Mechanochemical Synthesis of Histamine H1-Receptor Antigonists

Abstract

The present invention relates to the mechanochemical synthesis of histamine antagonists, which are benzhydryl ethers, asymmetrically substituting piperazines and their salts. The aforementioned antihistamine active pharmaceutical components may be diphenhydramine hydrochloride, cyclizine hydrochloride, and diphenylpyralin hydrochloride. These antihistamines are used in the treatment of allergies, urticaria, hay fever (allergic rhinitis), conjunctivitis, reactions to insect bites and stings, nausea, motion sickness, and insomnia.

Description

1 TARIFF Mechanochemical Synthesis of Histamine H1-Receptor Antigonists Technical Field to Which the Invention Relates The present invention describes benzhydryl ethers that bind piperazines and their salts symmetrically. mechanistic chemical synthesis of non-substituting histamine antagonists It is related to. The aforementioned antihistamine active pharmaceutical ingredient is diphenhydramine. These can be hydrochloride, cyclizine hydrochloride and diphenylpyralin hydrochloride. 10 State of the Art H1-blockers (antihistamines) are used to treat the symptoms of allergic reactions. It is widely used. Countertops selling cold, flu, and allergy products. In addition to these products, there are also sleep aids and products to treat motion sickness. They are available. Many prescription medications containing H1 blockers can treat seasonal allergies, allergic reactions, and other allergic reactions. reactions, depression, nausea and vomiting, motion sickness and headaches It is used to treat torsion. First-generation H1 antihistamines. It has a central effect and is therefore also used as a sedative, second generation H1 antihistamines tend to have less central effects and are primarily antiallergic. They are used as medicines. Diphenhydramine hydrochloride, cyclizine hydrochloride and Diphenylpyral hydrochloride is a first-generation antihistamine. Diphenhydramine hydrochloride (2-(Diphenylmethoxy)-N,N-dimethylethane-1-amine hydrochloride, DPH), antihistamine, antitussive, sedative, antiemetic, anticholinergic, and motion sickness medication. It is a well-known histamine antagonist with counteracting effects. Particularly useful for allergies, insomnia, 25 to treat vomiting, dizziness, nausea and cold symptoms Diphenhydramine [1] [2] used. Dimedrol®, Allergina®, Valdren® or Benadryl® commercial It is used in medications under these names. 2 Cyclizine hydrochloride (1-benzhydryl-4-methylpiperazine hydrochloride, CYC) is used to treat histamine H1- It is an antihistamine, a piperazine derivative with receptor antagonist activity. It is sold as a medicine under a number of brand names such as Marezine®, Vald®, and Nausicalm®. and to treat nausea, vomiting, and dizziness associated with motion sickness or vertigo, and 5 It is used to prevent this. Diphenylpyral hydrochloride (4-(benzhydryloxy)-1-methylpiperidine hydrochloride, DPP), Another first-generation diphenylpiperidine class with anticholinergic effects It is an antihistamine. It is marketed in Europe for the treatment of allergies and is known as Allergen®, Arbid®, 10. Belfene® and Diafen® are among the brand names under which it is sold as medicine. Bromodiphenylmethane in benzene at 120°C in the presence of anhydrous sodium carbonate. Parke, Davis & Co., which described the reaction of DPH with dimethylaminoethanol, gave 15 first reported synthesis (Equation 1) [3]. Previous technique to Merck & Co (Equation 2) Another synthesis given is of 1,1'-(diazomethanediyl)dibenzene and dimethylaminoethanol. It involves the reaction in an inert solvent in the presence of an inorganic base [4]. Searle The known technique given to & Co. (Equation 3) and Nopco Chem Co. (Equation 4) Diphenhydramine Diphenhydramine hydrochloride Cyclizine hydrochloride Cyclizine Diphenylpyralin, Diphenylpyralin hydrochloride 3 Other methods related to this situation involve the use of chlorinated substrates as described above. It offers similar ways[5], [6]. In the previous technique, two conventional synthetic routes were developed for cyclizine: one of them, This involves refluxing the mixture in acetonitrile for 18 hours (Equation 5)[7] and the other uses a flow reactor in the presence of water (Equation 6) [8]. On the other hand, Tsuji et al. condensed N-methyldiethanolamine and aminodiphenylmethane in 1,4-dioxane at 180°C for 10 days. with a 14-hour reaction, but with a very weak yield of only 14%, cyclizine synthesized. (Equation 7) [9]. Equation 1 Equation 2 in benzene, 6-7 hours, 125°C in benzene, 24 hours, 85°C 8-10 hours, 100°C Equation 3 Equation 4 in benzene, 6 hours, 125-150 °C 4 In the current state of the art, the synthesis of diphenylpyral (DPP) occurs in the presence of potassium carbonate. It is based on the coupling of 4-hydroxy-1-methylpiperidine with benzhydrylbromide.

[10] . 5 The reaction was refluxed in xylene at 140°C for 24 hours (Equation 8). Weis et al., with 1-methylpiperidin-4-ol with halodiphenylmethanes or diphenyldiazolomethanes He demonstrated the synthesis of DPP by means of etherification (Equation 9)

[11] . To Merck & Co. The given synthesis involves 1,1'-(diazomethanediyl)dibenzene and 4-hydroxy-1- in benzene. It includes the reaction of methylpiperidine (Equation 10)[4]. Given to Lapa et al. 10 The method presents a two-stage reaction in an N,N-dimethylformamide-toluene mixture. Reflow of diphenylethanol and 4-hydroxypiperidine in the presence of toluene-4-sulfonic acid the reaction (Equation 11a) and then the product formed in Equation 11a In the presence of potassium carbonate and alkyl halide, approximately in N,N-dimethylformamide It involves refluxing at 150oC for 24 hours (Equation 11b)

[12] . 15 in acetonitrile, 18 hours, 125°C Equation 5 Equation 6 Equation 7 In the water, 45 min, 100°C Cyclizine Cyclizine Cyclizine In 1,4-dioxane, clock, 180 oC As seen above, the synthesis of DPH, CYC, and DPP in the current state of the technique is 5 The reactions involved are mostly high, with reaction times lasting for hours. They are monitored at various temperatures. However, the antihistamine drugs described above, It is widely used and synthesized in large quantities worldwide. Mechanochemistry refers to chemical reactions caused by mechanical energy. It is causing problems. The lack of a solution means energy saving, high efficiency and low temperature. 10 Mechanochemistry has gained increasing interest due to its advantages such as process-based solutions. It is not just about mass production. the possibility of eliminating the need for solvent use and reducing waste generation not only did it offer, but it also synthesized active pharmaceutical ingredients (APIs). It has also opened the door to a different reaction environment. In industry, as mentioned above... As shown in the equations, prolonged exposure to high temperatures in toxic solvents for 15 hours For the synthesis of APIs that require heating throughout, only wet chemistry methods are currently available. Equation 8 Equation 9 Equation 10 Equation 11a Equation 11b In xylene, 24 clock, 140 oC in benzene, 24 hours, 85°C N,N-dimethylformamide-toluene inside for 4 hours, ~120 oC Dry N,N-dimethylformamide inside 24 hours, ~150 oC clock, 140 oC 6 is used. However, the mechanochemical synthesis of APIs is both room-based. using ball mills at both temperature and cryo conditions, or a simple one. This can be achieved by grinding with a mortar and pestle. Additionally, planetary gear can be used if needed. Mechanochemical synthesis of APIs using mills, twin-screw extrusion, etc. This can be achieved. These different techniques are suitable for large-scale industrial synthesis of APIs. It expands synthesis pathways. In particular, twin-screw extrusion allows for the processing of a wide variety of chemicals. It is used to achieve the continuous production of reactions and primarily It is preferred in industrial processes

