Query 1. Query
Query
Results
Date
RX.PXRN=2215784
13 reactions in Reaxys
2018-05-14 03h:33m:52s (UTC)
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Cu 2+
O
5 H O 2
H N
O N O
S
O
O–
OH
O HO
N O
O– HO
H
OH
Rx-ID: 47798352 View in Reaxys 1/13 Yield
Conditions & References 12 : Example 12 Example 12 Synthesis of Conjugate 7 of Lidocaine (4-Arm-PEG-Lidocaine, 10K) 4-arm-PEG-N3 (10 K, 2 g, 0.2 mmol), compound Y3 (564.5 mg, 1 mmol), vitamin C (440 mg, 2.5 mmol) were added to N, Ndimethylformamide (20 mL), the resulting mixture was rapidly stirred to dissolve, then added with an aqueous solution (4.4 mL, 2.2 mL/g PEG) of copper sulfate pentahydrate (250 mg, 1 mmol), the resulting mixture was reacted at room temperature overnight and precipitated with isopropanol to give 1.8 g of product. 1H NMR: (CDC13): 1.05 (m, 24H), 2.13 (s, 24H), 2.30 (s, 12H), 2.42 (m, 16H), 3.50 (s, 8H), 3.53 (m, 900H), 3.86 (m, 8H), 3.91 (m, 8H), 4.55 (s, 8H), 4.81 (s, 8H), 5.23 (s, 8H), 6.91 (d, 4H), 7.06 (s, 4H), 7.20 (m, 12H), 7.68 (s, 4H), 10.26 (s, 4H). Patent; JenKem Technology Co., Ltd. (Tianjin); Wang, Jinliang; Feng, Zewang; Zhu, Hui; Lin, Meina; Liu, Yan; Zhao, Xuan; (38 pag.); US2018/110867; (2018); (A1) English View in Reaxys 13 : Example 13 Example 13 Synthesis of Conjugate 8 of Lidocaine (8-Arm-PEG-Lidocaine, 20K) 8-arm-PEG-N3 (20 K, 2 g, 0.1 mmol), compound Y3 (618.5 mg, 1 mmol), vitamin C (440 mg, 2.5 mmol) were added to N, Ndimethylformamide (20 mL), the resulting mixture was rapidly stirred to dissolve, then added with an aqueous solution (4.4 mL, 2.2 mL/g PEG) of copper sulfate pentahydrate (250 mg, 1 mmol), the resulting mixture was reacted at room temperature overnight and precipitated with isopropanol to give 1.7 g of product. 1H NMR: (CDC13): 1H NMR: (CDC13): 1.07 (m, 48H), 2.14 (s, 48H), 2.31 (s, 24H), 2.41 (m, 32H), 3.52 (s, 16H), 3.54 (m, 1800H), 3.79 (m, 16H), 3.92 (m, 16H), 4.53 (s, 16H), 4.82 (s, 16H), 5.22 (s, 16H), 6.90 (d, 8H), 7.09 (s, 8H), 7.28 (m, 24H), 7.69 (s, 8H), 10.27 (s, 8H). Patent; JenKem Technology Co., Ltd. (Tianjin); Wang, Jinliang; Feng, Zewang; Zhu, Hui; Lin, Meina; Liu, Yan; Zhao, Xuan; (38 pag.); US2018/110867; (2018); (A1) English View in Reaxys 3 : Example 3 Example 3 Synthesis of Conjugate 1 of Lidocaine (mPEG-Lidocaine, 20 K) mPEG-N3 (20 K, 2 g, 0.1 mmol), compound Y1 (65.8 mg, 0.12 mmol), vitamin C (52.8 mg, 3 mmol) were added to N, Ndimethylformamide (20 mL), the resulting mixture was rapidly stirred to dissolve, then added with an aqueous solution (4.4 mL, 2.2 mL/g PEG) of copper sulfate pentahydrate (30 mg, 0.12 mmol), the resulting mixture was reacted at room temperature overnight and precipitated with isopropanol to give 1.9 g of product. 