toxicity of ionic liquids, a new generation of dissolver, called deep eutectic solvents, appeared at the beginning of this century [24]. Deep eutectic solvents are now widely accepted as a new class of ionic liquids because many of their properties and properties are common to ionic liquids. The terms “DES” and “IL” are used synonymously in the texts. Although they need to mentioned, these two are different types of solvents. DESs systems consisting of a eutectic mixture of Lewis acids, that can contain various anionic or cationic components. In contrast, ILs are composed mainly of combined systems of a kind of anions and separate cations, Although the physical properties of DESs are similar to those of other ILs, their chemical properties indicate areas of application that are significantly different [25].

Also, organolithium and Grignard reagents for ketones are one of the diverse and fundamental ways to generate new C–C bonds, which provides access to secondary alcohols [26]. However, this reaction is strictly limited by its low-temperature requirements to control their reactivity, as well as the need for dry organic solvents and environmental atmosphere protocols to prevent their rapid degradation from these polar reactions [27].

In 2014, Garcia Alvarez and colleagues found that ChCl/H2O and ChCl/glycerol eutectic compounds may be green and react reactive biologically to add organolithium chemistry or to Grignard ketone in the air at room temperature without the need for solvents Organic escape [28]. In this sense, low temperatures not required to cool the reaction, since DESs has high capacities. In all cases, the formation of secondary alcohols (3) chemically observed without any complications. In this process, ChCl may have a dual role as a component of the DES mixture, but also as a part of aluminum alloying, a halide source [29]. In short, deep solvent eutectic are a reactive green and biologically excellent for a large number of organic compounds of polar metals [30] (Fig. 3).

Fig. 3

Addition of organolithium or Grignard reagent to ketonesin ChCl-based eutectic mixtures.

2 Materials and methods

2.1 Materials & apparatus measurements

1-dimethylamino-2-propanol, thionyl Chloride, NaOH, sodium chloride, Sodium sulfate, magnesium, ethyl bromide, hydrochloric acid, activated charcoal, Choline chloride, Urea, glycerol from Merck companies. ¹H-NMR and ¹³C-NMR spectra of the compound were obtained in CDCl₃ using a FT-NMR Bruker (400 MHz) spectrometer. FTIR spectra were recorded using a Bruker rector 22 spectrophotometer. The Thermogravimetric analysis (TGA) of the samples was measured using Mettler Toledo instrument under N₂ with a heating rate of 10 °C min^-1. Energy Dispersive X-ray Spectroscopy (EDS) was performed by TeScan –Mira III. Field emission was 15 KV.

2.2 Preparation of 1-dimethylamino-2-chloropropane

A solution of 4.5 ml 1-dimethylamine-2-propanol and 10 ml of chloroform was introduced into the ice bath to 0 °C under an argon gas system, and then 4 ml of thionyl chloride and 2 ml of chloroform were added. The reaction mixture placed at ambient temperature for 30 minutes, and a white deposit was observed and then boiled under reflux for another 30 minutes, and the material was fluidized at 67 °C. 1-dimethylamino-2-chloropropane hydrochloride began to precipitate from a boiling solution, and the reaction mixture was cooled, washed with ether and filtered. The yellow sediment obtained with crystal ethanol and dried white crystals, which is the same as 1-dimethylamino-2-chloropropane, mp 191°C. 1-dimethylamino-2-chloropropane hydrochloride dissolved in equal amounts of water and 20%NaOH was added. The free 1-dimethylamino-2-chloropropane, which not dissolved in an alkaline solution of water, was extracted with 10 ml of ethyl ether, and its combined layers dried on NaSO_4, and 0.8 g of 1-dimethylamino-2-chloropropane obtained (Fig. 4).

Fig. 4

Synthesis of 1-dimethylamino-2-chloropropane.

2.3 Preparation of deep eutectic solvent

A mixture of urea (1.2 g, 20 mmol) and choline chloride (1.4 g, 10 mmol) was heated at 70°C to give a colorless liquid. The solvent is used without any purification (Fig. 5).

Fig. 5

Preparation reaction of deep eutectic solvent.

2.4 Preparation of 2.2-dimethylaminovaloronitrile

A solution of 1g diphenyl acetonitrile in a certain amount of DESs added with stirring to a slurry of 0.4 g finely ground sodium hydroxide under nitrogen. The dark red color of the nitrile anion observed immediately. The mixture heated to 78°C, and 0.8 ml of 1-dimethylamino-2-chloropropane added. The reaction mixture was stirred at 78°C under nitrogen for 24 hour, cooled and diluted with some water. In result, with increasing water, the eutectic solvent is removed from the reaction medium. The aqueous mixture was extracted with 20 ml toluene in three portions. Combined extracts were with saturated sodium chloride solution washed and then dried with anhydrous sodium sulfate. Removal of the toluene at reduced pressure afforded crude mixture appears as a yellow precipitate, which consists of two isomers and a little bit of diphenyl acetonitrile. To isolate the isomers washed several times with cold hexane the 2,2-diphenyl-3-methyl- 4-dimethylaminobutyronitrile isomer in cold hexane dissolved and separated from the sediment, and white crystal provided, mp 69°C. The 2,2-diphenyl-4-dimethylaminovaleronitrile isomer dissolved in hot hexane and segregate from the sediment, and white crystal by cooling prepared, mp 91°C (Fig. 6).