[13] –

[15] . The conventional synthesis of diphenhydramine hydrochloride (Equation 12) uses toxic solvents (i.e. toluene

[16] , benzene [3]), high temperatures leading to high energy consumption and more 10 This is achieved using long reaction times. Equation 12 The technique as we know it was first invented by George Rieveschl in 1947. And this method is still the main one for the synthesis and production of massive diphenhydramine hydrochloride. This is an option (Equation 1). The disadvantages of this technique are that it is costly and time-consuming. Technique for the synthesis of histamine antagonist active pharmaceutical components (APIs) Methods in their current state require higher temperature reaction conditions and longer processing times. reaction times, toxic solvents and more chemicals (e.g. bases, catalysts), multi-stage processes and studies, high waste production, high energy 20 limitations and disadvantages such as consumption of diphenhydramine hydrochloride, cyclizine active pharmaceutical histamine antagonists such as hydrochloride and diphenylpyralin hydrochloride a cost-effective, green, and faster synthesis method for components (APIs) This has made its development necessary. Brief Description and Objectives of the Invention 25 The present invention describes the use of histamine antagonist active pharmaceutical ingredients (APIs), specifically antihistamines include diphenhydramine hydrochloride, cyclizine hydrochloride, and diphenylpyral. This invention describes the mechanistic chemical synthesis method of hydrochloride. In the present invention, toluene, reflux, 18 hours Diphenhydramine hydrochloride Diphenhydramine min 7 diphenhydramine (DPH), cyclizine (CYC), and diphenylpyral (DPP) are mechanochemically related. synthesized and then these active pharmaceutical ingredients (APIs) hydrochloride Salts are formed. These active pharmaceutical ingredients (APIs) undergo mechanochemical processes. synthesis using ball milling, cryo milling and mortar and pestle milling. This is accomplished using these three techniques, grinding by converting mechanical energy into mechanical energy instead of heating. 5 to direct chemical transformations through direct absorption of energy It offers a way to advance mechanochemical reactions by incorporating mechanical force. In the grinding technique, the system is shaken at the desired frequency, and this movement of the balls... by colliding and mixing the reactants, they reduce particle sizes and the reactants It activates mechanically. Compared to traditional methods, the frequencies are 10 times higher. modifying it eliminates the need for heating to support the reactions. It provides. The starting materials are bromodiphenylmethane (MP: 35-39 oC), N-methyl Piperazine (MP: -5.57 °C) and N-methyl-4-piperidinol (MP: 31 °C) have low melting points. because of its properties, grinding under cryo conditions via a ball mill, especially Solid-state reactions for the synthesis of cyclizine hydrochloride and diphenylpyral hydrochloride 15 It has offered a way to advance the process. Thus, it creates a reaction environment that does not contain liquid. They freeze before the reaction begins. Furthermore, in this invention, the reactions... No solvents, bases, or catalysts are used to facilitate this process. Because the mechanical input is quite sufficient to sustain the synthesis. Regarding the present invention... The topic is the synthesis of APIs; while traditional methods take hours to complete, grinding takes 20 minutes. It is obtained within minutes using techniques. Furthermore, mechanochemical... The method incorporates multi-stage processes that are characteristic of traditional synthetic procedures, and It provides a single-step synthesis that eliminates the need for further studies. These APIs are used for hives, hay fever (allergic rhinitis), conjunctivitis, reactions to insect bites and stings, Treats symptoms of nausea, motion sickness, insomnia, and many other allergies. 25 It belongs to the class of antihistamine drugs. One of the aims of the present invention is to specifically target histamine antagonist APIs. diphenhydramine hydrochloride, cyclizine hydrochloride, and diphenylpyralin hydrochloride mechanical forces to drive reactions at high frequencies for synthesis With the help of this, reactions can be carried out in one to two steps in just minutes, 30 The aim is to provide a faster method. These APIs, in the current invention, mostly consist of 10 to 20 It is obtained with the highest yields between minutes. Mechanochemical synthesis Performed in just 1 to 5 minutes, it has yielded moderate to satisfactory results. 8 Another purpose of the present invention is to develop antihistamine APIs, diphenhydramine hydrochloride, The aim is to provide a green method for the synthesis of cyclizine hydrochloride and diphenylpyralin hydrochloride. In the present invention, synthesis is achieved using less toxic solvents, chemicals, and energy. This is being done in a way that ensures a green approach. Another purpose of the present invention is to develop antihistamine APIs, diphenhydramine hydrochloride, 5 A cost-effective way to synthesize cyclizine hydrochloride and diphenylpyralin hydrochloride. The aim is to provide a method. In the present invention, synthesis is achieved using fewer chemicals. This is carried out (for example, solvents, bases and to support the reaction). Catalysts are not required, and only small amounts of solvent are needed for the processing steps. (required). At the same time, traditional 10 that require hours of heating in backflow. Compared to its counterparts, it uses less electricity to operate the ball mill. Because it requires energy, it is an energy-efficient technique. According to the present invention, mechanochemical reactions between reactants occur via the solvent. without it is carried out at room temperature or -196 °C, and this is a direct This can be achieved with a grinding device. Therefore, the method of the invention is green. 15 Furthermore, these antihistamines are synthesized within minutes and require less energy. is consumed. In addition, as in the previous technique, the reaction process to facilitate this, bases (i.e., sodium carbonate) or other catalysts Since there is no longer a need to add chemicals, the total cost is also reduced. Therefore, the invention is an effective synthetic method in terms of cost, energy and time, and 20 A novel environmentally benign alternative for the conventional synthesis of diphenhydramine and its derivatives. The mechanochemistry used in the present invention is based solely on the bulk solvent. the possibility of eliminating the need for its use and reducing waste generation It not only offers a different kind of reaction, but also opens the door to a different kind of reaction environment. It opens. 