- 1,3,5-Triazinanes as Formaldimine Surrogates in the Ugi Reaction
-
In the present study, a new synthetic strategy towards N-acylated glycinamides was developed by the use of 1,3,5-triazinanes as formaldimine surrogates in the Ugi reaction. The targeted products were obtained in a combinatorial, diversity-oriented fashion in good yields. Further modifications allowed us to adapt this procedure for the one-pot two-step syntheses of a local anesthetic druglidocaine and several unsymmetrically substituted diketopiperazines.
- Golubev, Pavel,Guranova, Natalia,Krasavin, Mikhail
-
-
Read Online
- Direct injection gas chromatographic/mass spectrometric analysis for denatonium benzoate in specific denatured alcohol formulations
-
Direct injection GC/MS was investigated for the analysis of benzyldiethyl(2,6-xylylcarbamoylmethyl)ammonium benzoate (Bitrex), a quaternary ammonium salt, in various Canadian denatured alcohol formulations. Bitrex yielded predominantly a peak due to the neutral diethylamine derivative (I). The structure of I, elucidated by MS and NMR, is strongly related to that of the cation of Bitrex. Compound I was formed from Bitrex in the heated injector port of the GC via a decomposition reaction similar to Stevens rearrangement. The response of I was found to be dependent on the injector port temperature, and the optimal temperature was determined to be in the range 250-350°C. The GC/MS response of I in SIM mode was used to quantify Bitrex. The effects of the codenaturants sucrose octaacetate (SOA), diethyl phthalate (DEP), and camphor, which are present at much higher concentration than Bitrex in several formulations, were also investigated. The presence of SOA enhanced the response of the analyte considerably, while DEP and camphor had no significant effect. All standard curves of Bitrex (1-16 ppm) in different alcohol matrixes were fitted by second-order polynomial functions, with coefficients of determination (R2) routinely in the range 0.998-0.999. The analysis time was 18 min, and the within-run precision was 4%. The results of this study point to the potential of the GC/MS technique as a quantitative tool for Bitrex in various alcohol formulations.
- Ng, Lay-Keow,Hupe, Michel,Harnois, Jean,Lawrence, Andre H.
-
-
Read Online
- Direct Amidation of Esters by Ball Milling**
-
The direct mechanochemical amidation of esters by ball milling is described. The operationally simple procedure requires an ester, an amine, and substoichiometric KOtBu and was used to prepare a large and diverse library of 78 amide structures with modest to excellent efficiency. Heteroaromatic and heterocyclic components are specifically shown to be amenable to this mechanochemical protocol. This direct synthesis platform has been applied to the synthesis of active pharmaceutical ingredients (APIs) and agrochemicals as well as the gram-scale synthesis of an active pharmaceutical, all in the absence of a reaction solvent.
- Barreteau, Fabien,Battilocchio, Claudio,Browne, Duncan L.,Godineau, Edouard,Leitch, Jamie A.,Nicholson, William I.,Payne, Riley,Priestley, Ian
-
supporting information
p. 21868 - 21874
(2021/09/02)
-
- Carboxyesterase polypeptides for amide coupling
-
The present invention provides engineered carboxyesterase enzymes having improved properties as compared to a naturally occurring wild-type carboxyesterase enzymes, as well as polynucleotides encoding the engineered carboxyesterase enzymes, host cells capable of expressing the engineered carboxyesterase enzymes, and methods of using the engineered carboxyesterase enzymes in amidation reactions.
- -
-
Page/Page column 65-66; 73-84
(2021/05/28)
-
- Method for preparing lidocaine by continuous reaction (by machine translation)
-
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for preparing lidocaine by continuous reaction. To the method, the continuous reaction is adopted, and the crystallization of intermediate chloroacetyl -2 and 6 -dimethylaniline is not needed. The lidocaine finished product can be directly obtained through separation, purification and other treatment and drying processes, and the molar yield 93% or above can be obtained. The process operation is simplified, the solvent recovery sleeve is used, the sewage discharge amount is reduced, the production cost is reduced, energy conservation and consumption reduction are realized, and the technology is green and environment-friendly. (by machine translation)
- -
-
Paragraph 0027-0031
(2020/12/30)
-
- Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients
-
Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients, are provided. Certain of the systems and methods described herein are capable of manufacturing multiple chemical products without the need to fluidically connect or disconnect unit operations when switching from one making chemical product to making another chemical product.
