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[ CAS No. 144-62-7 ]

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Chemical Structure| 144-62-7
Chemical Structure| 144-62-7
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Product Details of [ 144-62-7 ]

CAS No. :144-62-7 MDL No. :MFCD00002573
Formula : C2H2O4 Boiling Point : 365.1°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :90.03 g/mol Pubchem ID :971
Synonyms :

Safety of [ 144-62-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P301+P312-P301+P330+P331-P302+P352 UN#:N/A
Hazard Statements:H302-H312 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 144-62-7 ]

  • Upstream synthesis route of [ 144-62-7 ]
  • Downstream synthetic route of [ 144-62-7 ]

[ 144-62-7 ] Synthesis Path-Upstream   1~59

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Reference: [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 8, p. 1337 - 1342
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Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
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  • [ 110-15-6 ]
  • [ 120-73-0 ]
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  • [ 18588-61-9 ]
Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
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YieldReaction ConditionsOperation in experiment
1.6 mg With copper(II) choride dihydrate In water at 80℃; for 24 h; General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference: [1] Biochemistry, 2016, vol. 55, # 19, p. 2806 - 2811
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Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
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  • [ 110-15-6 ]
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  • [ 18588-61-9 ]
Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
  • 7
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Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
  • 8
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Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
  • 9
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  • [ 95-54-5 ]
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YieldReaction ConditionsOperation in experiment
92%
Stage #1: at 110℃; for 5 h;
Stage #2: With trichlorophosphate In N,N-dimethyl-formamide; toluene at 110℃; for 1 h;
That 1 g O-phenylendiamine, 1.28 g oxalic acid and 3 g 200 - 300 mesh silica gel in the reaction bottle, adding 15 ml toluene, 110 °C lower reaction 5 hours, the reaction is finished, by adding 8.4 ml phosphorus oxychloride and 5 ml DMF, 110 °C continues reaction under 1 hour, the reaction is finished, adding 50 ml ice water quenching, adding 50 ml ethyl acetate, filtration, liquid, to continue to use the water layer is extracted with ethyl acetate, the combined ethyl acetate, washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, reduced-pressure drying to obtain white solid, yield 92percent
Reference: [1] Patent: CN108191778, 2018, A, . Location in patent: Paragraph 0019-0027
  • 10
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  • [ 125-33-7 ]
Reference: [1] Patent: US2637730, 1952, ,
  • 11
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  • [ 1575-37-7 ]
  • [ 1910-90-3 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 7, p. 1809 - 1814
  • 12
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  • [ 110-45-2 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1866, vol. <2> 5, p. 11[2] Bulletin de la Societe Chimique de France, 1882, vol. <2> 37, p. 107
[3] Finska Kemistsamf.Medd., 1930, vol. 38, p. 124[4] Chem. Zentralbl., 1930, vol. 101, # I, p. 2086
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YieldReaction ConditionsOperation in experiment
0.002 mg at 80℃; for 24 h; General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference: [1] Biochemistry, 2016, vol. 55, # 19, p. 2806 - 2811
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  • [ 57-13-6 ]
  • [ 18514-52-8 ]
YieldReaction ConditionsOperation in experiment
0.01 mg at 80℃; for 24 h; General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference: [1] Biochemistry, 2016, vol. 55, # 19, p. 2806 - 2811
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  • [ 57-13-6 ]
  • [ 18514-52-8 ]
YieldReaction ConditionsOperation in experiment
0.9 mg at 80℃; for 24 h; General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference: [1] Biochemistry, 2016, vol. 55, # 19, p. 2806 - 2811
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  • [ 2491-15-8 ]
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  • [ 71-30-7 ]
  • [ 120-73-0 ]
  • [ 144-62-7 ]
  • [ 113-00-8 ]
  • [ 127-17-3 ]
  • [ 66-22-8 ]
  • [ 56-06-4 ]
  • [ 66224-66-6 ]
  • [ 57-13-6 ]
  • [ 56-40-6 ]
  • [ 302-72-7 ]
  • [ 18588-61-9 ]
Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
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  • [ 18514-52-8 ]
Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
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  • [ 1455-77-2 ]
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Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
  • 19
  • [ 144-62-7 ]
  • [ 71-36-3 ]
  • [ 2050-60-4 ]
Reference: [1] Angewandte Chemie - International Edition, 2009, vol. 48, # 1, p. 168 - 171
[2] Journal of the Chemical Society, 1923, vol. 123, p. 2714
[3] Journal of the American Chemical Society, 1921, vol. 43, p. 369
[4] Kobunshi Kagaku, 1951, vol. 8, p. 85,91,103[5] Chem.Abstr., 1953, p. 7463
[6] Green Chemistry, 2010, vol. 12, # 4, p. 661 - 665
[7] Journal of Chemical and Engineering Data, 2011, vol. 56, # 4, p. 800 - 810
[8] Catalysis Letters, 2014, vol. 144, # 4, p. 585 - 589
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  • [ 144-62-7 ]
  • [ 71-36-3 ]
  • [ 13318-13-3 ]
  • [ 2050-60-4 ]
Reference: [1] Comptes Rendus Chimie, 2016, vol. 19, # 10, p. 1247 - 1253
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  • [ 56-41-7 ]
  • [ 144-62-7 ]
  • [ 71-36-3 ]
  • [ 2050-60-4 ]
  • [ 1246345-80-1 ]
Reference: [1] Organic Process Research and Development, 2013, vol. 17, # 12, p. 1498 - 1502
  • 22
  • [ 109-65-9 ]
  • [ 144-62-7 ]
  • [ 13318-13-3 ]
  • [ 2050-60-4 ]
Reference: [1] Tetrahedron, 1989, vol. 45, # 5, p. 1533 - 1536
  • 23
  • [ 109-65-9 ]
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  • [ 2050-60-4 ]
Reference: [1] Turkish Journal of Chemistry, 2010, vol. 34, # 2, p. 187 - 191
  • 24
  • [ 637-69-4 ]
  • [ 144-62-7 ]
  • [ 1929-29-9 ]
  • [ 942-54-1 ]
Reference: [1] Journal of Organic Chemistry, 1993, vol. 58, # 17, p. 4739 - 4741
  • 25
  • [ 13011-88-6 ]
  • [ 10421-85-9 ]
  • [ 144-62-7 ]
Reference: [1] Helvetica Chimica Acta, 1954, vol. 37, p. 1318,1325
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  • [ 13194-69-9 ]
  • [ 144-62-7 ]
Reference: [1] Chemische Berichte, 1906, vol. 39, p. 269
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  • [ 1113-38-8 ]
Reference: [1] Russian Journal of Applied Chemistry, 2008, vol. 81, # 9, p. 1483 - 1486
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  • [ 57-13-6 ]
  • [ 1113-38-8 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1923, vol. <2>106, p. 115,136
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  • [ 132335-49-0 ]
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YieldReaction ConditionsOperation in experiment
75.6%
Stage #1: With sodium hydride In N,N-dimethyl acetamide at 70℃; for 0.333333 h;
Stage #2: at 110℃; for 1 h;
DX-A 03 (2.0 g, 0.011 mol)Was dissolved in dimethylacetamide (100 mL)A solution of 60percent sodium hydride (463 mg, 0.012 mol)Dropwise.The resulting mixture was heated at 70 ° C. for 20 minutes.1-Fluoronaphthalene (1.27 mL, 0.012 mol)Was added dropwise to this mixed solution,And heated at 110 ° C. for 60 minutes.The reaction mixture was diluted with water,And extracted twice with diethyl ether.The extracts are combined,Wash with water,Then washed with saturated sodium chloride solution,It was dried over anhydrous sodium sulfate,After concentration under reduced pressure,To obtain an oily compound (DX-A 04, 3.28 g, 75.6percent).
