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[ CAS No. 110-17-8 ] {[proInfo.proName]}

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Chemical Structure| 110-17-8
Chemical Structure| 110-17-8
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Product Details of [ 110-17-8 ]

CAS No. :110-17-8 MDL No. :MFCD00002700
Formula : C4H4O4 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 116.07 Pubchem ID :-
Synonyms :
2-Butenedioic acid;Trans-Butenedioic acid;Tumaric acid;Kyselina fumarova;Fumarate;Lichenic acid;Donitic acid;Boletic acid;Allomaleic acid

Calculated chemistry of [ 110-17-8 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.0
Num. rotatable bonds : 2
Num. H-bond acceptors : 4.0
Num. H-bond donors : 2.0
Molar Refractivity : 24.41
TPSA : 74.6 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.25 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.32
Log Po/w (XLOGP3) : -0.34
Log Po/w (WLOGP) : -0.29
Log Po/w (MLOGP) : -0.64
Log Po/w (SILICOS-IT) : -0.81
Consensus Log Po/w : -0.35

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.85

Water Solubility

Log S (ESOL) : -0.21
Solubility : 71.0 mg/ml ; 0.612 mol/l
Class : Very soluble
Log S (Ali) : -0.76
Solubility : 19.9 mg/ml ; 0.172 mol/l
Class : Very soluble
Log S (SILICOS-IT) : 1.34
Solubility : 2520.0 mg/ml ; 21.7 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.8

Safety of [ 110-17-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P305+P351+P338 UN#:N/A
Hazard Statements:H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 110-17-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 110-17-8 ]
  • Downstream synthetic route of [ 110-17-8 ]

[ 110-17-8 ] Synthesis Path-Upstream   1~31

  • 1
  • [ 97-67-6 ]
  • [ 500-05-0 ]
  • [ 110-17-8 ]
Reference: [1] RSC Advances, 2014, vol. 4, # 86, p. 45657 - 45664
  • 2
  • [ 64-17-5 ]
  • [ 110-17-8 ]
  • [ 2459-05-4 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1872, vol. 164, p. 294
[2] Chemische Berichte, 1897, vol. 30, p. 2651
  • 3
  • [ 82639-48-3 ]
  • [ 623-91-6 ]
  • [ 2459-05-4 ]
  • [ 82639-46-1 ]
  • [ 110-17-8 ]
  • [ 123-25-1 ]
Reference: [1] Journal of the American Chemical Society, 1986, vol. 108, # 7, p. 1650 - 1659
  • 4
  • [ 64-17-5 ]
  • [ 110-17-8 ]
  • [ 2459-05-4 ]
  • [ 623-91-6 ]
Reference: [1] Journal of the Chemical Society, 1885, vol. 47, p. 858[2] Journal of the Chemical Society, 1887, vol. 51, p. 627
[3] Justus Liebigs Annalen der Chemie, 1872, vol. 164, p. 294
  • 5
  • [ 542-92-7 ]
  • [ 110-17-8 ]
  • [ 3813-52-3 ]
Reference: [1] Journal of the American Chemical Society, 1981, vol. 103, # 14, p. 4145 - 4154
  • 6
  • [ 311-28-4 ]
  • [ 110-17-8 ]
  • [ 2915-53-9 ]
Reference: [1] Patent: US4434091, 1984, A,
  • 7
  • [ 110-17-8 ]
  • [ 71-36-3 ]
  • [ 105-75-9 ]
YieldReaction ConditionsOperation in experiment
94% at 120℃; for 16 h; Fumaric acid (20.0 g, 172 mmol) was dissolved in n-butanol (250 mL). (0170) Concentrated sulfuric acid (2.5 mL) was then added dropwise. After stirring at 120 °C for 16 hours, the residual n-butanol was removed in vacuo. Ethyl acetate (100 mL) was then added to the residue, and the solution was washed with saturated sodium bicarbonate (20 mL) solution twice, and deionized water (20 mL) once. The organic layer was then dried over MgS04, filtered and concentrated under reduced pressure to provide a clear, colorless, oily liquid (36.8 g, 94percent) after distillation at 100 C° (40 mbar). 1H NMR (400 MHz, CDCI3): δ 6.85 (s, 2H), 4.20 (t, J = 6.6 Hz, 4H), 1 .63-1 .70 (m, 4H), 1 .36-1 .46 (m, 4H), 0.95 (t, J = 7.4 Hz, 6H). Spectral data are consistent with published values.26
Reference: [1] Journal of the American Chemical Society, 2014, vol. 136, # 28, p. 10116 - 10123
[2] Patent: WO2015/168809, 2015, A1, . Location in patent: Page/Page column 23; 24
[3] Patent: US2257384, 1939, ,
[4] Journal of the American Chemical Society, 1953, vol. 75, p. 4101
[5] Journal of the American Chemical Society, 1953, vol. 75, p. 4101
  • 8
  • [ 592-84-7 ]
  • [ 110-17-8 ]
  • [ 16062-88-7 ]
  • [ 105-75-9 ]
Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 20, p. 3023 - 3027
  • 9
  • [ 591-50-4 ]
  • [ 110-17-8 ]
  • [ 16110-98-8 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 4, p. 1099 - 1107
  • 10
  • [ 110-17-8 ]
  • [ 74-89-5 ]
  • [ 4226-18-0 ]
Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 5, p. 649 - 655
[2] Journal of the Chemical Society, Chemical Communications, 1994, # 13, p. 1601 - 1602
  • 11
  • [ 110-17-8 ]
  • [ 4226-18-0 ]
Reference: [1] Chemistry - A European Journal, 2008, vol. 14, # 32, p. 10094 - 10100
  • 12
  • [ 110-85-0 ]
  • [ 110-17-8 ]
  • [ 325145-35-5 ]
Reference: [1] Patent: US6638936, 2003, B1,
  • 13
  • [ 110-17-8 ]
  • [ 111974-69-7 ]
  • [ 111974-72-2 ]
YieldReaction ConditionsOperation in experiment
99% at 20℃; for 1.08333 h; Heating / reflux Example 2; Preparation of quetiapine hemifumarate; A suspension of 1.62 g (0.014 mol) of fumaric acid in 100 ml of ethyl acetate is brought to the boil. At this temperature, 100 ml of a toluene solution containing 10.77 g (0.028 mol) of pure quetiapine base is added, and the reaction mixture is allowed to boil for about 5 minutes.During this period a crystalline product starts to precipitate, which is then cooled to ca. 20 0C and is stirred at this temperature for 60 minutes. After being sucked off and dried, approximately 12.28 g (0.028 mol) of quetiapine hemifumarate is obtained, i.e. 99 percent of the theory, having the HPLC purity 99.76 percent, and melting point 175.7 0C.