- -
-
Page/Page column 35-36
(2020/12/14)
-
- Method for preparing lidocaine
-
The invention discloses a method for preparing lidocaine. The method comprises the following steps of: (1) by using 2, 6-dimethylnitrobenzene as a raw material, Pd/C as a catalyst and methanol as a solvent, carrying out reduction reaction with hydrogen at normal temperature and normal pressure to obtain an intermediate 2, 6-dimethylaniline; (2) reacting the obtained intermediate 2, 6-dimethylaniline with chloroacetyl chloride in the presence of potassium carbonate, and taking dichloromethane as a solvent to prepare an intermediate chloroacetyl-2, 6-dimethylaniline; and (3) reacting the obtained intermediate chloroacetyl-2, 6-dimethylaniline with diethylamine, taking normal hexane as a solvent, performing refluxing until the reaction is complete, performing washing with water and cooling toobtain lidocaine. The method disclosed by the invention is simple and convenient in technological process, few in operation links and relatively high in lidocaine yield, and the prepared lidocaine isgood in purity which reaches 99.5% or above, so that the method has a good industrial application prospect.
- -
-
-
- Preparation method of lidocaine hydrochloride
-
The invention relates to a preparation method of lidocaine hydrochloride, which comprises the following steps: carrying out acylation reaction by using 2, 6-dimethylaniline and chloroacetyl chloride as raw materials, directly adding diethylamine into the system to carry out amination reaction after the reaction is finished, filtering the product, and adding hydrochloric acid into the filtrate to carry out salification reaction. The preparation method of lidocaine hydrochloride provided by the invention is a one-pot method, avoids repeated purification of an intermediate product in a traditional process, and is simple in process, mild in condition, easy to control, high in product yield and high in purity.
- -
-
-
- Method for preparing lidocaine intermediate alpha-chloroacetyl-2, 6-dimethylaniline and lidocaine without adding extra alkali
-
The invention relates to a method for preparing lidocaine intermediate alpha-chloroacetyl-2, 6-dimethylaniline and lidocaine without adding extra alkali, which belong to the technical field of organicsynthesis. The invention discloses the method for preparing alpha-chloroacetyl-2, 6-dimethylaniline, which comprises the following steps: in the process of generating alpha-chloroacetyl-2, 6-dimethylaniline by carrying out a chloroacetylation reaction on 2, 6-dimethylaniline and chloroacetyl chloride, taking one or a mixed solution of more than two of an alkane solvent, an ether solvent and an ester solvent as an organic solvent. No extra alkali is added, so that the separation process can be reduced; the method can be applied to one-pot reaction to directly prepare lidocaine, namely, 2, 6-dimethylaniline, chloroacetyl chloride and diethylamine directly react to obtain lidocaine, the method is simple, no extra alkali is added, the separation process is simplified, the used solvents are three types of solvents, operation is safer, and the obtained product is high in purity, high in yield, low in cost and environmentally friendly.
- -
-
Paragraph 0065; 0070-0072; 0074; 0079-0080; 0082; 0087-0088
(2020/06/30)
-
- Across-the-World Automated Optimization and Continuous-Flow Synthesis of Pharmaceutical Agents Operating Through a Cloud-Based Server
-
The power of the Cloud has been harnessed for pharmaceutical compound production with remote servers based in Tokyo, Japan being left to autonomously find optimal synthesis conditions for three active pharmaceutical ingredients (APIs) in laboratories in Cambridge, UK. A researcher located in Los Angeles, USA controlled the entire process via an internet connection. The constituent synthetic steps for Tramadol, Lidocaine, and Bupropion were thus optimized with minimal intervention from operators within hours, yielding conditions satisfying customizable evaluation functions for all examples.