Reference: [1] Patent: JP2016/172704, 2016, A, . Location in patent: Paragraph 0027; 0053
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Reference: [1] Organic Process Research and Development, 2009, vol. 13, # 5, p. 854 - 856
[2] Patent: WO2009/87463, 2009, A2, . Location in patent: Page/Page column 7-8
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YieldReaction ConditionsOperation in experiment
84.2% at 20℃; for 21 h; Example 10; Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 moles, 0.8 eq) in water (30 mL) was then added. The resulting mixture was stirred for 21 hours and filtered. The filter cake was washed with isopropyl acetate (10 mL) and dried under vacuum at 40° C. to yield 10.87 g of the product as a white solid (Yield: 84.2percent; HPLC (peak area at 220 nm) oxalic acid 1.78percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.10percent, 1-naphthol 0.35percent, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 97.65percent; Titration: 99.5percent; Karl Fischer: 0.06percent; XRD as shown in FIG. 1 (Form A); IR essentially as shown in FIG. 3 (Form A); TGA DSC as shown in FIG. 2, mp onset 152.6° C.).
78.6% at 20℃; for 2 h; Example 12Preparation of (S)-N,N-dimethyl(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 mmoles, 0.8 eq) in isopropanol (30 mL) was then added dropwise. The resulting mixture was stirred for 2 hours and filtered. The filter cake was dried under vacuum at 50° C. to yield 10.14 g of the product as a white solid (Yield: 78.6percent; HPLC (peak area at 220 nm) oxalic acid 1.56percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol not detected, 1-naphthol not detected, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 98.36percent; Titration: 99.4percent; Karl Fischer: 0.06percent; IR essentially as shown in FIG. 3, Form A).
78.9% at 20℃; for 16 h; Example 11Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 mmoles, 0.8 eq) in methanol (4 mL) was then added. An additional volume of isopropyl acetate (50 mL) was added for improved stirring. The resulting mixture was stirred for 16 hours and filtered. The filter cake was washed with isopropyl acetate (10 mL) and dried under vacuum at 55° C. to yield 10.21 g of the product as a white solid (Yield: 78.9percent; HPLC (peak area at 220 nm) oxalic acid 1.66percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol not detected, 1-naphthol not detected, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 98.24percent; Titration: 100.1percent; Karl Fischer: 0.22percent; XRD as shown in FIG. 1 (Form A); IR as shown in FIG. 3 (Form A).
77% at 20℃; for 1 h; Preparation of DNT Oxalate
Example 6
To a solution of 2.1 g of DNT-base (12percent enantiomer R) dissolved in 12 ml of ethyl acetate was added a solution of 0.6 g of oxalic acid in 12 ml of ethyl acetate.
The resulting mixture was stirred at room temperature for an hour, filtrated and washed with ethyl acetate.
After drying, in a vacuum oven for overnight, 2 g (77percent yield) of DNT-oxalate were obtained containing 12percent of enantiomer R.
88 % ee
Stage #1: With pyridine-SO3 complex In dimethyl sulfoxide; toluene for 0.5 h;
Stage #2: for 16 h;
Example 1Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl) Propylamine Oxalic Acid Salt(S-3-Dimethylamino-1-(2-thienyl)-1-propanol (50 g, 0.270 moles) and sodium hydroxide (21.6 g, 0.540 moles, 2 eq.) were heated in DMSO (500 mL) at 60-80° C. for 1 hour. The temperature was controlled at 60° C.+/-4° C. before 1-fluoronaphthalene (43.6 g, 38.5 mL, 0.299 moles) was added. The mixture heated at this temperature for 64 hours. Water (500 mL) was added, and the mixture extracted with toluene (2.x.500 mL). The organic layers were then combined and washed with water (500 mL). HPLC analysis of an evaporated aliquot showed the molar ratio of Compound IV to Compound S-II to be 90:10 and Compound IV to be 88percent ee. Pyridine sulfur trioxide (6.4 g, 0.040 moles) was added to the mixture, the mixture was stirred for 30 minutes, and was then washed with water (500 mL). The organic layers were then concentrated by distillation until 600 mL of solvent was removed, and ethyl acetate (500 mL) was added. Oxalic acid dihydrate (27.2 g, 0.216 moles) was then added. The resulting suspension was stirred for 16 hours and filtered to yield the product as a white solid. The resulting product was slurried in additional ethyl acetate (200 mL), filtered and dried under vacuum to yield 63.3 g of the product as a white solid (0.158 moles, Yield: 59percent). The resulting product had a molar ratio of Product:(S)-3-dimethylamino-1-(2-thienyl)-1-propanol: 1-fluoronaphthalene of 99.53:0.46:0.02 and 88percent ee.