98%
Stage #1: With pyrographite In methanol for 0.5 h; Reflux
Stage #2: at 40℃;
To a 250 mL round-bottom flask containing quetiapine-free base (16.6 g, 43 mmol)were added MeOH (70 mL) and activated carbon (1 g) for decolorization. The resultingsuspension was heated at reflux for 30 min, then was filtered and allowed to cool to 40°C.Once at this temperature, solid fumaric acid was added slowly to the solution until thepH was adjusted to 4–5. Quetiapine hemifumarate precipitated after cooling the reactionmixture to 0–5°C. The resulting solid was filtered and dried to yield (16.5 g, 98percent) ofquetiapine hemifumarate as a white powder, mp = 173°C
94% at 10 - 25℃; for 1.58333 h; Heating / reflux LL- 4-[2-(2-HYDROXYETHOXY) ETHYL]-1- piperazinyl) dibenzo [b, f] [1.4] thiazepine hemifumarate 94.4 g (0.81 mols) of fumaric acid at 20-25°C are added to a stirred solution of the above residue of 0.580 (1.52 mols) of ll- (4- [2- (2-hydroxyethoxy) ethyl]-l- piperazinyl) dibenzo [b, f] [1.4] thiazepine in 3. 06 L of methanol. A solid is precipitated after 5-15 min. Stirring is maintained at 20-25°C for 30 min. The suspension is heated again at reflux for 5 min. and then cooled to 10- 15°C. The suspension is stirred at this temperature for 1 hour. The solid is filtered and washed with cold methanol (2 x 0.5 L) and then dried under vacuum at 45°C, yielding 0.63 kg (94percent) of the product of the title of high purity (> 99. 7percent).
81% for 2 h; Heating / reflux To a solution of quetiapine (Vl) (82.5 g, 215 mmol) in ethanol (660 ml) there was added fumaric acid (12.49 g, 108 mmol) and the mixture was heated under reflux for 2 hours in an inert atmosphere. A precipitate out of the solution formed shortly after starting the heating. After cooling the mixture to O0C, it was filtered, washed with ethanol (250 ml, 00C) and dried at reduced pressure to give quetiapine hemifumarate (77.4 g, 81percent) as a crystalline white solid.Melting point: 173-175°C EPO <DP n="17"/>IR 3315, 2944, 2869, 1600, 1572, 1459, 1413, 1335, 1306, 1130, 1082, 1064, 989, 794 and 768 cm"1.1H NMR (400 MHz, CDCI3/CD3OD) 7.52 (d, J = 7.6 Hz, 1 H), 7.40 (dd, J = 8.0 and 1.6 Hz, 1 H), 7.38-7.31 (m, 2 H), 7.19 (m, 1 H), 7.08 (dd, J = 8.0 and 1.2 Hz, 1 H), 6.92 (m, 1 H), 6.78 (s, 1 H), 3.87 (s, 4 H), 3.73 (m, 2 H), 3.67 (m, 2 H), 3.55 (m, 2 H), 3.03 (brm, 2 H) and 2.94-2.89 (m, 4 H).13C NMR (101 MHz, CDCI3/CD3OD) 170.1 , 160.3, 148.3, 139.8, 135.1 , 133.4, 132.11 , 132.09, 131.1 , 129.1 , 128.8, 128.5, 127.9, 125.1 , 123.3, 72.5, 65.9, 61.0, 57.2, 52.1 and 45.1.m/z (Cl, NH3) 384 (MH+, 100percent).