25 Explanation of the Figures FIGURE 1 ESI-MS spectrum of DPH after 1 minute of ball milling at 25 °C. FIGURE 2 ESI-MS spectrum of DPH after 5 minutes of ball milling at 25 °C. 9 FIGURE 3 ESI-MS of DPH after grinding with a mortar and pestle for 5 minutes at 25 oC. spectrum. FIGURE 4 ESI-MS spectrum of DPH after 1 hour of ball milling at 25 °C. FIGURE 5 - ESI-MS spectrum of DPH after 1 hour of ball milling at -196 °C. 5 FIGURE 6 Commercial reagents a) dimethylamino ethanol, b) bromodiphenylmethane, c) commercial Reference DPH HCl 1H NMR spectra, d) CDCl3 (+5 drops methanol- d4) 1H NMR of DPH HCl after ball milling at 25 °C for 1 hour. spectrum. FIGURE 7 a) 1H NMR spectrum of DPH HCl reference b) 1 minute at 25 °C c) 5 10 minutes, d) 10 minutes, e) 20 minutes and f) in CDCl3 (+5 drops of methanol-d4) 1H NMR spectra of 1-hour ball-ground DPH. FIGURE 8 a) After ball grinding in a ZrO2 container at 25 °C for 5 minutes, b) in an SS container 1H NMR spectra of DPH after 5 minutes of ball milling at °C c) Mix 5 15 in CDCl3 (+5 drops methanol-d4) at 25 oC with a mortar and pestle. 1H NMR spectrum of DPH after 1 minute grinding. FIGURE 9 a) After 1 hour of cryopreservation and b) CDCl3 (+5 drops methanol-d4) 1H NMR of DPH after ball milling at 25°C for 1 hour spectra. FIGURE 10 a) 13C NMR spectrum of commercial reference DPH HCl. b) DPH HCl and c) 20 Ball milling in CDCl3 (+5 drops methanol-d4) at 25°C for 1 hour. Then, the 13C NMR spectra of DPH. FIGURE 11 Ball milling in CDCl3 (+5 drops methanol-d4) at 25 °C for 1 hour. Next, the 1H NMR spectrum of DPH. FIGURE 12 25°C at 1 hour without ball milling in CDCl3 (+5 drops methanol-d4). Next, the 13C NMR spectrum of DPH. FIGURE 13 - ESI-MS of DPH HCl after ball milling at -196 °C for 60 minutes. spectrum. FIGURE 14 ESI-MS spectrum of CYC after 5 minutes of ball milling at 25 °C. FIGURE 15 ESI-MS spectrum of CYC after 10 minutes of ball milling at 25 °C. FIGURE 16 ESI-MS spectrum of CYC after 20 minutes of ball milling at 25 °C. FIGURE 17 - ESI-MS spectrum of CYC after 5 minutes of ball milling at -196 °C. FIGURE 18 - CYC's ESI-MS after ball milling at -196°C for 10 minutes. spectrum. 5 FIGURE 19 - CYC's ESI-MS after ball milling at -196 °C for 20 minutes. spectrum. FIGURE 20 - ESI-MS of CYC after ball milling at -196 oC for 60 minutes. spectrum. FIGURE 21 CYC's ESI-MS 10 after ball milling in an SS container at 25°C for 5 minutes. spectrum. FIGURE 22 - After ball milling in an SS container at -196 oC for 5 minutes, CYC's ESI- MS spectrum. FIGURE 23 CYC's ESI-MS after grinding with a mortar and pestle for 5 minutes at 25°C. spectrum. 15 FIGURE 24 Starting materials a) bromodiphenylmethane and b) 1H of N-methylpiperazine NMR spectra were obtained at -196 °C at c) 5 minutes, d) 10 minutes, e) 20 minutes, and f) CDCl3. 1H NMR of ball-ground CYC in (+5 drops methanol-d4) for 1 hour spectra FIGURE 25 Starting materials a) bromodiphenylmethane and b) N-methylpiperazine 1H 2O NMR spectra at 25°C at c) 5 minutes, d) 10 minutes, e) 20 minutes, and f) CDCl3. 1H NMR of ball-ground CYC in (+5 drops methanol-d4) for 1 hour spectra FIGURE 26 shows the mixture being prepared in CDCl3 (+5 drops of methanol-d4) at 25 °C using a mortar and pestle. Compared to the CYC spectrum after 25 minutes of grinding, 25 25 Ball milling in a ZrO2 container at -196°C for 5 minutes, ZrO2 container at -196°C for 5 minutes 5-minute ball milling, 5-minute ball milling in an SS container at 25°C Subsequently, 1H NMR spectra of CYC. 11 FIGURE 27 Ball bearing in CDCl3 (+5 drops methanol-d4) at -196 °C for 5 minutes. 1H NMR spectrum of CYC after grinding. FIGURE 28 Ball bearing in CDCl3 (+5 drops methanol-d4) at -196 °C for 5 minutes. 13C NMR spectrum of CYC after grinding. FIGURE 29 - ESI-MS 5 of CYC HCl after ball milling at -196 °C for 60 minutes. spectrum. FIGURE 30 CYC HC1 after ball milling at -196 °C for 60 minutes in MeOD. 1H NMR spectrum. FIGURE 31 CYCHC1 after ball grinding in CDCl3 at -196 °C for 60 minutes. 13C NMR spectrum. 10 FIGURE 32 ESI of DPP after ball milling in a ZrO2 container at 25 oC for 10 minutes. MS spectrum. FIGURE 33 After ball milling in a ZrO2 container at 25 °C for 10 minutes in MeOD. 1H NMR spectrum of DPP. FIGURE 34 After 10 minutes of ball milling in a ZrO2 container at 25 oC in MeOD, 15 113C NMR spectrum of DPP. FIGURE 35 DPP HCl after ball milling in a ZrO2 container at 25 °C for 10 minutes. ESI-MS spectrum. FIGURE 36 After 10 minutes of ball milling in a ZrO2 container at 25°C in MeOD. 1H NMR spectrum of DPP HCl. 20 FIGURE 37 After 10 minutes of ball milling in a ZrO2 container at 25 °C in MeOD. 13C NMR spectrum of DPP HCl. Detailed Description of the Invention The present invention describes the hydrochloride of histamine antagonist active pharmaceutical substances (APIs) 25 salts, especially diphenhydramine (DPH), cyclizine (CYC) and diphenylpyralin (DPP) first generation antihistamine active pharmaceutical components which are hydrochloride salts It is related to the mechanochemical synthesis method of its representatives. In the present invention, 12 diphenhydramine (DPH), cyclizine (CYC), and diphenylpyral (DPP) are mechanochemically related. synthesized and then these active pharmaceutical ingredients (APIs) hydrochloride Salts are formed. These active pharmaceutical ingredients (APIs) undergo mechanochemical processes. synthesis using ball milling, cryo milling and mortar and pestle milling. is being carried out. 5 In the present invention, ball milling induces chemical reactions through the transmission of mechanical force. Since it has proven effective in promoting synthesis, and most of these syntheses are performed without solvents. Since it can be carried out, the use of ball milling is preferred, and thus Compared to its solvent-based counterparts, this results in higher sustainability. Therefore, in our approach, mechanochemical reactions are used in room 10 of the ball mill. at a temperature of (25 oC) and with liquid nitrogen (-196 oC) from the integrated cooling system The experiments are carried out by cooling. The experiments use complementary ball materials (six grinding ball (10.06 mm diameter) for grinding both zirconia and stainless steel. This is carried out in containers (25 mL volumetric capacity). Furthermore, these APIs... Mechanochemical synthesis, reactants at room temperature (25 °C) with a mortar and pestle for 15 minutes. It is obtained by grinding. All antihistamines synthesized using the synthesis method of this invention are suitable for severe allergic reactions. reactions, nausea, hives, hay fever (allergic rhinitis), conjunctivitis, insect bites used in the treatment of reactions to bites and stings, motion sickness, and insomnia. It can be used successfully. 