1H NMR: (CDC13): 1.42 (m, 6H), 2.19 (s, 6H), 3.02 (m, 4H), 3.23 (m, 4H), 3.31 (s, 3H), 3.50 (m, 1800H), 3.80 (m, 2H) (m, 2H), 4.20 (m, 2H), 4.50 (s, 2H), 4.82 (s, 2H), 7.12 (m, 3H), 7.30 (d, 2H), 7.64 (d, 2H) s, 1H), 10.28 (s, 1H). Patent; JenKem Technology Co., Ltd. (Tianjin); Wang, Jinliang; Feng, Zewang; Zhu, Hui; Lin, Meina; Liu, Yan; Zhao, Xuan; (38 pag.); US2018/110867; (2018); (A1) English View in Reaxys 4 : Example 4 Example 4 Synthesis of Conjugate 2 of Lidocaine (4-Arm-PEG-Lidocaine, 10 K) 4-arm-PEG-N3 (10 K, 2g, 0.2 mmol), compound Y1 (548.5 mg, 1 mmol), vitamin C (440 mg, 2.5 mmol) were added to N, Ndimethylformamide (20 mL), the resulting mixture was rapidly stirred to dissolve, then added with an aqueous solution (4.4 mL, 2.2 mL/g PEG) of copper sulfate pentahydrate (250 mg, 1 mmol), the resulting mixture was reacted at room temperature overnight and precipitated with isopropanol to give 1.8 g of product. 1H NMR: (CDC13): 1.43 (m, 24H), 2.22 (s, 24H), 3.07 (m, 16H), 3.25 (m, 16H), 3.34 (s, 12H), 3.50 (m, 900H), 3.83 (m, 8H), 4.22 (m, 8H), 4.53 (s, 8H), 4.85 (s, 8H), 7.13 (m, 12H), 7.30 (d, 8H), 7.65 (d, 8H), 7.92 (s, 4H), 10.26 (s, 4H). Patent; JenKem Technology Co., Ltd. (Tianjin); Wang, Jinliang; Feng, Zewang; Zhu, Hui; Lin, Meina; Liu, Yan; Zhao, Xuan; (38 pag.); US2018/110867; (2018); (A1) English
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View in Reaxys 5 : Example 5 Example 5 Synthesis of Conjugate 3 of Lidocaine (8-Arm-PEG-Lidocaine, 20 K) 8-arm-PEG-N3 (20 K, 2 g, 0.1 mmol), compound Y1 (548.5 mg, 1 mmol), vitamin C (440 mg, 2.5 mmol) were added to N, Ndimethylformamide (20 mL), the resulting mixture was rapidly stirred to dissolve, then added with an aqueous solution (4.4 mL, 2.2 mL/g PEG) of copper sulfate pentahydrate (250 mg, 1 mmol), the resulting mixture was reacted at room temperature overnight and precipitated with isopropanol to give 1.6 g of product. 1H NMR: (CDC13): 1.44 (M, 48H), 2.22 (s, 48H), 3.09 (m, 32H), 3.23 (m, 32H), 3.37 (s, 24H), 3.51 (m, 1800H), 3.84 (m, 16H) (m, 16H), 4.23 (m, 16H), 4.54 (s, 16H), 4.86 (s, 16H), 7.12 (m, 24H), 7.31 (d, 16H), 7.66 (d, 16H), 7.93 (s, 8H), 10.27 (s, 8H). Patent; JenKem Technology Co., Ltd. (Tianjin); Wang, Jinliang; Feng, Zewang; Zhu, Hui; Lin, Meina; Liu, Yan; Zhao, Xuan; (38 pag.); US2018/110867; (2018); (A1) English View in Reaxys
H N
H N
Cl N H
N O
O
Rx-ID: 686065 View in Reaxys 2/13 Yield
Conditions & References With triethylamine in N,N-dimethyl-formamide, Time= 0.190278h, T= 60 °C Britton, Joshua; Chalker, Justin M.; Raston, Colin L.; Chemistry - A European Journal; vol. 21; nb. 30; (2015); p. 10660 10665 View in Reaxys With benzene Loefgren; Arkiv foer Kemi; vol. 22A; nb. 18; (1946); p. 11 View in Reaxys in water, toluene, Heating 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.; Bioorganic and Medicinal Chemistry Letters; vol. 18; nb. 3; (2008); p. 1162 - 1166 View in Reaxys 2.2.2. Preparation of Lidocaine (I) and Benzothiazolederivatives (II-VI) General procedure: 2-aminobenzothiazole and its derivatives (R-H, 0.1 mol),N-(2,6-dimethylphenyl) chloroacetamide (0.1 mol) andtriethylamine in 25 ml of dried dioxane were refluxed during5 days. After observing by TLC, the reaction mixture wascooled, extracted with potassium carbonate solution, filteredand re-crystallized with ethanol to yield I-VI) (Schemes 1and 2). With triethylamine in 1,4-dioxane, Time= 120h, Reflux Ahmadi, Abbas; Khalili, Mohsen; Mohammadinoude, Mohammad Kazem; Nahri-Niknafs, Babak; Combinatorial Chemistry and High Throughput Screening; vol. 19; nb. 6; (2016); p. 507 - 512 View in Reaxys