64.5% at 0℃; for 1.58333 h; Heating / reflux Example 3; Preparation of quetiapine hemifumarate; 0.8 g (0.007 mol) of fumaric acid is suspended in a solution of 30 ml of acetone and 0.3 ml of water. The suspension is brought to the boil, and 30 ml of a toluene solution containing 5.38 g (0.014 mol) of pure quetiapine base is added. The solution is refluxed for approximately5 minutes, then cooled to a temperature of 0 to 5 °C and stirred at this temperature for60 minutes. After being sucked off and dried, 5.7 g (0.013 mol) of quetiapine hemifumarate is obtained, i.e. 99.6 percent of the theory, having the HPLC purity 99.87 percent, and melting point175.9 0C.; Example 4; Preparation of quetiapine hemifumarate; 0.65 g (0.006 mol) of fumaric acid is suspended in a solution of 25 ml of acetone and 5 ml of water, the solution is brought to the boil, and 25 ml of a toluene solution containing 4.5 g (0.012 mol) of pure quetiapine base is added. The solution is refluxed for approximately5 minutes and then cooled to a temperature of 0 to 5 0C, at which crystals start to precipitate. It is stirred at this temperature for 90 minutes. After being sucked off and dried, 3.8 g(0.009 mol) of quetiapine hemifumarate is obtained, i.e. 64.5 percent of the theory, having theHPLC purity 99.82 percent, and melting point 172 °C.
53.2% at 20℃; for 1.08333 - 1.15 h; Heating / reflux Example 1; Preparation of quetiapine hemifumarate; A suspension of 1.62 g (0.014 mol) of fumaric acid in 100 ml of acetone is brought to the boil.100 ml of a toluene solution containing 10.77 g (0.028 mol) of pure quetiapine base is added to the boiling suspension, and the reaction mixture is heated to the boil for another 5 minutes. The precipitated crystalline product is cooled to approximately 20 °C, and the reaction mixture is stirred for another 60 minutes. The precipitated crystalline quetiapine hemifumarate is filtered, washed, and dried.The yield is 12.28 g (0.028 mol), i.e. 99 percent of the theory, having the HPLC purity 99.86 percent, and melting point 175.8 0C.; Example 9; Preparation of quetiapine hemifumarate; A suspension of 1.2 g (0.0103 mol) of fumaric acid in 10 ml of acetone is brought to the boil. 40 ml of a toluene solution containing 7.53 g (0.0196 mol) of pure quetiapine base is added to the boiling suspension. An oily suspension is formed, which crystallizes under boil during 3 to4 minutes. Reflux is maintained for 5 minutes and then the suspension is cooled to 20 °C and <n="9"/>stirred for 60 minutes. Precipitated crystalline quetiapine hemifumarate is isolated by filtration and dried.Yield: 4.6 g (0.0104 mol) of crystalline quetiapine hemifumarate, i.e. 53.2 percent of the theory, having the HPLC purity 99.6 percent, and melting point 175.1 °C.; Example 10; Preparation of quetiapine hemifumarate; A suspension of 0.8 g (0.007 mol) of fumaric acid in 120 ml of acetone is brought to the boil.30 ml of a toluene solution containing 5.06 g (0.0132 mol) of pure quetiapine base is added to the boiling suspension and the reaction mixture is stirred under boil for another 5 minutes. The precipitated crystalline product is cooled to approximately 20 °C and stirred for another 60 minutes. Precipitated crystalline quetiapine hemifumarate is isolated by filtration, washed and dried.Yield: 5.77 g (0.0131 mol) of crystalline quetiapine hemifumarate, i.e. 99.0 percent of the theory, having the HPLC purity 99.85 percent, and melting point 175.7 0C.
130 g for 1 h; Reflux With stirrer, condenser,Add 100 g (0.40 mol) to the thermometer's round bottom reaction flask11-Chloro-diphenylhydrazine [b,f][(1,4)thiazepine and 1L toluene,110 g (0.44 mol) of 1-[2-(2-hydroxyethoxy)ethyl]piperazine hydrochloride are added under stirring at room temperature.127 g (1.2 mol) of anhydrous sodium carbonate and 6 g (0.04 mol) of sodium iodide were added and the reaction mixture was heated at reflux for 12 hours.Only 1percent of the starting material is left. Cool the reaction to room temperature and mix with 2L 1N hydrochloric acid.A solution with a pH of 1-2 is obtained, an aqueous layer is separated, 1L of toluene is added, sodium carbonate is added to neutralize, and the liquid is separated.The aqueous layer was extracted twice with 1 L of toluene; the organic phases were combined, washed with water, and concentrated to give 120 g of an oil.The HPLC content was 98.5percent, showing 1percent excess piperazine starting material.The above oil was dissolved in 300 mL of isopropanol and 25 g (0.21 mol) of fumaric acid was added.After heating and refluxing for 1 hour, the solution was completely dissolved, cooled and allowed to stand. After suction filtration, 130 g of quetiapine fumarate was obtained.Content 99.5percent, single impurity less than 0.1percent; total yield 84percent.