Fig. 6

Synthesis of 2,2-Diphenyl-4-dimethylaminovaleronitrile.

2.5 Preparation of methadone

A solution of 0.5 g of 2,2-diphenyl-4-dimethylaminovaleronitrile isomer has reacted in a certain amount of DESs and in another system 0.5 g of magnesium and in 8 ml of THF dry, react one hour, then 1.5 ml ethyl bromide was added by syringe glass which, during the addition the reaction starts to rise in temperature and boils, which indicates the formation of ethylene-magnesium bromide which ethyl magnesium bromide solution in dry THF to the first system to during15 minutes added. The reaction temperature reaches 78°C, and then the mixture is heated to reflux for 5:30 minutes. A solution of 0.8 ml of hydrochloric acid (37.5%) and 0.8 ml of water added to the reaction mixture for 10 minutes, and hot mixture with 0.2 ml of 18%HCl washed, after cooling the acidic solution, crystalline Methadone hydrochloride obtained. Methadone hydrochloride added 2.8 ml of water containing 0.02 g boiling activated charcoal and then filtered the boiling solution. A solution of 0.08 g of sodium hydroxide in 0.2 ml of water was added to the mixture and, by cooling the methadone crystallized, which was then boiled in 10ml methanol and the solution filtered to remove amount of suspended solid, after cooling the solution, white methadone crystals are formed that they wash with a small amount of methanol and dry in a vacuum. The dried Methadone thus obtained, melted at 76°C (Fig. 7).

Fig. 7

Synthesis of 6-dimethylamino-4,4-diphenyl-3-heptanone.

3 Results and duscussion

3.1 FT-IR of the 2.2-dimethylamino-valoronitrile

Among the characteristic peaks of the FT-IR spectrum of 2.2-dimethylamino-valoronitrile, the tensile vibrations of the aromatic C–H bond observed in the region of 3067 cm^-1.

The tensile vibration of the C≡N bond in the 2241 cm^–1 region and the tensile vibrations of the aromatic rings are 1492 cm ^–1 and 1451 cm^–1 (Fig. 8)

Fig. 8

FT-IR of 2.2-dimethylamino-valoronitrile.

3.2 FT-IR of methadone

Among the index peaks in the FT-IR spectrum of combination b3, the tensile vibrations of the aromatic C–H bond are observed in the region of 3067 cm^–1.

The tensile vibrations of the C=O bond in the 1698 cm^–1 region and the tensile vibrations of the aromatic rings in the region are 1475 and 1446 cm^–1 (Fig. 9).

Fig. 9

FT-IR of methadone.

3.3 ¹H NMR of methadone

The dual peak observed in the ppm 0.4418 to 0.4582 was related to hydrogen number 3 and in 0.6943 to 0.7304 ppm of hydrogen 8 and in 1.93 to 2.01 ppm range was related to hydrogen 4 and in 2.19 to 2.33 ppm for hydrogen number 7 and in 2.82 to 2.88 ppm for hydrogen number 2 and in of 3.45 to 3.50 ppm for hydrogen 1 and also for the multiple peaks of observation in the 7.18 to 7.33 ppm range, it is associated with aromatic hydrocarbons (Fig. 10).

Fig. 10

¹H NMR of Methadone.

3.4 ¹³C NMR of methadone

The peak observed in the 8.5 ppm region carbon 8 and in 20.4 ppm related carbon number 3 and in 26.2 ppm carbon 7 and in 41.7 ppm carbon 1 and in 42.5 ppm carbon number 4 and in 62.1 ppm carbon 2 and in 65.5 ppm carbon number 5 and in 126.2 ppm carbon number 12 and in 128.2 ppm carbon number 10 and in 129.2 ppm carbon number 11 and in 141.2 ppm area related to carbon numbers 9 and peak observed in the 202.9 ppm region of C=O carbon (Fig. 11)

Fig. 11

¹³C NMR of Methadone.

3.5 EDX analyze

The EDX spectrum confirms the presence of oxygen, nitrogen, and carbon elements in the desired synthesis, indicating that methadone synthesis has been successfully performed (Fig. 12)

Fig. 12

Element percentage of Methadone.

3.6 TGA analyze

TGA methadone curve shows that complete decomposition starts at 228–400°C (Fig. 13).

Fig. 13

TGA of Methadone.

Green and bio, reducing the negative effects on human health and the environment, as well as the price of solvents, is one of the most significant determinants of the application of these materials in chemistry and industry [19].

Eutectic solvents due to the advantages of non-toxicity and reasonable price and greenness compared to other dissolvent, which are often toxic and flammable, known as the most significant pollutant and attracted a lot of attention. One of the disadvantages of organic dissolvent is the separation of solvents from the reaction medium and their recycling, which has caused environmental hazards and high costs [31].