92 % ee
Stage #1: With pyridine-SO3 complex In Isopropyl acetate; dimethyl sulfoxide at 20℃; for 1 h;
Stage #2: at 15 - 20℃; for 16 h;
Example 6Preparation of (S)-N-methyl-(3-(1-naphthyloxy)-3-thien-2-yl) Propylamine Hydrochloride (Duloxetine Hydrochloride)Sodium hydroxide (0.324 kg, 8.1 moles, 2 eq), potassium carbonate (126 kg, 9.1 moles, 2.25 eq.) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (750 g, 4.05 moles), were heated in DMSO (7.5 L) at 80° C. for 3 hours and cooled to 40° C. 1-fluoronaphthalene (770'gi.5.3 mol, 1.3 eq) was then added over 5 minutes. Next, the mixture was heated at 40° C. for 17 hour and then at 50-60° C. for 40 hours. The molar ratio of product (Compound IV) to staring alcohol (Compound S-II) was 85.3:14.7, and Compound IV was 92percent ee as determined by HPLC of an aliquot. The mixture was then cooled to 20° C. and quenched with water (5 L). The mixture was divided in two and each portion was extracted twice with isopropyl acetate (2.x.2 L). The four organic phases were combined, washed with water (5 L), and pyridine sulphur trioxide complex (110 g, 0.69 moles, 0.17 eq.) was added. The mixture was then stirred at 20° C. for 30 minutes, and washed with water (5 L). Oxalic acid dihydrate (0.38 kg, 3.0 moles, 0.75 eq.) was then added, and the mixture stirred at 15-20° C. for 16 hours. The mixture was then filtered and slurried in acetone (2.5 L) and isopropyl acetate (5 L) for one hour, and then filtered to yield 2.1 kg (wet product) of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt as an off-white solid (Yield: 75percent; equivalent to 1.21 kg, (dry product)). The molar ratio of product (Compound IV) to starting alcohol (Compound S-II) was 98.7:1.3 as determined by HPLC. Compound IV oxalate salt was 92percent ee as determined by chiral HPLC.Example 7Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine Oxalic Acid SaltSodium hydroxide (8.635 g, 216 mmol, 2 eq), potassium carbonate (33.565 g, 243 mmol, 2.25 eq.) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (20 g, 108 mmol), were heated in DMSO (200 mL) at 80° C. (temperature inside flask) under vacuum such that approximately 100 mL of DMSO were distilled in 1 hour. An additional 100 mL of DMSO were then added, and the mixture heated at 80° C. for a further 2 hours. Thereafter, the mixture was cooled to 40° C. and stirred under an atmosphere of nitrogen. 1-Fluoronaphthalene (17.35 g, 119 mmol, 1.1 eq) was then added, and the mixture maintained with stirring at 40° C. Samples were taken periodically and analysed by NMR. Once an approximately 92percent conversion had been achieved (24 hours), as determined by the ratio of Compounds IV and S-II in the 1H-NMR spectrum, the mixture was cooled to 25° C., quenched with water (150 mL) and extracted twice with isopropyl acetate (2.x.100 mL). The two organic phases were combined, washed with water (75 mL), and pyridine sulphur trioxide complex (1.72 g, 10.8 mmol, 0.1 eq.) was added. The mixture was then stirred at 20° C. for 60 minutes and washed with water (150 mL). The aqueous layer was analysed to be pH 6.8. Oxalic acid dihydrate (10.9 g, 86 mmol, 0.8 eq.) was then added, and the mixture stirred at 15-20° C. for 16 hours. The mixture was then filtered and homogenized to yield 41.83 g of (S)-N,N-dimethyl(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt as an off-white solid (Loss on drying: 6.94percent, Titration: 98.1percent, Karl Fischer: 0.06percent).

Reference: [1] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 6
[2] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 7
[3] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 6-7
[4] Patent: US2007/173541, 2007, A1, . Location in patent: Page/Page column 6
[5] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 4
[6] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 7
[7] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 7
[8] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 7-8
[9] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 5
[10] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 5-6
[11] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 6
[12] Patent: WO2010/79404, 2010, A2, . Location in patent: Page/Page column 7-8
  • 32
  • [ 13636-02-7 ]
  • [ 321-38-0 ]
  • [ 144-62-7 ]
  • [ 132335-47-8 ]
Reference: [1] Patent: WO2011/33366, 2011, A2, . Location in patent: Page/Page column 23
  • 33
  • [ 144-62-7 ]
  • [ 116817-11-9 ]
  • [ 932013-45-1 ]
  • [ 132335-47-8 ]
Reference: [1] Patent: WO2007/38253, 2007, A2, . Location in patent: Page/Page column 19
  • 34
  • [ 144-62-7 ]
  • [ 878757-08-5 ]
  • [ 132335-46-7 ]
  • [ 932013-45-1 ]
  • [ 132335-47-8 ]
Reference: [1] Patent: WO2007/86948, 2007, A1, . Location in patent: Page/Page column 15
  • 35
  • [ 38875-53-5 ]
  • [ 144-62-7 ]
  • [ 168123-82-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 22, p. 3679 - 3686
  • 36
  • [ 144-62-7 ]
  • [ 219861-08-2 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: With sodium hydroxide In diethyl ether; water at 25℃; for 0.5 h;
Stage #2: With triethylamine In diethyl ether; water; toluene at 5℃; for 0.5 h;
It acquired in Example 1 to the 100-mL three-neck flask furnished with an impeller and a thermometer (4.3g (8.0 mmol) of tartrates (4b)). The degree of chemical pure: 99.925percent, impurity (i) : Un-detecting, impurity (ii):0.002percent, Optical purity: 25 mL (it is 4.2 parts by mass to 1 parts by mass of tartrates (4b)) of diethylether, 25 mL (it is 5.8 parts by mass to 1 parts by mass of tartrates (4b)) of purified water, and 4 mL (16.0mmol, 2.0 Eq) of 2M sodium hydroxide aqueous solutions were added and stirred 99.96percent. The obtained mixed liquor was stirred at 25 degrees C for 30 minutes, and it checked by viewing that the tartrate (4b) had dissolved. After churning, by a 200-mL separating funnel, the organic layer and the water layer were separated, and 4.3 mL (it is 1.0 parts by mass to 1 parts by mass of tartrates (4b)) of purified water was added and rinsed to the organic layer. The organic layer and the water layer were separated after rinsing, the organic layer was concentrated in vacuum, and 2.7 g (8mmol, 100percent of yield) of-4-(1S) [4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile educt (5) was acquired. The obtained-4-(1S) [4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile educt (5) An impeller, It adds to the 100-mL three-neck flask furnished with a thermometer, 24 mL (1S) (it is 8.5 parts by mass to 1 parts by mass of-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile educt (5)) of toluene, 1.8 g (8.8mmol, 1.1 Eq) of triethylamine was added, and it agitated at 5 degrees C for 30 minutes. 1.7 g (8.8mmol, 1.1 Eq) of Para-toluene sulfonyl chloride was added after churning, and it agitated at 5 degrees C for 1 hour. After churning, 5 mL (1S) (it is 2.0 parts by mass to 1 parts by mass of-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile educt (5)) of purified water, The ammonia solution 1.4g (8.8mmol, 1.1 Eq) was added 25percent, and it warmed at 25 degrees C, and stirred for 30 minutes. A reaction solution is separated to an organic layer and a water layer by a 100-mL separating funnel after churning, The organic layer was rinsed with 5 mL (1S) (it is 2.0 parts by mass to 1 parts by mass of-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile educt (5)) of purified water. The organic layer and the water layer were separated after rinsing, the organic layer was concentrated in vacuum, and 2.3 g (7.2mmol, 89percent of yield) of escitalopram (6) was acquired. In addition to the 100-mL three-neck flask which attached the impeller and the thermometer for the obtained escitalopram (6), 18 mL (it is 7.9 parts by mass to 1 parts by mass of escitalopram (6)) of acetone was added, and it agitated at 45 degrees C for 30 minutes. The oxalic acid 0.7g (7.9mmol, 1.1 Eq) was added after churning, and precipitation of a crystal was checked. It cooled to 25 degrees C after the precipitation check of a crystal, and riped at the temperature for 1 hour. The crystal which deposited by filtration under reduced pressure was filtered after aging, and 2.3 mL (it is 0.8 parts by mass to 1 parts by mass of escitalopram (6)) of acetone washed the filtered crystal twice. The obtained white crystals were dried in vacuum at 40 degrees C for 12 hours, and 2.5 g (6.1mmol) of escitalopram (6) oxalates (7) were obtained as white crystals (yield: 85percent, chemical-pure degree:99.900percent, optical purity:99.95percent).