H N N O NH 2
Rx-ID: 22068211 View in Reaxys 3/13 Yield
Conditions & References Reaction Steps: 2 1: acetic acid; sodium acetate 2: benzene With sodium acetate, acetic acid, benzene
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Loefgren; Arkiv foer Kemi; vol. 22A; nb. 18; (1946); p. 11 View in Reaxys Reaction Steps: 2 1: triethylamine / chloroform / 0.02 h / Flow reactor 2: triethylamine / N,N-dimethyl-formamide / 0.19 h / 60 °C With triethylamine in chloroform, N,N-dimethyl-formamide Britton, Joshua; Chalker, Justin M.; Raston, Colin L.; Chemistry - A European Journal; vol. 21; nb. 30; (2015); p. 10660 10665 View in Reaxys Reaction Steps: 2 1: acetic acid; sodium acetate / water / 24 h / Reflux 2: triethylamine / 1,4-dioxane / 120 h / Reflux With sodium acetate, acetic acid, triethylamine in 1,4-dioxane, water Ahmadi, Abbas; Khalili, Mohsen; Mohammadinoude, Mohammad Kazem; Nahri-Niknafs, Babak; Combinatorial Chemistry and High Throughput Screening; vol. 19; nb. 6; (2016); p. 507 - 512 View in Reaxys
H N
O N
N
O
O NH 2
Rx-ID: 43922707 View in Reaxys 4/13 Yield
Conditions & References 1.2 : (2) Preparation of lidocaine hydrochloride Distillation apparatus is provided with three sequentially in the bottle by adding sodium methoxide 15.12g (0.28mol), intermediate 2,6-dimethyl aniline 24.24g (0.2mol) and N, N-diethyl amino methyl acetate 31.9g (0.22mol), heating to 95 °C, side reaction-side distillation to remove reaction generated methanol, the methanol is distilled until the free, to continue the reaction 30 min, cooling to room temperature, dissolved in dichloroethane, washing 2 times, static hierarchical, organic layer is lidocaine dichloroethane solution of alkali.The lidocaine in dichloroethane solution of alkali, adding hydrochloric acid 2.56g, then with hydrogen chloride for adjusting PH 3.5, reflux adding activated carbon to 20 min, filtering, concentrating the filtrate, the cooling crystallization, drying to obtain the lidocaine hydrochloride 48.28g, HPLC purity is 99.52percent, the yield is 88.72percent, overall yield is 84.04percent. With sodium methylate, Time= 0.5h, T= 95 °C , Concentration, Temperature Patent; Zhejiang Esigma Animal Health Co.,Ltd.; Wu, Zhonghua; Zhang, Xiaopeng; Chen, Guicai; Xu, Tianhua; He, Qilei; Wen, Ming; (6 pag.); CN105294477; (2016); (A) Chinese View in Reaxys
H N N O OH
Rx-ID: 43922708 View in Reaxys 5/13 Yield
Conditions & References Reaction Steps: 2 1: ammonium hydroxide; 2,6-dimethylcyclohexanone; 5-palladium/activated carbon / 5 h / 180 °C 2: sodium methylate / 0.5 h / 95 °C With 2,6-dimethylcyclohexanone, ammonium hydroxide, 5-palladium/activated carbon, sodium methylate Patent; Zhejiang Esigma Animal Health Co.,Ltd.; Wu, Zhonghua; Zhang, Xiaopeng; Chen, Guicai; Xu, Tianhua; He, Qilei; Wen, Ming; (6 pag.); CN105294477; (2016); (A) Chinese View in Reaxys
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H N
O N
N NH 2
O NH 2
Rx-ID: 40317722 View in Reaxys 6/13 Yield