20 In the present invention, the other fenhydramine derivatives shown below are also developed using the same method. It can be synthesized using: N,N-dimethyl-2-(phenyl(o- toyl)methoxy)ethane-1-amine Orphenadrine Dimenhydrinate (Diphenhydramine & 8- Chlorotheophylline combination drug) Medrilamine 2-((4- methoxyphenyl)(phenyl)methoxy )-N,N-dimethylethane-1-amine Bromazine 2-((4- bromophenyl(phenyl)methoxy) -N,N-dimethylethane-1-amine Embramine 2-(1-(4-bromophenyl)-1- phenylethoxy)-N,N- dimethylethane-1-amine 13 Equation A. Mechanistic chemical synthetic route of diphenhydramine hydrochloride. Diphenhydramine hydrochloride was successfully produced in high yields according to Equation A 5 It is synthesized and characterized by 1H NMR, 13C NMR and HRMS. HCl salt The formation of DPH involves adding 2-3 drops of concentrated HCl to methanol until the pH reaches 4-5. It can be easily obtained by processing. Until the product is completely melted. It can be heated and stirred. The mixture is diphenhydramine hydrochloride (DPH HCl). It can be slowly cooled to room temperature in order to crystallize. 10 Buclizine 1-(4-(tert-butyl)benzyl)-4-((4- chlorophenyl(phenyl)methyl) piperazine The Assembly 1-((4-chlorophenyl)(phenyl)methyl)-4-(4- methylbenzyl piperazine Sinnarizin 1-benzhydryl-4-cinnamylpiperazine Cetirizine 2-(2-(4-((4- chlorophenyl)(phenyl)methyl)piperazine- 1-yl)ethoxy)acetic acid Levosetirizine (S)-2-(2-(4-((4- chlorophenyl(phenyl)methyl)piperazine-1- i)ethoxy)acetic acid Hydroxyzine 2-(2-(4-((4- chlorophenyl(phenyl)methyl)piperazine-1- yl)ethoxy)ethan-1-ol Diphenhydramine Hydrochloride Diphenhydramine Cyclizine Cyclizine Hydrochloride 14 Equation B. Mechanochemical synthetic route of cyclizine hydrochloride. Cyclizine hydrochloride was successfully processed with satisfactory yield according to Equation B. It is synthesized and characterized by 1H NMR, 13C NMR and HRMS. Cyclizine Conversion to hydrochloride, following the procedure described for DPH HCl 5 It can be accomplished. Equation C. Mechanochemical synthetic route of diphenylpyral hydrochloride. Mechanochemical synthetic investigation on selected antihistamine APIs. To initiate, bromodiphenylmethane and N,N-dimethylethanolamine (DMAE) are initially used. They were selected as representative substrates for the synthesis of DPH. All DPH derivatives, several ball grinding parameters (type of ball grinding apparatus, nature of jars, It was prepared and tested using (time) (Table 1). As mentioned above, 15 Accordingly, if the traditional synthesis is followed, the completion of DPH synthesis takes hours. Therefore, first of all, the mechanochemical synthesis of DPH takes time. Its dependence has been investigated. DPH, reactants, a jar of zirconium dioxide, and balls. When ground at room temperature for 1 hour, it was obtained with a high yield (76%). (Table 1, entry 5). At this stage, a high throughput of 20% per hour is achieved through mechanochemical synthesis. It can be said that this is promising because traditional synthetic Alternatives involve heating the reaction mixture to 125-150°C, usually achieving 70% in 6 hours. It can provide a yield of around that amount. In subsequent experiments, the grinding time was reduced. (e.g., 1 to 20 minutes), in terms of efficiency compared to longer reaction processes. Even better results (80-90%) have been obtained (Table 1, inputs 1-4). Therefore, chemical 25 Mechanical force is used to direct the transformations, completing the grinding process in just minutes. Diphenylpyral Diphenylpyral Hydrochloride by carrying out the process within it, it is quite possible to convert the starting materials into DPH. We can conclude that it is sufficient. In both temperature conditions (room temperatures and cryotherapy) When syntheses are performed under the same conditions, this temperature difference results in the obtained DPH. It has been observed that it does not significantly alter its efficiency. (Table 1) Under cryo conditions Ball mill grinding is one way to sustain solid-state reactions. 5 is able to offer, but one of the starting materials is N,N-dimethylethanolamine. (DMAE) is liquid at room temperature and can freeze at -70°C. DMAE's it cannot freeze just before the reaction and the reaction environment is completely It can be said that it does not involve solid-state reactions. Therefore, cryo conditions... It does not have a significant effect on the variation in isolated DPH yields. 10 In mechanochemical approaches, the grinding materials are targeted by the chemical. This can vary depending on the reactions (e.g., zirconium dioxide, tungsten carbide, (stainless steel, agate, PMMA, glass). Therefore, subsequently, the grinding medium Using stainless steel (SS) (Table 1, entries 10, 11) jars and balls, both Grinding at room temperature and at -196 °C by changing the grinding medium to steel 15 The effect of the material has been investigated. Stainless steel (SS) containers are used in every No precise yield was recorded because it loosened during the experiment, but DPH formation was observed in 1H and Verified and confirmed by 13C NMR. Both grinding materials have DPH. We concluded that it is applicable to mechanosynthesis. Finally, a comparison. The DPH shown is ground using a mortar and pestle. Grinding with a mortar and pestle, 20 This resulted in a moderate efficiency of 45% (Table 1, input 12) and mechanical activation, because it cannot be achieved as efficiently as ball milling at high frequencies, It is expected to have a lower yield for manual grinding. Table 1. Investigation of Reaction Conditions for DPH Synthesis (SS: Stainless steel). Diphenhydramine (DPH) Entry Jar / Marble material Grinding Frequency (Hz) Time (min) Temperature (°C) Yield (%)b 1 ZrO2 30 Hz 1 min 25 oC 77 2 ZrO2 30 Hz 5 min 25 oC 88 3 ZrO2 30 Hz 10 min 25 oC 88 4 ZrO2 30 Hz 20 min 25 oC 81 ZrO2 30 Hz 60 min 25 °C 76 16 6 ZrO2 30 Hz 5 min -196 oC 77 7 ZrO2 30 Hz 10 min -196 oC 91 8 ZrO2 30 Hz 20 min -196 °C 85 9 ZrO2 30 Hz 60 min -196 °C 70 SS 30 Hz 5 min -196 °C No 11 SS 30 Hz 5 min 25 oC No 12 Mortar & Knob - 5 min 25 oC 45 aReaction conditions: Bromodiphenylmethane (2.03 mmol, 1.0 equivalent) and N,N- dimethylethanolamine (DMAE) (2.00 mmol, 1.0 equiv), 6 zirconia grinding balls (10.06 in a 25 mL zirconia grinding jar (mm diameter) or 6 stainless steel (SS) grind 25 