Reference: [1] Patent: WO2008/3270, 2008, A1, . Location in patent: Page/Page column 5
[2] Phosphorus, Sulfur and Silicon and the Related Elements, 2015, vol. 190, # 7, p. 1029 - 1034
[3] Patent: WO2005/14590, 2005, A2, . Location in patent: Page/Page column 16; 17
[4] Patent: CN106243061, 2016, A, . Location in patent: Paragraph 0058
[5] Patent: WO2006/94549, 2006, A1, . Location in patent: Page/Page column 15-16; scheme 5
[6] Patent: WO2008/3270, 2008, A1, . Location in patent: Page/Page column 6
[7] Patent: WO2008/3270, 2008, A1, . Location in patent: Page/Page column 5; 7-8
[8] Patent: WO2006/77602, 2006, A1, . Location in patent: Page/Page column 6-7
[9] Patent: WO2006/113425, 2006, A1, . Location in patent: Page/Page column 18; 19; 20-21
[10] Patent: US2009/76262, 2009, A1, . Location in patent: Page/Page column 3; 7-9
[11] Patent: WO2009/95529, 2009, A1, . Location in patent: Page/Page column 10
[12] Patent: CN107857742, 2018, A, . Location in patent: Paragraph 0030; 0032
  • 14
  • [ 628-89-7 ]
  • [ 110-17-8 ]
  • [ 111974-72-2 ]
Reference: [1] Patent: WO2010/100623, 2010, A1, . Location in patent: Page/Page column 24-25
  • 15
  • [ 110-17-8 ]
  • [ 111974-72-2 ]
Reference: [1] Patent: WO2007/48870, 2007, A1, . Location in patent: Page/Page column 6
  • 16
  • [ 13349-82-1 ]
  • [ 1176987-11-3 ]
  • [ 110-17-8 ]
  • [ 111974-72-2 ]
YieldReaction ConditionsOperation in experiment
83%
Stage #1: at 172 - 176℃; for 5 h;
Stage #2: at 20 - 65℃;
Stage #3: at 4 - 20℃;
Dibenzo[b,fJ[l,4]thiazepin-l l-ylamine hydrochloride (15.0 g, assay 99percent) and 1- [2-(hydroxyethoxy)-ethyl]piperazine (HEEP) (70.0 g) were heated with stirring at 172-176 0C for 5 h under continuous slow flow of argon.The reaction mixture was cooled to room temperature and diluted with water (180 ml). The resulting mixture was warmed to 65 0C and extracted three times with hot toluene (110, 60 and 60ml). The combined organic phases were evaporated to dryness under reduced pressure to obtain 22.4 g of thick oil. The oil was dissolved into hot isopropanol (50 ml) and fumaric acid (3.05 g) dissolved in hot isopropanol (60 ml) was added. The mixture was cooled to room temperature and left at 4 0C overnight. The solid formed was filtered off and dried to obtain 21.95 g of quetiapine hemifumarate (yield 83percent, <n="13"/>assay 95percent). Crystallization from isopropanol (~1.4 L) afforded 20.7 g of quetiapine hemifumarate (recovery 95percent, assay 98 percent,). M.p.172-174 0C.Solid K2CO3 (90 g) was added to the aqueous phase with stirring. The temperature of the solution increased to 500C and crude HEEP as an upper layer was formed. It was separated and purified by distillation. Water was removed under reduced pressure (10 mbar at room temperature) and HEEP was distilled under reduced pressure (134-1360C/ 4 mbar) to give a colourless liquid (50,89 g, assay 99.3percent).
79%
Stage #1: at 173 - 175℃; for 5 h;
Stage #2: With potassium carbonate In water at 20 - 75℃;
Stage #3: at 4 - 20℃;
Dibenzo[b,f][l,4]thiazepin-l l-ylamine hydrochloride (25.0 g, assay 99+percent) and l-[2-(hydroxyethoxy)-ethyl]piperazine (HEEP) (116.0 g) were heated with stirring at 173-175 0C for 5 h in a continuous slow flow of argon. The reaction mixture was cooled to room temperature and diluted with water (465 ml). After K2CO3 (6.56 g) was added it was warmed to 70 0C and extracted two times with hot (70-75 0C) toluene.The combined organic phases were evaporated to dryness under reduced pressure to obtain 35.1 g of thick oil. Fumaric acid (4.78 g) dissolved in hot isopropanol (85 ml) was added to the oil dissolved in hot isopropanol (85 ml). The mixture was cooled to room temperature and left at 4° C overnight. The solid formed was filtered off and dried to obtain 34.40 g (assay 97percent, yield 79percent) of quetiapine hemifumarate. Re-crystallization from isopropanol (1.4 L) afforded 30.7 g (assay 99percent, recovery 91 percent,) of quetiapine hemifumarate. M.p.172-173 0C The aqueous phase was reduced in volume (-80percent) by evaporation of water under reduced pressure (60 °C/60 mbar). The residue was distilled at room temperature and 10 mbar after the rest of water was removed. Two fractions of l-[2-(hydroxyethoxy)-ethyl]piperazine (HEEP) were collected: at 168-170 °C/20 mbar (15.88 g ) and 174 °C/25 mbar (74.68 g). The total recovery of HEEP was 90percent.