98.8 % ee
Stage #1: With ammonia In dichloromethane; water
Stage #2: With triethylamine; p-toluenesulfonyl chloride In dichloromethane at 5℃; for 1 h;
(S)-4-(4-Dimethylamino)-1 -(4'-fluorophenyl)-1 -hydroxybutyl-3-hydroxymethylbenzonitrile, hemi (+)-di-p- toluoyl-tartaric acid salt (16.64g; 29.7mmol) is suspended in a mixture of 180ml water and 180ml dichloromethane. After pH-correction with aqueous ammonia to pH 9 the phases are separated. Triethylamine (5.7ml; 41mmol) is added to the cooled and dried organic phase (100ml) followed by p- toluolsulfonyl chloride (6.1g; 32mmol) and the resulting solution is stirred for one hour at a temperature below 5°C. Subsequently the reaction mixture is washed with water at pH 6 and pH 12, followed by a concentrating step under reduced pressure and dilution with acetone. Oxalic acid (2.52g; 28mmol) is added to the final solution and escitalopram oxalate crystallizes. The crystals are collected by filtration and washed with cold acetone. The wet cake is dried in vacuum to give 11.4g of Escitalopram oxalate, (purity HPLC: 99.7percent; ee = 98.8percent).1H-NMR (DMSOd6, 300MHz): δ 1.39-1.60 (m, 2H, CH2), 2.21-2.27 (t, 2H, CH2) 2.50 (s, 3H, CH3), 2.51 ( s, 3H, CH3), 2.94-2.99 (t, 2H, CH2), 5.13-5.26 (q, 2H, CH2), 7.11-7.19 (m, 2H, aryl), 7.54-7.61 (m, 2H, aryl), 7.61-7.68 (m, 3H, aryl).
Reference: [1] Patent: JP2018/12654, 2018, A, . Location in patent: Paragraph 0022; 0070-0072
[2] Patent: WO2007/82771, 2007, A1, . Location in patent: Page/Page column 25
  • 37
  • [ 144-62-7 ]
  • [ 488787-59-3 ]
  • [ 219861-08-2 ]
YieldReaction ConditionsOperation in experiment
65%
Stage #1: With methanesulfonyl chloride; triethylamine In dichloromethane at 5℃; for 2 h;
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile(373.43 mmol)600 mL of methylene chloride was injected and dissolved,156 mL of triethylamine is introduced.The reactants 5 BelowAnd 51.32 g of methanesulfonyl chloride 5 Or less,5 inStir 2 hours.1,000 mL of purified water was injected into the reaction,Followed by stirring.After the separated organic layer was concentrated,Oxalic acid dihydrate To give an off-white powdery form ((S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile oxalat eObtain(Yield: 65percent).
Reference: [1] Patent: KR2017/48878, 2017, A, . Location in patent: Paragraph 0067; 0068
[2] Patent: WO2006/21971, 2006, A2, . Location in patent: Page/Page column 18
  • 38
  • [ 144-62-7 ]
  • [ 219861-08-2 ]
YieldReaction ConditionsOperation in experiment
82%
Stage #1: With sodium hydrogencarbonate In water; ethyl acetate
Stage #2: With potassium carbonate In dimethyl sulfoxide at 90 - 100℃; for 2 h;
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(4-nitrobenzoyloxymethyl)benzonitrile hydrochloride(164.78 mmol), 445 mL of ethyl acetate was poured, 890 mL of an aqueous solution of sodium hydrogencarbonate was poured, and the mixture was stirred to separate layers. After the separated organic layer was concentrated,250 mL of dimethyl sulfoxide was injected and dissolved,And the temperature was raised to 90 deg.48.93 g of potassium carbonate was added to the reaction mixture, followed by stirring at 100 DEG C for 2 hours. The reaction was cooled to 20 330 mL of ethyl acetate and 745 mL of an aqueous sodium hydroxide solution were injected and stirred to separate the layers. The separated organic layers were combined, washed with brine, and then concentrated. Oxalic acid was added to the concentrated residue to obtain (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile oxalate was obtained (yield: 82percent).
Reference: [1] Patent: KR2017/48878, 2017, A, . Location in patent: Paragraph 0065; 0066
  • 39
  • [ 144-62-7 ]
  • [ 128196-01-0 ]
  • [ 219861-08-2 ]
YieldReaction ConditionsOperation in experiment
98.57% at 25 - 30℃; Industry scale Preparation of Escitalopram OxalateThe residue obtained in Example 1 was dissolved in acetone (120 lit) at 25-30° C. A solution of oxalic acid dihydrate (17 Kg, 0.135 kmoles) in acetone (34 lit) was introduced over 30 minutes. The reaction mass was stirred for 2 hrs, cooled to 10° C. and further stirred for 1 hr. The solid obtained was isolated by filtration, washed with acetone (2.x.40 lit) and dried in a vacuum oven for 4-5 hrs at 50-55° C. to obtain the title compound.Yield: 40.0 Kg, 98.57percentChiral purity:->99.5percent
89% at 50℃; for 0.5 h; 2.3 g (7.2 mmol) of the obtained escitalopram (6) was added to a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 12 mL of acetonitrile was added thereto and dissolved, and the mixture was stirred at 50 ° C. for 30 minutes. After stirring, 0.7 g (7.9 mmol) of oxalic acid was dissolved in acetonitrile 12 mL, and the mixture was stirred for 30 minutes,Seed crystal2.3 mgIs added,Precipitation of crystals was confirmed. After stirring, the solution was cooled to 5 ° C. and aged for 1 hour. After filtration under reduced pressure, the crystals were washed twice with 2.3 mL of acetonitrile, and the obtained white crystals were dried under reduced pressure at 40 ° C. for 15 hours,2.6 g of white crystals of (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran- 5-carbonitrile oxalate (escitalopram oxalate) (Yield: 89percent, purity 99.90percent, optical purity 98.81percent)
85% at 25 - 45℃; for 1.5 h; The obtained escitalopram (6) was added to a 100 mL three-necked flask equipped with a stirring blade and a thermometer, and 18 mL of acetone (7.9 parts by mass based on 1 part by mass of escitalopram (6)) was added, and the mixture was stirred at 45 ° C for 30 minutes. After stirring, 0.7 g (7.9 mmol, 1.1 eq) of oxalic acid was added to confirm the precipitation of crystals. After precipitation of the crystal was confirmed, it was cooled to 25 ° C and calcined/aged at the same temperature for 1 hour. After aging, the crystals precipitated were filtered off by filtration under reduced pressure, and the crystals separated by filtration were washed twice with 2.3 mL of acetone (0.8 parts by mass based on 1 part by mass of escitalopram (6)). The obtained white crystals were dried under reduced pressure at 40 ° C for 12 hours to obtain 2.5 g (6.1 mmol) of escitalopram oxalate (7) as white crystals (yield: 85percent, chemical purity: 99.900percent Optical purity: 99.95percent).