- Fitzpatrick, Daniel E.,Maujean, Timothé,Evans, Amanda C.,Ley, Steven V.
-
p. 15128 - 15132
(2018/10/31)
-
- Overcoming solid handling issues in continuous flow substitution reactions through ionic liquid formation
-
Substitutions such as acylations, arylations, and alkylations are some of the most commonly run reactions for building complex molecules. However, the requirement of a stoichiometric base to scavange acid by-products creates significant challenges when operating in continuous flow due to solid handling issues associated with precipitating base·HX salts. We present a general and simple strategy to overcome these solid handling issues through the use of acid scavenging organic bases that generate low- to moderate-melting ionic liquids upon protonation. The application of these bases towards the most commonly run substitutions are demonstrated, enabling reactions to be run in flow without requiring additional equipment, specific solvents, or dilute reaction conditions to prevent clogging.
- Kashani, Saeed,Sullivan, Ryan J.,Andersen, Mads,Newman, Stephen G.
-
supporting information
p. 1748 - 1753
(2018/04/30)
-
- Method for preparing lidocaine hydrochloride
-
The invention provides a method for preparing lidocaine hydrochloride, and belongs to the technical field of anesthetic synthesis. The method comprises the following steps: by taking 2,6-xylenol as a raw material, Pd/C as a main catalyst and 2,6-dimethylcyclohexanone as a promoter, performing liquid phase amination with ammonia water at high temperature, thereby obtaining a midbody 2,6-dimethylaniline; enabling sodium methylate, 2,6-dimethylaniline and N,N-lignocaine methyl acetate as raw materials to react at 90-95 DEGC, distilling while reaction is performed to remove methanol till no methanol can be evaporated out, continuously reacting for 30 minutes, cooling to the room temperature, adding dichloroethane, washing with water, and leaving to stand to layer, thereby obtaining an organic layer, namely, a lidocaine based dichloroethane solution; further adding hydrochloric acid into the lidocaine based dichloroethane solution, adjusting the pH value to be 3.5-4 by using hydrogen chloride, adding activated carbon to reflux for 20-40 minutes, filtering, concentrating the filtrate, cooling, crystallizing, and dying, thereby obtaining lidocaine hydrochloride. The lidocaine hydrochloride prepared by using the method is simple in synthesis process and high in product purity, that is, the purity can be greater than 99%, and the total yield is greater than 84%.
- -
-
-
- Synthesis and analgesic properties of lidocaine derivatives with substituted aminobenzothiazoles
-
Local anesthetics are the most widely consumed drugs in the practice of medicine which provide a loss of sensation in a certain body part without loss of consciousness or impairment of central control of essential functions. Lidocaine (I) is the most commonly local anaesthetic drug which is widely used in all species due to its fabulous diffusing and penetrating properties as well as prompt onset of surgical analgesia. In this study, new aminobenzothiazole (with many useful biological and pharmacological properties) analogues were synthesized by changing of amine moiety of I. Both acute and chronic pain properties of new compounds (II-VI) were studied by using the tail immersion and formalin tests on mice and the outcomes were compared with control and lidocaine groups. According to the results, aminobenzothiazole derivatives are better candidates than diethylamine group for replacement on amine moiety of I. Also, derivatives with electron-withdrawing groups on this amine (V and VI) could decrease pain better than electron-donating ones (II and III) (specially on position 6 of this amine, II and V) which may be of concern for blockade of specific sodium channels by these new compounds.
- Ahmadi, Abbas,Khalili, Mohsen,Mohammadinoude, Mohammad Kazem,Nahri-Niknafs, Babak
-
p. 507 - 512
(2016/07/06)
-
- A metal-free approach for transamidation of amides with amines in aqueous media
-
An efficient, environmentally benign and a mild protocol for transamidation of amides with a variety of amines in the presence of K2S2O8 using stoichiometric quantity in aqueous conditions has been established. This method works under conventional thermal conditions and in microwave irradiation as well. A series of amides have been prepared using this reaction and this is a greener protocol for transamidation, which offers a diverse kind of substrate scope with exclusive product formation (yields 90-98%).