Conditions & References General procedure for microwave reaction General procedure: Amide (1.0 mmol), amine (1.0 mmol) and K2S2O8 (1.5 mmol) were charged in microwave vial added water (2.0 mL), the reaction mixture was treated at 100°C and 100W for 10 min. After the complete conversion (by TLC) of the amine, distilled water (10 mL) was added and extracted with ethyl acetate (2 ×10 mL). The combined organic phase was dried over Na2SO4, and then concentrated using rotary vacuum evaporator. The crude product was purified by column chromatography (30percent Ethyl acetate/hexane) to get pure compound. With dipotassium peroxodisulfate in water, Time= 0.166667h, T= 100 °C , Microwave irradiation, Green chemistry Srinivas, Mahesuni; Hudwekar, Abhinandan D.; Venkateswarlu, Vunnam; Reddy, G. Lakshma; Kumar, K. A. Aravinda; Vishwakarma, Ram A.; Sawant, Sanghapal D.; Tetrahedron Letters; vol. 56; nb. 33; (2015); p. 4775 - 4779 View in Reaxys
O
O H
O
H H
H O
O
O O
O H
HO
O
HO
O
OH
H
O
O
H N
H O
O
HO O
N
O H
HO
O
O
H
H
O OH O
O H
O
OH O O
H
O O
H
O H
O O
O
O
H
O
H O
O O O
O
O HO
H HO
O H N N
O
OH
O
O
O
O
O
H
HO O
OH O O
HO
O
OH
H
O
O O O H
O
O
O
O H O
Rx-ID: 29980968 View in Reaxys 7/13 Yield
Conditions & References With pluronic copolymer F290 in water, T= 25 °C , Equilibrium constant, Reagent/catalyst
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Valero, Margarita; Dreiss, Cecile A.; Langmuir; vol. 26; nb. 13; (2010); p. 10561 - 10571 View in Reaxys O O
P
–O
O
HO
O–
F
H N
H N
O–
N
N+
F F
O
O
2
HO
Na +
Rx-ID: 23586722 View in Reaxys 8/13 Yield
Conditions & References With alkaline phosphatase in water, Time= 6h, T= 37 °C , pH= 7.4, Enzymatic reaction, Enzyme kinetics Patent; CORUS PHARMA; WO2005/63777; (2005); (A1) English View in Reaxys O O
P
–O
O O–
F O
H N
H N
–
N
N+
F F
O
O
2
Na +
Rx-ID: 23586723 View in Reaxys 9/13 Yield
Conditions & References With rat lung homogenate, Time= 3h, T= 37 °C , Enzyme kinetics Patent; CORUS PHARMA; WO2005/63777; (2005); (A1) English View in Reaxys
O H N
F O–
O–
N+
O
F F
2
O
P –O
O
Na +
H N N
OH
O
HO
Rx-ID: 23586725 View in Reaxys 10/13 Yield
Conditions & References With alkaline phosphatase in water, Time= 6h, T= 37 °C , pH= 7.4, Enzymatic reaction, Enzyme kinetics Patent; CORUS PHARMA; WO2005/63777; (2005); (A1) English View in Reaxys
H N N O
Rx-ID: 7369970 View in Reaxys 11/13
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Yield
Conditions & References Ugi,I.; Steinbrueckner,C.; Chemische Berichte; vol. 94; (1961); p. 734 - 742 View in Reaxys Grosztonyi; Walde; Journal of Labelled Compounds; vol. 2; (1966); p. 155,158, 160 View in Reaxys Patent; Astra; GB941195; (1963); ; vol. 65; nb. 19941; (1966) View in Reaxys Patent; Aktiebolaget Astra Apotekarnes Kemiska Fabriker; DE1103337; (1961); ; vol. 57; nb. 12503b; (1962) View in Reaxys Dzindziel; Lodzinska; Polish Journal of Chemistry; vol. 52; (1978); p. 1141 View in Reaxys Goto; Itano; Yakugaku Zasshi; vol. 99; (1979); p. 146,147,148,151-153 View in Reaxys Shurawlew; Nikolajew; J. Gen. Chem. USSR (Engl. Transl.); vol. 30; (1960); p. 1155,1172; ; nb. 424; (1961) View in Reaxys Patent; Astra