Reference: [1] Patent: WO2009/95529, 2009, A1, . Location in patent: Page/Page column 11-12
[2] Patent: WO2009/95529, 2009, A1, . Location in patent: Page/Page column 10-11
  • 17
  • [ 628-89-7 ]
  • [ 110-17-8 ]
  • [ 111974-72-2 ]
Reference: [1] Patent: US2012/71649, 2012, A1, . Location in patent: Page/Page column 10
  • 18
  • [ 13349-82-1 ]
  • [ 13745-86-3 ]
  • [ 110-17-8 ]
  • [ 111974-72-2 ]
Reference: [1] Organic Process Research and Development, 2009, vol. 13, # 4, p. 792 - 797
  • 19
  • [ 753475-15-9 ]
  • [ 628-89-7 ]
  • [ 110-17-8 ]
  • [ 111974-72-2 ]
Reference: [1] Organic Process Research and Development, 2009, vol. 13, # 4, p. 792 - 797
  • 20
  • [ 110-17-8 ]
  • [ 73573-87-2 ]
  • [ 43229-80-7 ]
Reference: [1] Organic Process Research and Development, 1998, vol. 2, # 2, p. 96 - 99
  • 21
  • [ 110-85-0 ]
  • [ 491-30-5 ]
  • [ 110-17-8 ]
  • [ 126653-00-7 ]
Reference: [1] Patent: US4950670, 1990, A,
  • 22
  • [ 35180-01-9 ]
  • [ 110-17-8 ]
  • [ 147127-20-6 ]
  • [ 202138-50-9 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With triethylamine In 1-methyl-pyrrolidin-2-one at 63℃; for 0.5 h;
Stage #2: at 63℃; for 4 h;
Stage #3: at 50℃; for 0.5 h;
In a tenofovir (PMPA) 4.0g prepared in Example 1 was added to the kettle and N- methylpyrrolidone 15 and triethylamine 5.8. The reaction solution was heated to about 63 and stirred for 30 minutes In the chloromethyl isopropyl carbonate 10gAnd then stirred for 4 hours at this temperature. After cooling the reaction solution to room temperature and again it cooled to 5°C ,Below 15°C cold water were added to maintain 25ml. At 15°C stirred for one hour, And extracted twice with methylene chloride 15ml.After washing twice, the organic layer was then partitioned with water 10ml and the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the remaining filtrate tenofovir disoproxil (TD) as an oil.The tenofovir disoproxil (TD) of the oil phase Isopropyl alcohol 35ml And 1.6g of fumaric acid Added and the temperature was raised to about 50°C Dong was completely dissolved for 30 minutes.Then slowly cooled to about 25 the reaction solution was cooled, dissolved again in 3 was stirred for 4 hours and kept at this temperature.Crystals were filtered and washed with isopropyl alcohol and then dried in vacuo at about 40 10 desired compound of tenofovir disoproxil fumarate (TDF), 4.7g (yield: 53percent) was obtained.The obtained tenofovir disoproxil fumarate (TDF) in 4.7g In the 40ml and isopropyl alcohol and heated to about 50°C Open completely dissolved during 30 minutes.Then slowly cooled to about 25°C the reaction solution was cooled, dissolved again in 3°C kept at said temperature and stirred for 4 hours.Crystals were filtered, washed with isopropyl alcohol 100 mland vacuum-dried at about 40°C tenofovir disoproxil fumarate (TDF), 4.3g (Yield: 90percent) of the crystal form was obtained.
63.6%
Stage #1: With tetrabutylammomium bromide; triethylamine In 1-methyl-pyrrolidin-2-one; toluene at 45 - 55℃; for 5 h;
Stage #2: at 50 - 55℃; for 2 h;
25 g of the terpovorin anhydride obtained in the above example was dissolved in 100 ml of N-methyl-2-pyrrolidinone (NMP)Toluene (50 ml) was added and distilled under reduced pressure at 60 ° C to remove moisture. 50 ml of toluene was further added to distill once more.The reaction solution was cooled to 35 DEG C, and 35.2 g (4 equiv.) Of triethylamine was added thereto to produce crystals. However, homogenization was suspended with stirring, 28 g (1.0 Equiv.) Of tetrabutylammonium bromide was added RTI ID = 0.0 & gt; 45 C. & lt; / RTI & gt;To this was added 66.4 g (5.0 Equiv.) Of chloromethylisopropyl carbonate and stirring was continued at 45 to 55 .After 5 hours, the progress of the reaction was monitored by TLC and HPLC. When the reaction was completed and the viscous liquid turned transparent red, it was cooled to room temperature, 150 ml of cyclohexane was added thereto,The supernatant was removed with a vacuum syringe tube and again washed with 100 ml of cyclohexane to remove.300 ml of ethyl acetate and 100 ml of cold water were added to the reaction layer and the mixture was stirred to remove the aqueous layer. The aqueous layer was washed twice with 50 ml of ethyl acetate and added to the undiluted solution.The organic layer was washed with 50 ml of cold water and 50 ml of a saturated aqueous solution of sodium chloride, dehydrated with magnesium sulfate, and then vacuum-dried to obtain 53 g of crystalline sludge, Tenofovir disoproxil.The product was further cooled at a lower temperature for crystallization, and the content was analyzed by HPLC (purity 85percent, actual amount 45 g compared to area, yield 96percent).(0.087 mol) of terpovorbidisopropylsilane crystals were dissolved in 120 ml of isopropyl alcohol, 12.5 g (0.107 mol, 1.2 Equiv.) Of fumaric acid was added, and the mixture was stirred at 50 to 55 ° C for 2 hours .The reaction solution was cooled to 3 to 5 , and the resulting crystals were sufficiently stirred and then filtered.The crystals were suspended in 250 ml of ethyl acetate and stirred for 1 hour. The reaction solution was warmed to 10 DEG C or lower, filtered and washed. The crystals obtained in this way were vacuum-dried at 40 DEG C to obtain 35 g of terpovorbidisoproxyl fumarate (HPLC area Purity 98.5percent, yield 63.6percent).