85%
Stage #1: at 45℃; for 0.5 h;
Stage #2: at 25℃; for 1 h;
Production of Escitalopram (6) obtained was stirred with a stirring blade,Into a 100 mL three-necked flask equipped with a thermometer,18 mL of acetone (7.9 parts by mass based on 1 part by mass of escitalopram (6)) was added and stirred at 45 ° C. for 30 minutes.After stirring,Oxalic acid 0.7 g (7.9 mmol, 1.1 eq) was added to confirm the precipitation of crystals. After precipitation of crystals was confirmed,It was cooled to 25 ° C.,And aged at the same temperature for 1 hour.After aging,The precipitated crystals were separated by filtration under reduced pressure,With 2.3 mL of acetone (0.8 parts by mass based on 1 part by mass of escitalopram (6)),The filtered crystals were washed twice.The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours,2.5 g (6.1 mmol) of escitalopram (6) oxalate (7) as a white crystal was obtained (yield: 85percent, chemical purity: 99.900percentOptical purity: 99.95percent).
81%
Stage #1: at 45℃; for 0.5 h;
Stage #2: at 25 - 40℃; for 16 h;
2.3 g (7.2 mmol) of the obtained escitalopram (6)Was added to a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 18 mL of acetone was added to dissolve, and the mixture was stirred at 45 ° C. for 30 minutes.After stirring, 0.7 g (7.9 mmol) of oxalic acid was added,The mixture was stirred for 30 minutes,Precipitation of crystals was confirmed.The solution was cooled to 25 ° C. and aged for 1 hour.Filtration under reduced pressure and washing twice with acetone (2.3 mL) was carried out to obtain white crystals, which were dried under reduced pressure at 40 ° C. for 15 hours,(1 S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-5-carbonitrile oxalate(Yield: 81percent, purity 99.49percent, optical purity 99.94percent) as white crystals of white crystals (escitalopram oxalate).
14.5 g at 20 - 40℃; S-Cyanodiol-(+)-DPTTA salt (VI) (30g, 0.056 moles) prepared in Example 19 was charged into a biphasic mixture of dichloromethane (120ml) and water (150ml) at 25-30° C and cooled to 5-15° C. Then aqueous ammonia (8g, 0.112 moles) was added to the biphasic reaction mixture which was stirred further at 5- 15° C for 1 hour. Then the lower organic layer was separated and dried over sodium sulfate (6g) which provided S-Cyanodiol (VII) as a dichloromethane solution. To this obtained dried S-Cyanodiol solution triethyl amine (15.87g, 0.156 moles) followed by p-toluene sulfonyl chloride (11.75g, 0.061 moles) was added at -5 to 5°C and the reaction mass maintained further at the same temperature for 1-2 hours. After maintaining was over the reaction mass was sequentially washed with 10percent brine solution (98 ml), water (96ml) and then dried over sodium sulfate (6g). The obtained organic layer was then concentrated under vacuum at 25-35°C to an oily residue. Traces of dichloromethane was removed by its co-distillation with acetone (18 ml) under vacuum at 25-35° C which provided escitalopram base (VIII) as a yellow colored oil. To this obtained escitalopram base (VIII) acetone (36ml) followed by a solution of oxalic acid dihydrate (7.77g, 0.062moles) in acetone (36ml) was added at 20-30°C. After maintaining the reaction mass for 1-2 hours at 20-40° C the reaction mass was cooled to 0-5°C whereupon the precipitated solid was filtered and washed with acetone (9 ml) wherein crude escitalopram oxalate (IX) was isolated as a white solid. The obtained crude escitalopram oxalate (IX) was then suspended in acetone (60ml) and stirred for 1 hour at 25-40°C. The slurry obtained was then further cooled and maintained at 0-5° C for 1 hour. The solid was then filtered, washed with acetone (9 ml) and finally dried at 50-60° C under vacuum which afforded the title compound as a white solid. Yield: 14.5g (62.44percent by Theory) 1H-NMR in DMSO-d6 at 300MHz (ppm): 1.34-1.35 (m, 2H), 2 20-2 25 (t, 2H), 2.62 (s, 6H), 2.95 - 3.00 (t, 2H), 5.13 - 5.26 (q, 2H), 7.12 - 7.19 (t, 2H), 7.56 - 7.60 (m, 2H), 7.73 - 7.76 (m, 3H) 13C-NMR in DMSO-d6 at 75MHz (ppm): 19.57, 37.42, 42.51, 56.88, 71.61, 90.75, 111.11, 115.53-115.81, 119.25, 126.24, 127.36-127.47, 132.57, 140.31- 140.53, 149.31, 160.18, 163.41, 165.22 FT-IR as such (cm"1): 3022, 2856, 2232, 1666, 1036 Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 325.22a.m.u which corresponds to (M+H)+ peak of freebase of the title compound XRPD Analysis (Observed 2Θ values):7.07, 9.02, 10.89, 13.49, 14.12, 16.39, 17.65, 18.62, 19.22, 19.54, 21.24, 22.82, 24.33, 24.56, 25.46, 27.42, DSC Analysis: Endotherm peaks observed at 152.16°C Purity by HPLC : 99.8percent Chiral Purity: S-Isomer - 99.36percent R-Isomer - 0.64percent

Reference: [1] Patent: US2010/204493, 2010, A1, . Location in patent: Page/Page column 8
[2] Patent: JP2018/90521, 2018, A, . Location in patent: Paragraph 0063
[3] Patent: JP2018/16569, 2018, A, . Location in patent: Paragraph 0016; 0047
[4] Patent: JP2018/16568, 2018, A, . Location in patent: Paragraph 0018; 0065; 0067
[5] Patent: JP2018/12653, 2018, A, . Location in patent: Paragraph 0020; 0050; 0052
[6] Patent: WO2004/85416, 2004, A1, . Location in patent: Page 4
[7] Patent: WO2004/85416, 2004, A1, . Location in patent: Page 4
[8] Patent: WO2004/14821, 2004, A1, . Location in patent: Page 77
[9] Patent: WO2005/77891, 2005, A1, . Location in patent: Page/Page column 27
[10] Patent: WO2003/87081, 2003, A1, . Location in patent: Page/Page column 15
[11] Patent: WO2006/37714, 2006, A2, . Location in patent: Page/Page column 7
[12] Patent: US2007/21499, 2007, A1, . Location in patent: Page/Page column 7-8
[13] Patent: US2009/48336, 2009, A1, . Location in patent: Page/Page column 3
[14] Patent: EP2017271, 2009, A1, . Location in patent: Page/Page column 10
[15] Patent: US2009/99375, 2009, A1, . Location in patent: Page/Page column 5
[16] Journal of Medicinal Chemistry, 2010, vol. 53, # 16, p. 6112 - 6121
[17] Patent: WO2007/12954, 2007, A1, . Location in patent: Page/Page column 10-11
[18] Patent: EP1896439, 2011, B1, . Location in patent: Page/Page column 8
[19] Patent: US2011/92719, 2011, A1, . Location in patent: Page/Page column 6
[20] Patent: WO2017/9866, 2017, A1, . Location in patent: Page/Page column 28; 29
  • 40
  • [ 878007-22-8 ]
  • [ 144-62-7 ]
  • [ 219861-08-2 ]
YieldReaction ConditionsOperation in experiment
64%
Stage #1: at 100℃; for 0.5 h;
85ml ofTetrahydrofuran of (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile (16.35 mmol)To the solution was added 2.02 g of potassium tertiary butoxide 5 CStir for 10 minutes.3.14 g of 2,5-dichloronitrobenzene5 inAdd to the reaction and stir at room temperature for 15 hours,The solvent was evaporated in vacuo,40 ml of water were added,Extracted with toluene,The toluene layer was washed with water and 10percent sodium hydroxide solution and distilled to obtain an oily product,This is purified by column chromatography using silica gel and ethyl acetate.The oily product was dissolved in isopropanol (IPA) at 30 DEG C,2.0 ml of IPA-HCl was added, stirred,The solvent was evaporated under vacuum,Crystallized in IPA (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-chlorophenoxymethyl)benzonitrile hydrochloride was obtained.In 75 ml of (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-chlorophenoxymethyl)benzonitrile hydrochloride(15.06 mmol) 2.71 g of potassium carbonate was added , and the mixture was stirred at 100 for 30 minutes. 225 ml of water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer was concentrated, and then an oxalic acid dihydrate was added to give a product (S) - (+) - 1- [3- (dimethylamino) propyl] -1- (4-Fluorophenyl) -1,3-Dihydro-5-isobenzofurancarbonitrile oxalate is obtained. (Yield: 64percent).