Apotekarnes Kem. Fabr.; GB810212; ; nb. 2253; (1960) View in Reaxys Patent; Aktiebolag Astra Apotekarnes Kemiska Fabriker; SE183395; (1954); ; vol. 60; nb. 2821h; (1964) View in Reaxys McKenzie; Journal of pharmaceutical sciences; vol. 58; nb. 10; (1969); p. 1297 - 1298 View in Reaxys 3 : EXAMPLE 3 Lidocaine: m.p. 66°-69° C. (local anesthetic; white crystal) Epineprine (Adrenaline): m.p. 210° C. (sympathomimetic agent; crystalline powder) Patent; Research Development Corp. of Japan; Stanley Electric Co., Ltd.; US5354563; (1994); (A) English View in Reaxys non-steroidal anti-inflammatory agents selected from the group consisting of indomethacin, ibuprofen, sulindac, diclofenac, ketorolac and naproxen; dexametasone; anti-glaucoma agents selected from pilocarpine or thymolol; lidocaine; codeine; alpha-tocopherol; thymine; diazepam; Patent; Lipotec S.A.; US5736161; (1998); (A) English View in Reaxys 2.B : EXAMPLE 2 The aqueous acid extracts are made strongly basic by the addition of 30percent aqueous sodium hydroxide. The resulting oily precipitate which separates is taken up in diethyl ether (1 liter), the ether phase is dried over anhydrous potassium carbonate, and the resulting dry, filtered ether solution is distilled. Following distillation of the ether at atmospheric pressure, the remainder of the fractionation is carried out in vacuo at about 2 mm. Hg. pressure. The product, alpha-diethylamino-2,6-dimethyl-acetanilide boils at about 159° 160° C. at 2 mm. Hg. Patent; Taro Pharmaceuticals, Ltd.; US4831054; (1989); (A) English View in Reaxys (Production method) A tape preparation containing 2.14 mg/cm2of lidocaine was obtained in the same manner as in Example 1. Patent; Yutoku Pharmaceutical Ind. Co. Ltd.; Maruho Kabushiki Kaisha; EP1125578; (2001); (A1) English View in Reaxys (Production method) A tape preparation containing 2.14 mg/cm2of lidocaine was obtained in the same manner as in Comparative Example 1. Patent; Yutoku Pharmaceutical Ind. Co. Ltd.; Maruho Kabushiki Kaisha; EP1125578; (2001); (A1) English
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View in Reaxys (Production method) A tape preparation containing 4.28 mg/cm2of lidocaine was obtained in the same manner as in Example 1. Patent; Yutoku Pharmaceutical Ind. Co. Ltd.; Maruho Kabushiki Kaisha; EP1125578; (2001); (A1) English View in Reaxys
O
OH
H N
P
HO
N
OH
O
O
Rx-ID: 24320868 View in Reaxys 12/13 Yield
Conditions & References 3 : Cream of Foscarnet 1.5percent and Lidocaine 1percent EXAMPLE 3 Cream of Foscarnet 1.5percent and Lidocaine 1percent By simple mixing of Foscarnet Cream (3percent) and lidocaine cream (2percent, Xylocain.(R)., Astra AB, Sweden) a combination cream was obtained having the following composition: Patent; Astra Aktiebolag; US6068860; (2000); (A) English View in Reaxys
NH O O
N+
O–
H N
NH
N O
O
N
Rx-ID: 5114844 View in Reaxys 13/13 Yield
Conditions & References T= 250 °C Ng, Lay-Keow; Hupe, Michel; Harnois, Jean; Lawrence, Andre H.; Analytical Chemistry; vol. 70; nb. 20; (1998); p. 4389 4393 View in Reaxys
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