- Srinivas, Mahesuni,Hudwekar, Abhinandan D.,Venkateswarlu, Vunnam,Reddy, G. Lakshma,Kumar, K. A. Aravinda,Vishwakarma, Ram A.,Sawant, Sanghapal D.
-
supporting information
p. 4775 - 4779
(2015/07/20)
-
- Rapid Vortex Fluidics: Continuous Flow Synthesis of Amides and Local Anesthetic Lidocaine
-
Thin film flow chemistry using a vortex fluidic device (VFD) is effective in the scalable acylation of amines under shear, with the yields of the amides dramatically enhanced relative to traditional batch techniques. The optimized monophasic flow conditions are effective in ≤80seconds at room temperature, enabling access to structurally diverse amides, functionalized amino acids and substituted ureas on multigram scales. Amide synthesis under flow was also extended to a total synthesis of local anesthetic lidocaine, with sequential reactions carried out in two serially linked VFD units. The synthesis could also be executed in a single VFD, in which the tandem reactions involve reagent delivery at different positions along the rapidly rotating tube with in situ solvent replacement, as a molecular assembly line process. This further highlights the versatility of the VFD in organic synthesis, as does the finding of a remarkably efficient debenzylation of p-methoxybenzyl amines.
- Britton, Joshua,Chalker, Justin M.,Raston, Colin L.
-
p. 10660 - 10665
(2015/07/20)
-
- Growth, shrinking, and breaking of pluronic micelles in the presence of drugs and/or β-cyclodextrin, a study by small-angle neutron scattering and fluorescence spectroscopy
-
The associative structures between F127 Pluronic micelles and four drugs, namely, lidocaine (LD), pentobarbital sodium salt (PB), sodium naproxen (NP), and sodium salicylate (SAL), were studied by small-angle neutron scattering (SANS). Different outcomes for the micellar aggregates are observed, which are dependent on the chemical nature of the drug and the presence of charge or otherwise: the micelles grow with LD, are hardly modified with PB, and decrease in size with both NP and SAL. The partition coefficient, determined by fluorescence spectroscopy, is directly correlated to the amount of charge, following NP ≈ SAL a slightly deeper localization of LD and more superficial for PB. All drugs can form inclusion complexes with heptakis(2,6-di-O-methyl) β-cyclodextrin (hep2,6 β-CD). Hep2,6 β-CD, as shown in previous studies (Joseph, J.; Dreiss, C. A.; Cosgrove, T. Langmuir, 2008, 24, 10005-10010; Dreiss, C. A.; Nwabunwanne, E.; Liu, R.; Brooks, N. J. Soft Matter, 2009, 5, 1888-1896), is also able to form a complex with F127, resulting in micellar breakup. In the ternary mixtures, a fine balance of forces is involved, which results in drastic micellar changes, as observed from the SANS patterns. Depending on the ratio of drug, polymer, and hep2,6 β-CD and the nature of the interactions (which is directly linked to the drug chemical structure), the presence of drug either hinders micellar breakup by β-CD (at high enough concentration of LD or PB) or leads to micellar growth (NP). These effects are mainly attributed to a preferential drug/β-CD interaction (except for PB), which, at least in the conditions studied here, explains the higher β-CD concentration needed for micellar breakup to occur.
- Valero, Margarita,Dreiss, Cecile A.
-
experimental part
p. 10561 - 10571
(2011/01/12)
-
- Synthesis and antispasmodic activity of lidocaine derivatives endowed with reduced local anesthetic action
-
The present structure-activity relationship (SAR) study focused on chemical modifications of the structure of the local anesthetic lidocaine, and indicated analogues having reduced anesthetic potency, but with superior potency relative to the prototype in preventing anaphylactic or histamine-evoked ileum contraction. From the SAR analysis, 2-(diethylamino)-N-(trifluoromethyl-phenyl) and 2-(diethylamino)-N-(dimethyl-phenyl) acetamides were selected as the most promising compounds. New insights into the applicability of non-anesthetic lidocaine derivatives as templates in drug discovery for allergic syndromes are provided.