Reference: [1] Patent: KR2017/48878, 2017, A, . Location in patent: Paragraph 0067; 0068
  • 41
  • [ 50-00-0 ]
  • [ 144-62-7 ]
  • [ 219861-08-2 ]
Reference: [1] Patent: WO2005/47274, 2005, A1, . Location in patent: Page/Page column 33
  • 42
  • [ 1073819-95-0 ]
  • [ 144-62-7 ]
  • [ 219861-08-2 ]
Reference: [1] Patent: EP1988086, 2008, A1, . Location in patent: Page/Page column 5
  • 43
  • [ 144-62-7 ]
  • [ 219861-08-2 ]
Reference: [1] Patent: US2007/21499, 2007, A1, . Location in patent: Page/Page column 7-8
[2] Patent: US2007/21499, 2007, A1, . Location in patent: Page/Page column 7-8
[3] Patent: US2007/21499, 2007, A1, . Location in patent: Page/Page column 7-8
  • 44
  • [ 13573-28-9 ]
  • [ 144-62-7 ]
  • [ 1159599-99-1 ]
YieldReaction ConditionsOperation in experiment
51.1%
Stage #1: With magnesium In methanolSonication; Inert atmosphere
Stage #2: for 0.0833333 h; Inert atmosphere
To a solution of 9 (7.5 g, 29.6 mmol) in 500 mL MeOH, magnesium turnings (5.04 g, 207 mmol) were added and reaction mass was sonicated for 1 h. Then solvent was evaporated and 1 L of diethyl ether was added along with sodium sulphate decahydrate (4.21 g, 29.6 mmol) and stirred for 1 h at RT. The reaction mixture was filtered through celite and dried over anhyd. Na2SO4 and then oxalic acid (1.33 g, 14.80 mmol) dissolved in 2 mL EtOH added and stirred for 5 min to get oxalate salt of amine (10) (1.5 g). Yield: 51.1percent; off-white solid; 1H NMR (300 MHz, DMSO-d6) δ (ppm): 4.65 (s, 4H, 2CH2, spiro morpholine), 4.16 (s, 4H, 2CH2, spiro morpholine); LC-MS (ESI + ve) m/z 100.0 [M+H]+.
Reference: [1] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 475 - 487
[2] Patent: WO2017/15106, 2017, A1, . Location in patent: Page/Page column 138; 139
  • 45
  • [ 174-78-7 ]
  • [ 144-62-7 ]
  • [ 1159599-99-1 ]
Reference: [1] Organic Process Research and Development, 2016, vol. 20, # 3, p. 675 - 682
[2] Fitoterapia, 2014, vol. 92, p. 111 - 115
  • 46
  • [ 144-62-7 ]
  • [ 1159599-99-1 ]
Reference: [1] Synthesis (Germany), 2017, vol. 49, # 11, p. 2394 - 2401
  • 47
  • [ 110-91-8 ]
  • [ 1004316-93-1 ]
  • [ 64-17-5 ]
  • [ 144-62-7 ]
  • [ 1247119-36-3 ]
YieldReaction ConditionsOperation in experiment
122 g
Stage #1: With trimethylsilyl bromide In dichloromethane at 0 - 25℃;
Stage #2: at 0 - 25℃; for 17 h;
Stage #3: for 1 h; Reflux
Example 6: Preparation of morpholine thiazole ethyl ester oxalate (salt Formula 2) A stirred mixture of (R)-(+)-a-amino-Y-butyrolactone hydrobromide (92 g) and dichloromethane (500 ml) was cooled to -5 to -8 °C. Carbonyl diimidazole (92 g) was then added to this mixture lot-wise. Triethylamine (45 g) was then added drop-wise with continued stirring until the starting material disappeared. 2-Isopropyl-4-[( - methylamino) methyl] thiazole di-hydrochloride (100 g) and triethylamine (92 g) were then slowly added to the mixture. The reaction mixture was stirred at about at 20-25°C for 15 hours. Water (200 ml) was added, and the organic layer was separated. The organic layer was washed with water (200 ml). The combined aqueous layers were back extracted with dichloromethane (100 ml). The collected the organic layers were then washed with 20percent aqueous citric acid solution (40 g). The combined organic layer was then washed with water (200 ml). The organic layer was concentrated under reduced pressure at about 38-40°C to obtain the crude urea N-methyl-N-[[2-(l-methylethyl)-4- thiazolyl]methyl]-N'-[(3S)-tetrahydro-2-oxo-3-furanyl] (80 g). The solution of urea N-methyl-N-[[2-(l-methylethyl)-4-thiazolyl]methyl]-N'-[(3S)- tetrahydro-2-oxo-3-furanyl] (100 g) dichloromethane (500 ml) was stirred at room temperature and ethanol (100 ml) was added. The reaction mass was cooled to 0-5 °C and trimethylsilyl bromide (183 g) was slowly added drop-wise. The reaction mass temperature was then raised to 19-25 °C and stirred until reaction was complete. The reaction mass was cooled to 0-5 °C and morpholine was added (230 g) drop wise slowly. The temperature was then raised to 19-25 °C and the reaction mass was stirred over a period of 17 hours. The reaction mixture was then filtered to remove morpholine hydrobromide salt. The filter cake was rinsed with dichloromethane. The filtrates were washed with water and the combined organic layer was concentrated under vacuum to dryness to give a residue. The residue was dissolved in acetone (500 ml). Oxalic acid dihydrate (60 g) in acetone (400 ml) was slowly added. The resulting slurry was refluxed for about one hour and cooled to 0-5 °C. The product was filtered and rinsed with acetone (200 ml) and dried under vacuum at 40°C to produce morpholine thiazole ethyl ester oxalate formula 2 as a white to off- white solid (122 g).