mL of stainless steel (SS) with grinding ball (10.06 mm diameter) 5 in a jar or at the specified time and temperature with a mortar and pestle and ball. It has been ground. Isolated yield. In the subsequent reaction sequence, structural similarity to previously studied DPH and the same mechanochemical due to the use of bromodiphenylmethane as the starting material The aim was to evaluate the applicability of the approach to the cyclical nature of the study. The results are 10. Ball mill and manual grinding techniques summarized in Table 2. Zirconia and Supplementary ball in stainless steel grinding cups (25 mL volumetric capacity) Grinding experiments with materials (six grinding balls, diameter 10.06 mm) This was carried out. First, different reaction times were investigated. At 25 °C for one hour... After the experiment, cyclizine was obtained with 57% yield (Table 2, input 4). Reaction 20 15 When performed at 63% efficiency for 63 minutes, the yields increased slightly (Table) 2, entry 3). Further research on the mechanochemical reactions of CYC, cryo This was carried out under certain conditions. The results show that lower temperatures produce better results in the shapes. with defined 1H NMR spectra with approximately 75-80% efficiency (Table 2, entries 5-9) It has shown extraordinary progress. The initial materials were completely 20 It has been transformed into a product. Grinding via ball mill under cryo conditions, The starting materials are bromodiphenylmethane (MP: 35-39 °C) and N-methylpiperazine. Because cyclizine has a low melting point (MP: -5.57 oC), it is suitable for solid-state synthesis. It has provided a way to advance the reactions. Thus, a reaction without liquid. 25 before the reaction starts, creating the environment and increasing the reaction yield 17 They are frozen. Grinding is also done using stainless steel jars at 25°C and -196°C. Grinding in a zirconia medium at oC for 5 minutes (Table 2, entries 9 and 10) or Higher yields than those obtained by grinding with a mortar and pestle for 5 minutes. This has been accomplished. Manual grinding, mechanical activation as in the case of DPH. Since it could not be obtained in high amounts, it led to lower yields as expected. 5 In summary, the experimental results of the invention show that the secondary halide is methyl piperazine. It exhibited good mechanochemical reactivity with and the expected benzhydryl piperazine at 45%. It shows that it provides it with an efficiency of 84. Table 2. Examination of Reaction Conditions for CYC Synthesis. Cyclizine (CYC) Entry Jar / ball bearing material Grinding Frequency (Hz) Time (min) Temperature (°C) Yield (%)b 1 ZrO2 30 Hz 5 min 25 oC 41 2 ZrO2 30 Hz 10 min 25 oC 55 3 ZrO2 30 Hz 20 min 25 oC 63 4 ZrO2 30 Hz 60 min 25 oC 57 ZrO2 30 Hz 5 min -196 °C 75 6 ZrO2 30 Hz 10 min -196 °C 78 7 ZrO2 30 Hz 20 min -196 oC 73 8 ZrO2 30 Hz 60 min -196 °C 84 9 SS 30 Hz 5 min -196 oC 68 SS 30 Hz 5 min 25 oC 64 11 Mortar & Knob - 5 min 25 oC 35 aReaction conditions: Bromodiphenylmethane (0.81 mmol, 1.0 equivalent) and N-Methyl piperazine (0.81 mmol, 1.0 equiv) with 6 zirconia grinding balls (10.06 mm diameter) for 25 mL zirconia grinding jar or 6 stainless steel (SS) grinding balls (10.06 ball ground or in a 25 mL stainless steel (SS) jar (mm diameter) It was ground using a mortar and pestle for the specified time and temperature. 15 18 Another antihistamine derivative - DPP, is a different type of bromodiphenylmethane and N-methyl 4-piperidinol. It was successfully synthesized by grinding under applied grinding conditions. (Table 3). Briefly, the experiments investigated different reaction times at room temperature. Six complementary balls (10.06 mm diameter) in zirconia grinding cups (25 mL) (volume capacity) has been achieved. The products were isolated with satisfactory yields, 5 However, the highest yield is obtained when the reaction mixture is ball milled for 10 minutes. obtained (Table 3, input 2). The effect of low temperature on product formation Reactions were also carried out under cryopreservation conditions to investigate this. Surprisingly... In this way, the products were obtained in low yields (Table 3, inputs 5-9), which indicates diphenylpyral. It has been shown that its formation is preferred at higher temperatures. DPP, hammer and 10 It was synthesized with good yield by manual grinding using a mortar and pestle (Table 3, input). 11). In summary, ball mill in the synthesis of (4-(benzhydryloxy)-1-methylpiperidine Mechanics chemistry can be successfully applied at room temperature using this method, and the expected results are as follows: Efficiency rates range from 66% to 84%. Table 3. Investigation of Reaction Conditions for DPP Synthesis. 15 Diphenylpyralin (DPP) a Entry Jar / ball bearing material Grinding Frequency (Hz) Time (min) Temperature (°C) Yield (%)b 1 ZrO2 30 Hz 5 min 25 oC 71 2 ZrO2 30 Hz 10 min 25 oC 84 3 ZrO2 30 Hz 20 min 25 oC 67 4 ZrO2 30 Hz 60 min 25 oC 66 ZrO2 30 Hz 5 min -196 °C No 6 ZrO2 30 Hz 10 min -196 oC 5 7 ZrO2 30 Hz 20 min -196 oC 23 8 ZrO2 30 Hz 60 min -196 oC 29 9 SS 30 Hz 5 min -196 oC No SS 30 Hz 5 min 25 oC No 11 Mortar & Knob - 5 min 25 oC 67 aReaction conditions: Bromodiphenylmethane (1.85 mmol, 1.0 equivalent) and N-Methyl 4- piperidinol (1.85 mmol, 1.0 equiv) with 6 zirconia grinding balls (10.06 mm diameter) 25 19 mL zirconia ground in a grinding jar, ball ground or ground using a mortar and pestle as specified. It was ground at a specific time and temperature. b Isolated yield Hydrochloride salts of histamine antagonist active pharmaceutical ingredients (APIs) The mechanochemical synthesis method involves the following process steps: 5 i) 6 complementary parts made of zirconia (ZrO2) or stainless steel (SS) with grinding balls in a 25 mL grinding jar at a 1:1 ratio. Starting materials with a diameter of 10.06 mm at 25 °C or -196 °C 30 Ball grinding or mortar and pestle grinding for 5-60 minutes at 25 Hz Grinding at °C for 5 minutes, 10 ii) reaction mixture from ball grinding pots or from pestle and mortar scraping and transferring into a bottle, iii) purification of the reaction mixture, iv) 2- of purified active pharmaceutical ingredients (APIs) in 5-10 mL of methanol Treatment with 3 drops of concentrated HCl until pH reaches 4-5, 15 v) Heating and stirring the processed products until they are completely melted, vi) first, the mixture should be slowly cooled to room temperature, and then the mixture should be Cooling in an ice bath to crystallize hydrochloride salts. In the mechanochemical synthesis method of the present invention, the starting materials are 20 It is selected according to the