55 g
Stage #1: With triethylamine In cyclohexane at 80 - 85℃; for 2 h;
Stage #2: With triethylamine In 1-methyl-pyrrolidin-2-one at 50 - 55℃; for 4 h;
Stage #3: at 50 - 55℃; for 0.833333 h;
Example 9 Preparation of Tenofovir Disoproxil Fumarate [0092] To a clean 3-necked 1 L round bottom flask equipped with a mechanical stirrer, thermometer socket, addition funnel and dean-stark apparatus was charged cyclohexane (400 ml) and tenofovir (50 gms, obtained from example 1) and triethyl amine (34 gms) at temperature 20° C. to 35° C. Heated to 80° C. to 85° C. and stirred for 2 hours and simultaneously removed water liberated. The solvent was removed completely from the reaction mixture by distillation under vacuum at below 65° C. and to the obtained residue N-methyl pyrrolidinone (150 ml) and triethyl amine (34 gms) were charged at 25° C. to 30° C. Heated to 50° C. to 55° C. and chloromethyl isopropyl carbonate (125 gms) was added at same temperature and stirred for 4 hours. After completion of the reaction, the reaction mass was cooled to 20° C. to 25° C. and washed with cyclohexane (200 ml). Methylene chloride (500 ml) was charged into the organic layer and stirred for 1 hour at 10° C. to 15° C. Filtered the salts formed and washed the filtrate with water (500 ml), separated the layers and charged water (500 ml) to the organic layer. Adjusted pH to 6.5 to 7.5 with 10percent ammonia solution and separated the organic layer from the aqueous layer. The solvent was removed from the organic layer under vacuum at below 35° C. to obtain oily product and then the oily product was diluted with isopropanol (150 ml). [0093] In a clean another 3-necked 1 L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged isopropanol (350 ml) and Fumaric acid (19 gms). Heated to 50° C. to 55° C. and stirred for 20 minutes and above obtained oily product solution was added at 50° C. to 55° C. Stirred for 30 minutes at this temperature and cooled to 0° C. to 5° C. Filtered the product and washed with chilled isopropanol (75 ml). The wet product was dried at 35° C. to 40° C. under reduced pressure to provide the title compound as crude (80 gms). [0094] In another clean 3-necked 1 L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged ethyl acetate (450 ml) and crude product (80 gms) at temperature 10° C. to 15° C. Stirred the slurry for 1 hour and filtered the product and washed with chilled ethyl acetate (50 ml). The wet product was dried at 35° C. to 40° C. for 6 hours under reduced pressure to provide the title compound. [0095] Yield: 55 gms. [0096] HPLC purity: 98.9percent
35 g
Stage #1: at 60℃;
Stage #2: at 45 - 55℃; for 5 h;
Stage #3: at 50 - 55℃; for 2 h;
25 g of the anhydrous tenofovir obtained in the Example was added to 100 ml of n-methyl-2-pyrrolidinone (NMP) and 50 ml of toluene, and the resultant solution was distilled under reduced pressure at 60° C. and removed of water. 50 ml of toluene was further added and distillation was performed. The reactant solution was cooled down to 35° C., and 35.2 g (4 eq.) of triethylamine was added to form crystals. Agitation was continued to make a homogeneous suspension. 28 g (1.0 eq.) of tetrabutylammonium bromide was added, and the resultant solution was heated up to 45° C. 66.4 g (5.0 eq.) of chloromethyl isopropyl carbonate was added to the solution, which was continuously stirred at 45-55° C. In 5 hours of the reaction, TLC and HPLC were used to estimate the progress of the reaction, and the reaction was terminated. As the sticky solution became clear and reddish, it was cooled down to the room temperature, mixed with 150 ml of cyclohexane, and vigorously stirred. The solution was removed of the supernatant using a low-pressure pipette and washed with 100 ml of cyclohexane. 300 ml of ethyl acetate and 100 ml of cold water were added to the reactant layer, which was then stirred and removed of the aqueous layer. The aqueous layer thus obtained was washed twice with 50 ml of ethyl acetate and combined with the crude solution. The organic layer was washed with 50 ml of cold water and 50 ml of saturated saline solution, dehydrated with magnesium sulfate and then isolated under reduced pressure to yield 53 g of tenofovir disoproxil in the form of crystalline sludge. The sludge was further cooled down to the lower temperature to form crystals and then subjected to quantitative analysis through HPLC (purity 85percent, actual amount per area 45 g, yield 96percent).[Synthesis Method for Tenofovir Disoproxil Fumarate (Teno-DF]53 g (actual 45 g) (0.087 mol) of tenofovir disoproxil coarse crystals were dissolved in 120 ml of isopropyl alcohol, and 12.5 g (0.107 mol, 1.2 eq.) of fumaric acid was added. The resultant solution was stirred at 50 to 55° C. for 2 hours and sufficiently cooled down to 3 to 5° C. to form crystals. After sufficient agitation, the crystals were filtered out and suspended with 250 ml of ethyl acetate. After one-hour agitation, the reactant solution was cooled down to 10° C. or below, filtered and washed. The crystals thus obtained were dried under vacuum at 40° C. to yield 35 g of tenofovir disoproxil fumarate (HPLC area purity 98.5percent, yield 63.6percent).