52.5 g
Stage #1: With chloro-trimethyl-silane; sodium iodide In dichloromethane at 10 - 30℃; for 6 h; Inert atmosphere
Stage #2: at 0 - 25℃; for 12 h;
Stage #3: at 25 - 60℃; for 0.75 h;
Sodium iodide (88.2 gm) was added to a mixture of (S)-i -((2-isopropylthiazol-4-yl)methyl)- 1 -methyl-3-(2-oxo- tetrahydrothran-3-yl)urea (50 gm), ethanol (60 ml) and dichloromethane (250 ml) at 25-30° C. under nitrogen atmosphere. Cooled the reaction mixture to 10-15° C. and trimethyl silyl chloride (70.3 gm) was slowly added to the reaction mixture at 10-15° C. Raised the temperature of the reaction mixture to 20-25° C. and stirred for 6 irs at the same temperature. Cooled the reaction mixture to 0-5° C. Morpholine (147 ml) was slowly added to the reaction mixture at 0-5° C. and temperature of the reaction mixture was raised to 20-25° C. Stirred the reaction mixture for 12 irs at 20-25° C. Water and dichioromethane were added to the reaction mixture and stirred for 30 minutes. Both the organic and aqueous layers were separated. Water was added to the organic layer and adjusted the pH of the reaction mixture to 6.0 with oxalic acid. Both the organic and aqueous layers were separated and organic layer was dried with sodium sulphate. Distilled off the solvent completely from the organic layer under reduced pressure and codistilled with acetone. Acetone (250 ml) was added to the obtained compound and stirred for 10 minutes at 25-30° C. A solution of Oxalic acid (30 gm) dissolved in acetone (200 ml) was added to the reaction mixture at 25-30° C. Heated the reaction mixture to 55-60° C. and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 25-30° C., further cooled to 0-5° C. and stirred the reaction mixture for 4 irs at 0-5° C. The obtained solid was filtered, washed with acetone. The obtained compound was recrystallized using acetone and dried to get the title compound. Yield: 52.5 gm; M.R.: 142-145° C.
Reference: [1] Patent: WO2015/83066, 2015, A1, . Location in patent: Page/Page column 14
[2] Patent: US2018/30043, 2018, A1, . Location in patent: Paragraph 0169
  • 48
  • [ 110-91-8 ]
  • [ 1051461-77-8 ]
  • [ 144-62-7 ]
  • [ 1247119-36-3 ]
Reference: [1] Patent: US2010/256366, 2010, A1, . Location in patent: Page/Page column 21
  • 49
  • [ 1265919-24-1 ]
  • [ 144-62-7 ]
  • [ 1402149-98-7 ]
Reference: [1] Patent: CN108084145, 2018, A, . Location in patent: Paragraph 0019
  • 50
  • [ 144-62-7 ]
  • [ 1402149-98-7 ]
Reference: [1] Patent: WO2012/138981, 2012, A2, . Location in patent: Page/Page column 41
  • 51
  • [ 1402149-97-6 ]
  • [ 144-62-7 ]
  • [ 1402149-98-7 ]
Reference: [1] Patent: WO2012/138981, 2012, A2, . Location in patent: Page/Page column 42
  • 52
  • [ 1416134-60-5 ]
  • [ 144-62-7 ]
  • [ 1416134-48-9 ]
YieldReaction ConditionsOperation in experiment
65.4%
Stage #1: With sulfuric acid In ethyl acetate at -20 - -15℃; for 1 h;
Stage #2: With sodium tris(acetoxy)borohydride In ethyl acetate at -20 - -15℃; for 5 h;
Stage #3: at 45℃; for 2 h;
To stir,Thermometer in a 2000 ml four-necked flask500 grams of ethyl acetate,110.0 g (0.4 mole) of ethyl 5-benzyloxyiminopiperidine-2S-carboxylate (III2) are added,Maintaining negative 20°C to negative 15°C,201.0 grams of concentrated sulfuric acid (2.0 moles) was added dropwise.After dripping, stir for 1 hour.At negative 20°C,Add 190.0 g (0.9 moles) of sodium triacetoxyborohydride,The reaction was stirred at -20°C to -15°C for 5 hours.Keep the temperature below 0°C,Add 200 grams of water to quench the reaction;Ammonia is neutralized until the system has a pH of 7-8. Layered, withThe organic layer was washed twice with 100 g each time with saturated saline.The organic phase is concentrated to recover the solvent,Then 320 g of ethyl acetate was added to the resulting residue.160 grams of methanol,52.0 g (0.42 mol) of oxalic acid dihydrate,Heat to 45°C,After stirring for 2 hours, cool and filter.The filter cake was washed with 100 g of a mixture of ethyl acetate/methanol (2:1) and washed with 50 g of ethyl acetate. All the filtrates were combined and used in Example 5.The filter cake was vacuum dried to give 96.3 g of a single isomer5R-Benzyloxyaminopiperidine-2S-ethyl formate oxalate, chiral HPLC purity 99.6percent, yield 65.4percent.
Reference: [1] Patent: CN107540600, 2018, A, . Location in patent: Paragraph 0052-0054
[2] Patent: US2012/323010, 2012, A1, . Location in patent: Page/Page column 17-18
  • 53
  • [ 64-17-5 ]
  • [ 1171080-45-7 ]
  • [ 141-52-6 ]
  • [ 144-62-7 ]
  • [ 1416134-48-9 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: at 0℃; for 1 h;
Stage #2: at 35℃;
Example 1fEthyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) was prepared as described below.A slurry of benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) (100 g, 232 mmol) in ethanol (2000 ml) was cooled to 0° C. A solution of sodium ethoxide in ethanol (216 ml, 580 mmol, 21 wt percent solution) was added slowly and the mixture was stirred for 1 h at 0° C. Acetic acid (13.3 ml, 232 mmol) was added and the mixture was concentrated under vacuum below 35° C. to a final volume of 300 ml. Ethyl acetate (700 ml) was added and the mixture was concentrated to 300 ml. This procedure was repeated twice. Water (1800 ml) was added to the mixture followed by aqueous ammonia (variable) until the pH of the aqueous layer was 7.5 to 8. The layers were separated and the aqueous layer was extracted with ethyl acetate (2.x.300 ml). The combined organic layers were washed with water (500 ml) and concentrated to a final volume of 300 ml. The solution was filtered and diluted with ethyl acetate (700 ml) and warmed to 35° C. A solution of oxalic acid dihydrate (30 g, 237 mmol) in acetone (200 ml) was added and the mixture was cooled to room temperature. The solids were isolated by filtration, washed with ethyl acetate and dried under vacuum at 35° C. to obtain ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) as a white solid (80.7 g, 94percent).