histamine antagonist to be synthesized. In step (i) of the method Bromodiphenylmethane and N,N- are used as starting materials for the mechanistic synthesis of DPH. Dimethylethanolamine (DMAE) is used. In step (i) of the method, the mechanical properties of CYC are investigated. bromodiphenylmethane and N-methylpiperazine as starting materials for synthesis. is used. In step (i) of the method, the starting 25 for the mechanistic synthesis of DPP. Bromodiphenylmethane and 4-hydroxy-1-methylpiperidine are used as the materials. The present invention is applied in step (iii) of the mechanochemical synthesis method The purification processes also depend on which histamine antagonist is being synthesized. It varies. The present invention for diphenhydramine (2-(benzhydryloxy)-N,N-dimethylethane-1-amine) (DPH) is 30 In the purification process applied in step (iii) of the mechanochemical synthesis method; The reaction mixture is washed three times with 5 mL of dichloromethane, DPH is collected, and The collected DPH is dried under vacuum. The present invention is a mechanochemical treatment for Cyclizine (1-benzhydryl-4-methylpiperazine) (CYC). The purification process applied in step (iii) of the synthesis method includes the following steps: is implemented: 5 i. The collected reaction mixture is mixed with 10 mL of ethyl acetate and 10 mL of distilled water. is being resolved, ii. Saturated HCl is added to the solution until the pH reaches 3. iii. The essence of the creamy white aqueous phase is extracted with ethyl acetate (3 x 15 mL), iv. The aqueous phase is treated with a 2.5 M NaOH solution until the pH reaches 10. v. The final solution is extracted with ethyl acetate (3 x 15 mL) over sodium sulfate. It is dried and ethyl acetate is extracted under reduced pressure. The present invention for diphenylpyral (4-(benzhydryloxy)-1-methylpiperidine) (DPP) purification process applied in step (iii) of the mechanochemical synthesis method The following steps are applied: 15 i. Raw material, column chromatography (washing solution: methanol / diethyl ether 1:1) being purified, ii. The solvent is removed under reduced pressure, and the product is stored in a vacuum. It is being dried. In one application of the invention, 20 is used instead of bromodiphenylmethane as the starting material. chlorodiphenylmethane, diphenylmethane, or 1,1'-(diazomethanediyl)dibenzene It can be used. If diphenylethanol is used, diphenhydramine (DPH) is obtained. Dimethylaminoethanol should be replaced with 2-chloro-N,N-dimethylethylamine. In one application of the invention, cyclizine is used as a starting material for synthesis. Aminodiphenylmethane or chlorodiphenylmethane is preferred instead of bromodiphenylmethane. 25 This is possible. Furthermore, when aminodiphenylmethane is chosen as the other reactant, N-methyl N-methyldiethanolamine should be used instead of piperazine. In an application of the invention, DPP, chlorodiphenylmethane, diphenylmethane or 1,1'- (diazomethanedyl)dibenzene is a similar substance that reacts with 4-hydroxy-1-methylpiperidine. It can also be obtained with starting materials. 30 21 In the synthesis method of the invention, the reactions take place without any solvent. This is being done, but if the quantity of starting materials is small, the products are mostly After the reactions are complete, the products adhere to the surface of the containers. when it cannot be scraped off the surface, by using a sufficient amount of solvent that can dissolve the APIs. These are removed from the containers (approximately 5-10 mL of solvent for 250 mg of product). 5 Increasing the quantity of starting materials results in more products, which are then processed more efficiently. Easier than a container that uses little or no solvent. (It can be engraved. This can be considered an advantage for the mass production of APIs). In the present invention, for filtering, extraction or, if necessary, crystallization parts 10% less toxic when compared with suitable solvents and chloroform, hexane, etc. Solvents (i.e., water, methanol) are selected. In the present invention, reaction progresses are achieved on aluminum pre-coated with silica gel. using supported plates and / or an aqueous potassium permanganate (KMnO4) by immersing in the solution and heating the stained plates at 200 °C until they dry. It was monitored by thin-layer chromatography (TLC) by heating with a gun and at 254 nm and 15 Visualized under a UV lamp with λ at 365 nm. Extraction or filtration. After the process, all organic solutions are dried on anhydrous Na2SO4 and rotated. concentrated using an evaporator and the products dried overnight Then yields were obtained. APIs were 1H NMR and 13C NMR, as mentioned earlier. and characterized by HRMS. 1H and 13C NMR spectra were used as the internal standard for 20 1H using tetramethylsilane (TMS) and deuterium solvents (CDCl3-d, methanol-d4) In the spectrometer operating at 400 MHz for NMR and 100 MHz for 13C NMR Chemical shifts were recorded and reported in ppm values. Shifts (δ) are now given as parts per million (ppm) relative to solvent peaks (1H NMR δ = 7.26 ppm; 13C NMR δ = 77.16 ppm for CDCl3; 1H NMR δ = 3.31 ppm; 13C 25 NMR δ = 49.00 ppm for methanol-d4). Spin multiplicities are reported as follows: s (single), d (double), t (triple), m (multiple), bs (wide signal). DPH: 2-(benzhydryloxy)-N,N-dimethylethane-1-amine Chemical formula: C17H21NO Total Mass: 255.16 30 22 Molecular weight: 255.36 m / z: 255.16 (100.0%), 256.17 (18.4%), 257.17 (1.6%) Elemental analysis: C, 79.96; H, 8.29; N, 5.49; O, 6.27 MS (TOF-ESI): Calculated for m / z C17H21NO [M+H]+: 256.16959, for [M+H]+: For figures 1-5, the values ​​are 256.16889, 256.16978, 256.17059, 256.16974, 256.16818, and 5 respectively. It has been found. 1H NMR (400 MHz, CDCl3): δH 7.86-7.80 (m, 5H) 7.42-7.38 (m, 5H), 6.30 (s, 1H), 3.95 (t, 2H), 3.56 (t, 2H), 3.25 (s, 6H) (Figures 7-9, 11) 13C NMR (100 MHz, CDCl3): δC 135.9, 135.3, 134.4, 133.5, 86.6, 68.4, 60.0, 53.3 (Figures 10, 12) 10 DPH HCl: 2-(benzhydryloxy)-N,N-dimethylethane-1-amine hydrochloride 1H NMR (400 MHz, CDCl3): δH 7.83-7.81 (m, 4H) 7.42-7.37 (m, 6H), 6.30 (s, 1H), 3.97 (t, 2H), 3.57 (t, 2H), 3.24 (s, 6H) (Figure 6). 