72 g
Stage #1: With triethylamine In 1-methyl-pyrrolidin-2-one at 20 - 30℃; for 0.5 h; Inert atmosphere
Stage #2: at 60 - 80℃; Inert atmosphere
Stage #3: at 40℃; Inert atmosphere
Diesterification reaction: Under a nitrogen atmosphere, 100 g Tenofovir (PMPA) And 300ml N-methylpyrrolidone (NMP), the control temperature at 25 ~ 30 , shaking 30min, To dissolve, and then add 106g triethylamine (TEA), 20 ~ 30 shaking 30min until uniform; The above mixture was warmed to 60 ~ 65 , and stirred, In 15 ~ 20min rapid dropping 266g chloromethyl isopropyl carbonate (CMIC) Then warmed to 75 ~ 80 , shaking reaction 60 ~ 70min, When TLC real-time monitoring of the basic reaction of the reaction material completely (3percent or less), and monoester content of 15percent or less, When the area of the main peak of the product is more than 80percent, the double esterification reaction is complete; Then the reaction system first use water bath cooling 5min, After using ice-water bath in 10-15 min the reaction system rapidly reduced to 10-15 ;Extraction and Separation: To the reaction system in step (1) was added 600 ml of ethyl acetate (EA) Heated at 10 ~ 15 , stirred for 15min and filtered, each time with 200ml ethyl acetate (EA) washed the filter cake three times, And the filtrate and the resulting filtrate was combined, to which was added 400ml 10 ~ 15 distilled cold water, Full shock, extraction and separation, the separated aqueous phase was extracted with ethyl acetate twice, The resulting organic phase was combined with the EA layer, washed twice with 1000 ml of distilled water, 300g of sodium chloride was added into the obtained water washing solution twice, dissolved with stirring and cooled down to 10 to 15 ° C, And then extracted with 500ml of ethyl acetate once, the organic phase was extracted and combined, Washed with 900 to 1000 ml of saturated saline (300 g of sodium chloride dissolved in 850 ml of distilled water) Finally, the organic phase was added 400g anhydrous sodium sulfate 60min after drying filtration;Salt-forming reaction: to step (2) dried and filtered about 2000ml filtrate was added to the reaction vessel, Then 32g fumaric acid (FMA) was added and the temperature was raised to 40 ° C in a nitrogen atmosphere and the reaction was stirred until the solution became clear. (4) Preparation of tenofovir disoproxil fumarate crude product: Step (3) The reaction solution was concentrated under reduced pressure at 40 ° C, most of the solvent was distilled off until a large amount of crystals were precipitated, Then the concentrate was naturally cooled to room temperature, and then placed in a -5 ° C freezer was allowed to cool more than 2h, filtered, The resulting filter cake was washed with a small amount of ethyl acetate 2 to 3 times, pumping dry weighed about 130g, 40 under blast drying 2h, weighed to give 85g Tenofovir disoproxil fumarate crude product, The HPLC detector purity of 98percent or more;Recrystallization: Under a nitrogen atmosphere, the reaction vessel was charged with step (4) 85 g crude Tenofovir disoproxil fumarate and 500 ml isopropanol (IPA) The nitrogen atmosphere was warmed to 55 ° C and stirred for 15 min to clarify the solution. If not, the filtrate should be filtered and the filtrate rapidly crystallized. After the resulting solution was left to cool to room temperature, Placed in a freezer at 4 frozen 2h above, so recrystallized, filtered, rinsed with cold isopropyl alcohol cake, Drained, to obtain white wet crystal 108g, at 40 blast drying 2h or 40 under reduced pressure drying 4h, 72 g of tenofovir disoproxil fumarate finished product was obtained. Tenofovir disoproxil fumarate obtained by the above method was tested by HPLC, Its purity is higher than 99.5percent, monoester is less than 0.5percent, the sum of other impurities is not more than 0.1percent, with tenofovir, The total molar yield is about 35-40percent.
216.1 g
Stage #1: With triethylamine In N,N-dimethyl acetamide for 0.166667 h;
Stage #2: at 55℃; for 7 h;
Stage #3: at 55℃;
120 g (0.418 mol) of tenofovir was heated to 80 ° C and dried under reduced pressure for 2 hours to remove water.After adding 600 g of DMAc (dimethylacetamide) and stirring uniformly, 120 g of triethylamine (1.186 mol) was added and stirred for 10 minutes, and then 280 g (1.835 mol) of CMIC (isopropylchloromethyl carbonate) was added.The reaction was incubated at 55 ° C for 7 hours.Sampling HPLC control,The reaction purity is 84.3percent,2.2percent of raw materials,Monoester 7.5percent.The reaction was cooled to 5 ° C and filtered.The filter cake was washed with 850 g of dichloromethane.Combine the filtrate,Add 1200g of purified water cooled to 5 ° C with stirring.Let stand, dispense,Collect the lower organic layer,The upper aqueous layer was extracted once with 400 g of dichloromethane.The combined organic layer solutions were washed twice with purified water.The methylene chloride solution was concentrated to a pale yellow oil and then was stirred at 30 ° C for 30 min with 200 g of isopropanol and 240 g of n-hexane.Then cool down to 0 ° C for 2 h,filter,Decofolvir dipivoxil wet product 231.2g (about 185.4g dry),The molar yield was 85.3percent and the purity was ≥99.8percent.231.2 g (0.445 mol) of tenofovir disoproxil wet product (about 185.4 g, 0.357 mol) and 55.4 g(0.477 mol) fumaric acid was added to 950 g of isopropanol and dissolved at 55 ° C.After being dissolved, it is filtered while hot.The filtrate was slowly cooled to 35-40 ° C. After crystallization for 2 h, the temperature was lowered to 0 ° C for 2 h.Filtered, pre-cooled isopropyl alcohol wash filter cake,About 120.6g of tenofovir disoproxil fumarateThe temperature was controlled to dry at 50 ° C for 10 hours under reduced pressure;Tenofovir disoproxil fumarate 216.1g,Molar yield 95.2percent,Purity ≥ 99.8percent.