Reference: [1] Patent: US2012/323010, 2012, A1, . Location in patent: Page/Page column 17
  • 54
  • [ 1133931-74-4 ]
  • [ 144-62-7 ]
  • [ 1171080-45-7 ]
YieldReaction ConditionsOperation in experiment
69%
Stage #1: With sulfuric acid In ethyl acetate at -20 - -15℃; for 1 h;
Stage #2: With sodium tris(acetoxy)borohydride In ethyl acetate at -20 - -15℃; for 5 h;
Stage #3: at 45℃; for 2 h;
To stir,Thermometer in a 2000 ml four-necked flask500 grams of ethyl acetate,135.0 g (0.4 mole) of benzyl 5-benzyloxyiminopiperidine-2S-carboxylate (III3) are added,Maintaining negative 20°C to negative 15°C,201.0 grams of concentrated sulfuric acid (2.0 moles) was added dropwise.After dripping, stir for 1 hour.At negative 20°C,Add 190.0 g (0.9 moles) of sodium triacetoxyborohydride,The reaction was stirred at -20°C to -15°C for 5 hours.Keep the temperature below 0°C,Add 200 grams of water to quench the reaction;Ammonia is neutralized until the system has a pH of 7-8.The layers were separated and the organic layer was washed twice with 100 g each of saturated saline.The organic phase is concentrated to recover the solvent,Then, 320 g of ethyl acetate and 160 g of methanol were added to the resulting residue.52.0 g (0.42 mol) of oxalic acid dihydrate,After heating to 45°C and stirring for 2 hours,Cool, filter.The cake was washed with 100 g of a mixture of ethyl acetate/methanol (2:1) and washed with 50 g of ethyl acetate.All filtrates were combined for Example 6.The filter cake was dried under vacuum to obtain 118.8 g of the single isomer 5R-benzyloxy aminopiperidine-2S-carboxylic acid benzyl oxalate, the chiral HPLC purity was 99.7percent, and the yield was 69.0percent.
Reference: [1] Patent: CN107540600, 2018, A, . Location in patent: Paragraph 0052-0054
[2] Patent: US2012/323010, 2012, A1, . Location in patent: Page/Page column 14-15
  • 55
  • [ 1133931-68-6 ]
  • [ 144-62-7 ]
  • [ 1171080-45-7 ]
YieldReaction ConditionsOperation in experiment
37.7% at 0 - 45℃; for 6 h; The benzyl (2S)-5-((benzyloxy)amino)piperidine-2-carboxylate solution (50 mL) as obtained in the previous step was heated to 45 °C, 40°C methanol (20 mL) and oxalic aicd (2.4 g, 26.7 mmol) in methanol (5 mL) solution were added, and the system was cooled to 0°C, still stood for 6 h, filtrated, and the filter cake was washed with ethyl acetate (20 mL), added to methanol (25 mL), heated to 80°C, dissolved completely, cooled to 25 °C, still stood for 2h, filtered, and the filter cake was washed with methanol (5 mL), dried to obtain the title compound in white color (4.3 g, yield 37.7 percent).
Reference: [1] Patent: EP3281942, 2018, A1, . Location in patent: Paragraph 0181; 0182
  • 56
  • [ 1133931-74-4 ]
  • [ 144-62-7 ]
  • [ 1171080-45-7 ]
  • [ 1401540-64-4 ]
Reference: [1] Patent: WO2014/135929, 2014, A1, . Location in patent: Page/Page column 6; 8; 9
  • 57
  • [ 1171080-44-6 ]
  • [ 144-62-7 ]
  • [ 1171080-45-7 ]
YieldReaction ConditionsOperation in experiment
0.542 g at 60℃; Example 1
Production of
(2S,5R)-5-benzyloxyamino-piperidine-2-carboxylic acid benzyl ester oxalate
To the above product (0.946 g, 2.78 mmol), ethyl acetate was added to adjust the total weight at 8.63 g.
The obtained mixture was heated up to 60°C, and methanol solution (0.875 g) containing oxalic acid (0.228 g, 2.53 mmol) was added for 5 minutes.
The obtained reaction mixture was cooled down to room temperature, and the precipitate was filtrated.
The precipitate was washed with ethyl acetate (2 ml) for 3 times, and dried under reduced pressure to obtain (2S,5R)-5-benzyloxyamino-piperidine-2-carboxylic acid benzyl ester oxalate (0.903 g, 2.10 mmol, yield: 76percent).
The diastereo ratio of this solid was (2S,5R)/(2S,5S)=99.3/0.7 (98.6 percent de).
To the above solid (0.597 g), methanol (3.0 g) was added, and the obtained mixture was stirred for 1 hour at 60°C.
The reaction mixture was cooled down to room temperature, and the precipitate was filtrated.
The precipitate was washed with methanol (2 ml) for 2 times, and dried under reduced pressure to obtain (2S,5R)-5-benzyloxyamino-piperidine-2-carboxylic acid benzyl ester oxalate (0.542 g).
The diastereo ratio of this solid was (2S,5R)/(2S,5S)=99.93/0.07 (99.9 percent de).
Reference: [1] Patent: EP2650281, 2013, A1, . Location in patent: Paragraph 0071; 0072
  • 58
  • [ 144-62-7 ]
  • [ 1171080-45-7 ]
  • [ 1401540-64-4 ]
YieldReaction ConditionsOperation in experiment
74.5 % de for 2 h; Example 10
purification of (2S,5R)-5-benzyloxyamino-piperidine-2-carboxylic acid benzyl ester oxalate
To 5-benzyloxyamino-piperidine-2-carboxylic acid benzyl ester (0.806 g, 2.37 mmol) having diastereo ratio of (2S,5R)/(2S,5S)=77.4/22.6 (54.8 percent de), ethanol (4.75 g) and oxalic acid (0.217 g, 2.41 mmol) were added, and the obtained mixture was stirred for 2 hours.
The precipitate was filtrated, washed with ethanol (0.80 g) for 2 times, and dried at 50°C under reduced pressure to obtain 5-benzyloxyamino-piperidine-2-carboxylic acid benzyl ester oxalate (0.947g, 2.20mmol), yield: 93percent).
The diastereo ratio of this solid was (2S,5R)/(2S,5S)=87.2/12.8 (74.5 percent de).
Reference: [1] Patent: EP2650281, 2013, A1, . Location in patent: Paragraph 0081
  • 59
  • [ 365998-36-3 ]
  • [ 144-62-7 ]
  • [ 1353893-22-7 ]
YieldReaction ConditionsOperation in experiment
94.1% With water In acetonitrile at 50 - 75℃; for 6 h; Acetonitrile (595 ml) and water (43 ml) were added to compound (1a) (45.61 g, 0.16 mol), and the mixture was heated to an internal temperature of 50 to 70°C with stirring. To this solution, a solution prepared in advance from anhydrous oxalic acid (18.87 g, 0.21 mol) and acetonitrile (255 ml) was added dropwise over 1 hour with the internal temperature kept at 50 to 70°C. After completion of the dropwise addition, the reaction mixture was stirred at 50 to 70°C for 5 hours and then cooled to an internal temperature of 20 to 40°C. The precipitated crystals were collected, washed with acetonitrile, and then dried to obtain monohydrate crystals of the compound represented by formula (1b) (59.14 g, 94.1percent) The powder x-ray diffraction diagram of the obtained monohydrate crystals represented by formula (1b) and the results of thermal analysis thereon were the same as those of the Form 2 monohydrate crystals of Example 2 shown in Figures 4 and 8.
Reference: [1] Patent: EP2589590, 2013, A1, . Location in patent: Paragraph 0163-0166
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