13C NMR (100 MHz, CDCl3): δC 135.9, 135.3, 134.4, 133.5, 86.6, 68.4, 60.0, 53.3 (Figure 15) 10). HRMS data for DPH HCl show the same m / z ratio as DPH, where C17H21NO The calculated m / z for [M+H]+ is 256.16959, and for [M+H]+ it is 256.16781 and 256.16974 respectively. It was found that DPH ionizes into HCl, [DPH+H]+ and chloride ions (Figure 13). Since it has one proton, the m / z ratio for [DPH+H]+ is 20, which takes one proton from methanol. It is similar to DPH. 1H NMR spectra of DPHs show specific proton activity of bromodiphenylmethane at δ = 5.3 ppm. the peak disappears and the aliphatic protons of dimethylaminoethanol are in the low range It has well-resolved characteristic signals when shifted. At δ = 6.3 ppm The singlet can be attributed to a proton on -CH, and this is a 25 of DPH formation. It is an indicator. The 13C NMR spectrum of DPH also shows a total of eight carbon peaks, indicating a complete conversion. This proves that due to the symmetry of DPH, there are four aromatic carbons at around 134 ppm. 23 While the signal is observable, the peak at δ = 86.6 ppm indicates carbon-bound oxygen and aromatics. They originate from the rings. The signals at δ = 68.4 ppm and δ = 60.0 ppm are in the -CH2s. It can be attributed to carbons. Cyclizine (CYC): 1-benzhydryl-4-methylpiperazine Chemical formula: C18H22N2 5 Total Mass: 266.18 Molecular weight: 266.39 m / z: 266.18 (100.0%), 267.18 (19.5%), 268.19 (1.8%) Elemental analysis: C, 81.16; H, 8.32; N, 10.52 MS (TOF- ESI): Calculated m / z for C17H21N2 [M+H]+: 267.18558, for [M+H]+: 10 For figures 14-23, the values ​​are 267.19054, 267.18351, 267.18507, 267.18558, and 267.18483, respectively. The following values ​​were found: 267.18381, 267.18394, 267.18462, 267.18454, 267.18498. 1H NMR (400 MHz, CDCl3): δH 7.45 (m, 4H) 7.25 (m, 4H), 7.18 (m, 2H), 4.26 (s, 1H), 2.5 (s, broad, 8H), 2.3 (s, 3H) (Figures S24-27). 13C NMR (100 MHz, CDCl3): δC 142.6, 128.5, 127.9, 126.9, 76.3, 55.2, 51.6, 45.7 (Figure 15) S28). Cyclizine HCl: 1-benzhydryl-4-methylpiperazine hydrochloride MS (TOF-ESI): Calculated m / z for C18H22N2 [M+H]+: 267.18558, for [M+H]+: 267.18508 were found (Figure S29) 1H NMR (400 MHz, MeOD): δH 7.97-7.95 (m, 4H) 7.50-7.40 (6H, m) 4.84 (1H, bs) 3.90 20 (bs, 4H), 3.69 (bs, 4H) 3.07 (bs, 3H) (Figure S30) 13C NMR (100 MHz, CDCl3): δC 142.6, 128.5, 127.9, 126.9, 76.3, 55.2, 51.5, 45.6 (Figure S31) 24 The formation of the cyclizine was confirmed by HRMS data, with CYC having a total mass of 266.18. The separated ions were characterized along with their relative abundances and m / z ratios. It was measured at the location where it was stored. Since a CYC sample contains H+ ions, each The mass / charge (m / z) ratio calculated for the product is [M+H]+: 267.18558 (H molecular weight = It was found to be around 1.0079 g / mol) (Figures S13-S22, S28). 5 1H NMR spectra of CYCs show specific proton activity of bromodiphenylmethane at δ = 5.3 ppm. It has well-resolved characteristic signals where the peak point disappears. N- The aliphatic protons of methylpiperazine are also absent in the CYC spectra. δ = 4.26 The single expected CYC product at ppm can be attributed to the -CH proton. Nitrogen Four -CH2 atoms bonded to the molecules lead to a broad singlet at δ = 2.5 ppm. 10 The 13C NMR spectra of the CYCs also showed the expected eight carbon signals, confirming the complete pattern. This proves the transformation. Due to the symmetry of CYC, three and around 127 ppm. There is an aromatic carbon signal at around 142 ppm. The signal at δ = 76.3 ppm, It originates from carbon-bonded nitrogen and aromatic rings. δ = 55.2 ppm and δ = 51.6 Signals at ppm can be directly attributed to carbons in -CH2s that are bound to nitrogen atoms. 15 The signal at 45.7 ppm corresponds to the carbon on -CH3. DPP: 4-(benzhydryloxy)-1-methylpiperidine Chemical formula: C19H23NO Total Mass: 281.18 Molecular weight: 281.40 20 m / z: 281.18 (100.0%), 282.18 (20.5%), 283.18 (2.0%) Elemental analysis: C, 81.10; H, 8.24; N, 4.98; O, 5.69 MS (TOF-ESI): For C19H23NO [M+H]+, calculated m / z: 267.18558, for [M+H]+: 282.18452 were found (Figure S32). 1H NMR (400 MHz, MeOD): δH 7.93-7.91 (m, 4H) 7.58-7.54 (m, 6H) 5.90-5.84 (m, 1H) 25 4.04-3.78 (m, 2H) 3.54-3.41 (m, 2H) 3.25 (bs, 3H) 3.21 (s, 1H) 2.24-2.14 (m, 2H) 1.93- 1.83 (m, 2H) (Figure S33). 13C NMR (100 MHz, MeOD): δC 132.2, 131.4, 131.3, 130.1, 130.0, 129.3, 129.2, 83.6, 59.5, 58.3, 54.0, 42.9, 28.4, 27.1 (Figure S34). DPP HCl: 4-(benzhydryloxy)-1-methylpiperidine hydrochloride MS (TOF-ESI): Calculated m / z for C19H23NO [M+H]+: 267.18558, for [M+H]+: 282.18435 were found (Figure S35). 5 1H NMR (400 MHz, MeOD): δH 8.02-7.98 (m, 4H) 7.50 (m, 6H) 6.19-6.06 (m, 1H) 4.01- 3.63 (m, 4H) 3.28 (m, 3H) 3.19 (bs, 1H) 2.21-2.17 (m, 2H) 1.90-1.87 (m, 2H) (Figure S36) 13C NMR (100 MHz, MeOD): δC 132.2, 131.4, 131.4, 130.1, 130.0, 129.3, 129.3, 83.7, 59.4, 58.3, 54.1, 42.8, 28.4, 27.1 (Figure S37) 10 1H NMR spectra of DPPs are attributed to a -CH proton adjacent to aromatic rings. and good including multiple (multiplet) at δ = 6.2-6.1 confirming DPP formation. It has resolved characteristic signals. Furthermore, the starting material... The proton peak at δ = 5.3 ppm attributed to bromodiphenylmethane's -CHBr has disappeared. It has disappeared, and this indicates its consumption and the formation of the product. 15 DPPs were observed in the 13C NMR spectrum at 8 = 27.1, 28.4, 58.3 and 59.5 ppm. Four signals indicated the presence of two CH2 groups. -NCH3 The methylene carbon atom of the group appeared as a singlet at δ = 42.9 ppm. The carbon peak at 54.0 ppm is assigned to the -OCH group. The signal derived from ArCHAr is δ = appeared singly at 83.1 ppm. Aromatic carbon 20 at δ = 132.2-129.2 ppm. The signals also confirmed the presence of four carbon atoms. 26 REFERENCES [1] R. S. Vardanyan and V. J. Hruby, “Antihistamine Drugs,” in Synthesis of Essential Drugs, Elsevier, 2006, syf. 219–235. doi: 10.1016 / B978-044452166- 8 / 50016-9. [2] M. Wahl, “Diphenhydramine,” in Encyclopedia of Toxicology, Elsevier, 2005, syf. 5 72–73. doi: 10.1016 / B0-12-369400-0 / 00342-2. [3] G. Rieveschl, “Dialkylaminoalkyl benzhydryl ethers and salts thereof,” US2421714 (A), 1947 [4] R. Phillips and N. J. Westfield, “Benzhydryl ethers of tropines and their production,” US2595405A, 1952 10 [5] J. Cusic, “Production of aminoalkyl ethers of diaryl carbinols,” US2577234A, 1947 [6] J. Levy, “Process for preparing benzhydryl ethers,” US2751388A, 1950 [7] S. Borukhova, T. Noël, and V. Hessel, “Continuous-Flow Multistep Synthesis of Cinnarizine, Cyclizine, and a Buclizine Derivative from Bulk Alcohols,” 15 ChemSusChem, cilt. 9, no. 1, 2016, doi: 10.1002 / cssc.201501367. [8] T. Gant and S. Sarshar, “Substituted Dibenzhydrylpiperazines,” 2009 [9] Y. Tsuji, K. T. Huh, Y. Ohsugi, and Y. Watanabe, “Ruthenium Complex Catalyzed N-Heterocyclization. Syntheses of N-Substituted Piperidines, Morpholines, and Piperazines from Amines and 1,5-Diols,” Journal of Organic 20 Chemistry, cilt. 50, no. 9, syf. 1365–1370, 1985, doi: 10.1021 / jo00209a004.