- Costa, Jorge C.S.,Neves, Josiane S.,de Souza, Marcus V.N.,Siqueira, Rodrigo A.,Romeiro, Nelilma C.,Boechat, Nubia,Silva, Patricia M.R.e,Martins, Marco A.
-
p. 1162 - 1166
(2008/09/20)
-
- BENZYLPHOSPHATE AND SUBSTITUTED BENZYLPHOSPHATE PRODRUGS FOR TRE TREATMENT OF PULMONARY INFLAMMATION
-
A prodrug of a corticosteroid, lidocaine or related local anesthetic composition for formulation for delivery by aerosolization to inhibit inflammation in asthmatic lungs is described. The prodrug is preferably formulated in a 5 ml solution of a quarter normal saline having pH between 5.0 and 7.0 for the treatment of respiratory tract inflammation by an aerosol having mass medium average diameter predominantly between 1 to 5 μ produced by nebulization or dry powder inhaler.
- -
-
-
- TAPE MATERIAL FOR TRANSCUTANEOUS ABSORPTION
-
A preparation for transdermal absorption is disclosed which is suited for alleviating lasting pains caused by herpes zoster or postherpetic neuralgia and is practical and more improved in drug efficacy, safety and application characteristics. This tape preparation for transdermal absorption is obtained by causing an adhesive mass prepared by incorporating 1-30 parts by weight of a local anesthetic as an active ingredient in 100 parts by weight of a nonaqueous adhesive mass base comprising 5-50% by weight of a styrene-isoprene-styrene block copolymer, 1-60% by weight of an alicyclic saturated hydrocarbon resin, 5-60% by weight of liquid paraffin and 1-30% by weight of butyl rubber to be supported on a backing.
- -
-
-
- Pharmaceutical formulation
-
PCT No. PCT/SE96/00123 Sec. 371 Date Mar. 8, 1996 Sec. 102(e) Date Mar. 8, 1996 PCT Filed Feb. 2, 1996 PCT Pub. No. WO96/24359 PCT Pub. Date Aug. 15, 1996The invention relates to a pharmaceutical composition for topical administration comprising a combination of foscarnet and an antiinflammatory glucocorticoid, in admixture with a carrier based on galactolipids and a polar solvent. The pharmaceutical composition can be used in a prophylactic and/or curative treatment of herpesvirus infections in mammals including man. The invention also relates to the use of said pharmaceutical composition in the manufacture of a medicament for said prophylactic or curative treatment.
- -
-
-
- Pharmaceutical preparation for improving the bioavailability of drugs which are difficult to absorb and a procedure for obtaining it
-
The preparation consists of millispheres, microspheres, nanospheres or array-type particles consisting of a nucleus of a gellable hydrocolloid onto which has been deposited a film of a cationic polysaccharide, and incorporating inside a pharmacologically useful drug. The procedure consists of dissolving, suspending or emulsifying the drug in a solution of the gellable hydrocolloid; adding the resulting mixture to a gelling solution; and suspending the resulting millispheres, microspheres, nanospheres or array-type particles in a solution of the cationic polysaccharide.
- -
-
-
- Water dispersion containing ultrafine particles of organic compounds
-
A water-dispersible condensate of water-insoluble ultrafine particles of medicine or hormones having a particle size of at largest 4 μm prepared by the steps of heating the medicine or hormone in a vacuum vessel at a temperature of 30° C. higher than the boiling point and at a pressure between 0.01 Torr and 10 Torr to evaporate the medicine or hormone and condensing the medicine or hormone on a recovery plate to obtain the condensate.
- -
-
-
- 2-Alkyl-3-benzoylbenzofurans useful for treating cardiac arrhythmia
-
New 2-alkyl-3-[4-(omega-N,N-dialkylaminoacylamino)-3,5-dialkylbenzoyl]benzofurans useful for treating cardiac arrhythmia, as well as pharmaceutical compositions containing these benzofurans and the method of treating cardiac arrhythmia therewith are disclosed.
- -
-
-