Eutectic solvents have used as the most widely used solvents due to the advantage of fast removal from reaction media. Due to the advantages of the eutectic solvents mentioned above, the use of these solvents in medicine, pharmacy, agriculture, commerce and... has become more pronounced, particularly, the role of this solvent in pharmacy is very important [20].

Eutectic solvents generally consist of two or three components that are inexpensive and non-hazardous, and through hydrogen bonding interactions, they can communicate with one another to form a eutectic mixture. Eutectic solvents are obtained from a quaternary ammonium salt with a hydrogen bonding agent (HBD) [22].

According to the articles on solvent eutectics, our goal was to become a highly-consumed Methadone drug that is an opiate drug, synthesize in the presence of eutectic solvents.

As mentioned, eutectic solvents, in addition to the advantage of being green and affordable and easy to remove from the reaction environment due to their superior ability to form intermolecular hydrogen bonding, cause the interconnection of the reactive primary material, and the process speed It speeds up the efficiency of the reaction [25, 32]. Therefore, in the synthesis of methadone with eutectic solvent, we expected an increase in process speed and efficiency.

In this research, a very unstable, 1-dimethylamino-2-chloropropane pre-produced product was first prepared by firstly containing a solution of 1-dimethylamine-2-propanol and chloroform in the system under gas was brought to 0°C by ice bath, then diluted with chloroform to the thinly chloride (If pure thinly chloride added, brown deposition appears in the system, and the reaction is entirely degraded). The reaction mixture exposed to ambient temperature for 30 minutes, and a white deposit was observed and then exposed to reflux for 30 minutes (HCl and SO₂ gas released) and 1-dimethylamino-2-chloropropane hydrochloride began to precipitate from a boiling solution. The reaction mixture was cooled, diluted with ether and filtered. The yellow sediment obtained with crystal ethanol and dried white crystals, which is the same as 1-dimethylamino-2-chloropropane, mp 191°C. 1-dimethylamino-2-chloropropane hydrochloride dissolved in equal amount of water and 20%NaOH was added. The free 1-dimethylamino-2-chloropropane, which not dissolved in an alkaline solution of water, was extracted with 10 ml of ethyl ether, and its combined layers dried on Na₂SO₄, and 0.8 g of 1-dimethylamino-2-chloropropane obtained.

A solution of diphenyl acetonitrile in a certain amount of DESs added with stirring to a slurry of finely ground sodium hydroxide under nitrogen. The dark red color of the nitrile anion observed immediately. The mixture heated to 78°C, and 1-dimethylamino-2-chloropropane added. The reaction mixture was stirred at 78°C under nitrogen for 24 hour, cooled and diluted with some water. In result, with increasing water, the eutectic solvent is removed from the reaction medium.

The aqueous mixture was extracted with 20 ml toluene in three portions. Combined extracts were with saturated sodium chloride solution washed and then dried with anhydrous sodium sulfate. Removal of the toluene at reduced pressure afforded crude mixture appears as a yellow precipitate, which consists of two isomers and a little bit of diphenyl acetonitrile. To isolate the isomers washed several times with cold hexane the 2,2-diphenyl-3-methyl- 4-dimethylaminobutyronitrile isomer in cold hexane dissolved and separated from the sediment, and white crystal provided, mp 69°C. The 2,2-diphenyl-4-dimethylaminovaleronitrile isomer dissolved in hot hexane and segregate from the sediment, and white crystal by cooling prepared, mp 91°C. A solution of 2,2-diphenyl-4-dimethylaminovaleronitrile isomer has reacted in a certain amount of DESs and another system magnesium in THF dry, and react one hour, then ethyl bromide was added by syringe glass which, during the addition the reaction starts to rise in temperature and boils, which indicates the formation of ethylene-magnesium bromide which ethyl magnesium bromide solution in dry THF to the first system to during 15 minutes added. The reaction temperature reaches 78°C, and then the mixture is heated to reflux for 5:30 minutes. A solution of hydrochloric acid (37.5%) and water added to the reaction mixture for 10 minutes, and hot mixture with 18%HCl washed, after cooling the acidic solution, crystalline Methadone hydrochloride obtained. Methadone hydrochloride added in water containing boiling activated charcoal and then filtered the boiling solution. A solution of sodium hydroxide in water was added to the mixture and, by cooling the methadone crystallized, which was then boiled in methanol and the solution filtered to remove amount of suspended solid, after cooling the solution, white methadone crystals are formed that they wash with a small amount of methanol and dry in a vacuum. The dried Methadone thus obtained, melted at 76°C.

4 Conclusions

In this study, methadone-opioid drug, widely used in medicine and pharmacy, was synthesized using eutectic solvent. Eutectic solvent as mentioned above, bio-and catalytic properties are reactive in the process. A remarkable point using the eutectic solvent was that we were able to synthesize Grignard ethyl magnesium bromide in a polar environment, without decomposing Grignard reagent.

Conflict of interest

All authors declare no conflict of interest and have not any relation

Footnotes

Acknowledgment

This work was supported by the office of the research vice chancellor of Azarbaijan Shahid Madani University.

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