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Claims

28 REQUESTS 1. Mechanical effects of hydrochloride salts of active pharmaceutical components that are histamine antagonists. It is a chemical synthesis method, and its characteristic feature is; i) 6 complementary 5 made of zirconia (ZrO2) or stainless steel (SS) with grinding balls in a 25 mL grinding jar at a 1:1 ratio. Starting materials with a diameter of 10.06 mm at 25 °C or -196 °C 30 Ball grinding or mortar and pestle grinding for 5-60 minutes at 25 Hz Grinding at °C for 5 minutes, ii) 10 of the reaction mixture from ball grinding pots or from a pestle and mortar scraping and transferring into a bottle, iii) purification of the reaction mixture, iv) 2- of purified active pharmaceutical ingredients (APIs) in 5-10 mL of methanol Treatment with 3 drops of concentrated HCl until pH reaches 4-5. v) Heating and stirring the processed products until they are completely melted, 15 vi) first, the mixture should be slowly cooled to room temperature, and then the mixture should be cooling in an ice bath to crystallize hydrochloride salts It includes the steps.

2. The method according to claim 1, its characteristic is that the histamine antagonist in question, 20 diphenhydramine (2-(benzhydryloxy)-N,N-dimethylethane-1-amine; DPH) or cyclizine (1- benzhydryl-4-methylpiperazine; CYC) or diphenylpyraline (4-(benzhydryloxy)-1- It is methylpiperidine (DPP).

3. A method according to claim 2, characterized by; mechanical treatment of DPH hydrochloride salts 25 Bromodiphenylmethane and N,N- are starting materials for its synthesis. It is dimethylethanolamine (DMAE).

4. A method according to claim 2, characterized by the mechanical processing of DPH hydrochloride salts. Bromodiphenylmethane and N,N-30 are starting materials for its synthesis. It is dimethylethanolamine (DMAE). 29 5. A method according to claim 2, characterized by the mechanical processing of DPH hydrochloride salts. The starting materials for its synthesis are 1,1'-(diazomethanediyl)dibenzene and N,N- It is dimethylethanolamine (DMAE).

6. It is a method according to claim 2, the characteristic of which is; mechanical treatment of DPH hydrochloride salts. 5 The starting materials for its synthesis are diphenylethanol and 2-chloro-N,N- It is dimethylethylamine.

7. A method according to claim 2, characterized by the mechanical treatment of CYC hydrochloride salts. The starting materials for its synthesis are bromodiphenylmethane and N-methylpiperazine 10 It is the fact that.

8. A method according to claim 2, characterized by the mechanical treatment of CYC hydrochloride salts. Chlordiphenylmethane and N-methylpiperazine are the starting materials for its synthesis. that is. 15 9. A method according to claim 2, characterized by the mechanical treatment of CYC hydrochloride salts. aminodiphenylmethane and N- are the starting materials for its synthesis. It is methyldiethanolamine.

10. A method according to Claim 2, characterized by the mechanical processing of hydrochloride salts of DPP. The starting materials for its synthesis are bromodiphenylmethane and 4-hydroxy-1- It is methylpiperidine.

11. A method according to claim 2, characterized by; mechanical treatment of DPP hydrochloride salts 25 The starting materials for its synthesis are chlorodiphenylmethane, diphenylmethane, or These are 1,1'-(diazomethanediyl)dibenzene and 4-hydroxy-1-methylpiperidine.

12. A method according to Claim 2, characterized by its properties; diphenhydramine (DPH) hydrochloride Purification process of the reaction mixture for mechanical synthesis of salts 30 It includes the following steps; i) The reaction mixture is washed three times with 5 mL of dichloromethane, ii) DPH is being collected and iii) The collected DPH is dried under vacuum. 35 13. A method according to Claim 2, characterized by; cyclizine hydrochloride salts (CYC) The purification process of the reaction mixture for mechanical synthesis is as follows: It includes the following steps; i) The collected reaction mixture is mixed with 10 mL of ethyl acetate and 10 mL of distilled water. in progress, 5 ii) Saturated HCl is added to the solution until the pH reaches 3. iii) The essence of the creamy white aqueous phase is extracted with ethyl acetate (3 x 15 mL), iv) The aqueous phase is treated with a 2.5 M NaOH solution until the pH reaches 10, v) The final solution is extracted with ethyl acetate (3 x 15 mL) and sodium sulfate. It is dried on the surface and ethyl acetate is reduced under pressure at 10°C. is being removed.

14. A method according to Claim 2, characterized by its properties; diphenylpyralin (DPP) hydrochloride Purification process of the reaction mixture for the mechanical synthesis of salts It includes the following steps; 15 i) raw material, column chromatography (washing liquid: methanol / diethyl ether) 1:1) being purified, ii) the solvent is removed under reduced pressure and the product is stored in a vacuum. It is being dried.

15. The method is based on Claim 1 and its characteristic feature is that the histamine antagonist in question... is one of the following compounds N,N-dimethyl-2-(phenyl(o- toyl)methoxy)ethane-1-amine Orphenadrine Dimenhydrinate (Diphenhydramine & 8- Chlorotheophylline combination drug) Medrilamine 2-((4- methoxyphenyl)(phenyl)methoxy )-N,N-dimethylethane-1-amine Bromazine 2-((4- bromophenyl(phenyl)methoxy) -N,N-dimethylethane-1-amine Embramine 2-(1-(4-bromophenyl)-1- phenylethoxy)-N,N- dimethylethane-1-amine 31 10 Buclizine 1-(4-(tert-butyl)benzyl)-4-((4- chlorophenyl(phenyl)methyl) piperazine The Assembly 1-((4-chlorophenyl)(phenyl)methyl)-4-(4- methylbenzyl piperazine Sinnarizin 1-benzhydryl-4-cinnamylpiperazine Cetirizine 2-(2-(4-((4- chlorophenyl)(phenyl)methyl)piperazine- 1-yl)ethoxy)acetic acid Levosetirizine (S)-2-(2-(4-((4- chlorophenyl(phenyl)methyl)piperazine-1- i)ethoxy)acetic acid Hydroxyzine 2-(2-(4-((4- chlorophenyl(phenyl)methyl)piperazine-1- yl)ethoxy)ethan-1-ol

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