Reference: [1] Patent: KR2016/38627, 2016, A, . Location in patent: Paragraph 0121; 0122; 0123; 0124
[2] Patent: KR2016/135112, 2016, A, . Location in patent: Paragraph 0113; 0114; 0115; 0116; 0118; 0119
[3] Patent: US2013/5969, 2013, A1, . Location in patent: Page/Page column 4
[4] Patent: US2014/303368, 2014, A1, . Location in patent: Paragraph 0092; 0093; 0094; 0095; 0096
[5] Patent: US2017/354668, 2017, A1, . Location in patent: Paragraph 0129-0132
[6] Patent: CN107400145, 2017, A, . Location in patent: Paragraph 0018
[7] Patent: CN108329352, 2018, A, . Location in patent: Paragraph 0006; 0019; 0047-0071
[8] Patent: JP2015/164934, 2015, A, . Location in patent: Paragraph 0166; 0167; 0181
  • 23
  • [ 110-17-8 ]
  • [ 202138-50-9 ]
YieldReaction ConditionsOperation in experiment
92.2% at 50 - 55℃; for 1 h; To 14.9 g (0.0287 mol) of powdered tenofovir dipivoxil was added 149 ml of isopropanol,After the mixture was completely clear, the organic filter was added, and 3.31 g (0.0285 mol) of fumaric acid was added to the filtrate,To 50-55 & lt; 0 & gt; C and stirred at this temperature for 1 h. After completion of the reaction, slowly cool to 0-5 ° C and at this temperatureContinue for 2h. The dinofloxacin fumarate wet product was obtained by filtration and the wet product was vacuum dried at 30 ° CThe yield of the product was 16.8 g, the yield was 92.2percent and the purity was 99.91percent.
90% at 0 - 75℃; for 0.5 h; The compound of Formula 2 (30 g) prepared in Reference Example 2 was dissolved in methanol (50 ml), purified water (150 ml) was added, and the mixture was cooled to 0 to 5 .Fumaric acid (7 g) is added to the other reaction part, methanol (20 ml) is added, purified water (150 ml) is added and the temperature is raised to 70 to 75 ° C to dissolve.The fumaric acid solution is added dropwise over 30 minutes to the mixed solution of the formula (2) cooled to 0 to 5 so that the temperature does not exceed 25 .After cooling naturally to 20 ° C to 30 ° C, crystallization is carried out for 4 hours.Filtered, washed with purified water (20 ml) and then dried under nitrogen for 2 hours to obtain an off-white colored tepofovir disoproxylfumarate salt (33 g).Purity: 99.96percent
90% at 5 - 50℃; for 3 h; 70 ml of isopropyl alcohol and 3.2 g of fumaric acid were added to the oil-like residue, and the temperature was raised to about 50 °C to dissolve completely. The reaction solution was slowly cooled to 5 °C and stirred for 3 hours. The resulting crystals were filtered and washed with 20 mL of isopropyl alcohol. The obtained solid was vacuum-dried at 40 to obtain 9.4 g (yield: 53percent) of crude terpovirdisopropyl fumarate (TDF). 80 ml of isopropyl alcohol was poured into 9.4 g of the above-mentioned tenofovir disoproxyl fumarate (TDF), and the temperature was raised to about 50 °C to dissolve completely. The reaction solution was slowly cooled to 5 °C and stirred at 5 °C for 3 hours. The resulting crystals were filtered, washed with 100 mL of isopropyl alcohol, and vacuum-dried at 40 °C to give tenofovir disoproxyl fumarate (TDF) 8.6 g (yield 90percent) was obtained.
88% at 0 - 50℃; 20 g of tenofovir disoproxil and 4.5 g of fumaric acid were charged into a container, After adding a solvent of 160 ml of isopropyl alcoholThe temperature was raised to about 50 DEG C and stirred for 30 to 60 minutes to completely dissolve.The dissolved reaction solution was cooled to about 25 After cooling slowly, the mixture was cooled to 0 to 5 ° C and stirred for 2 to 3 hours.The resulting crystals were filtered, washed with 60 ml of isopropyl alcohol, and dried under a humid atmosphere at about 40 ° C to obtain 21.5 g (yield: 88percent) of the title compound.
83% at 10 - 50℃; for 4 h; The above Step into a salt to concentrate the raffinate 200ml of isopropanol was added, with stirring and heated to 50 ° C, the reaction flask until clear solution was added 15g of fumaric acid, the addition was complete the reaction was cooled to l ° C incubation crystallization stirred 4 hours, filtered, and the filter cake was washed with a small amount of isopropyl alcohol after 40 ° C and dried under vacuum to dryness 69g tenofovir disoproxil fumarate finished. 83percent overall yield, 99.4percent purity.
83% at 10 - 50℃; for 4 h; The upward step in the concentrated residual liquid by adding 200 ml of isopropanol, heating under stirring to 50 °C, after in the bottle dissolves clear to be reaction, adding 15g fumaric acid, the reaction for cooling to 10 °C preserving heat and stirring crystallization 4 hours, filter, with a small amount of isopropanol washing after the 40 °C vacuum drying to doing 69g fumaric acid for Fuwei ester finished product. The overall yield is 83percent, purity 99.4percent.
83% at 10℃; for 4 h; Add 200ml isopropanol to the concentrated solution and warm to 50 ° C with stirring. After dissolving in the reaction flask, add15g fumaric acid, add the finished solution cooled to 10 ° C insulation and stirring crystallization for 4 hours, filter, filter cake with a small amount of isopropyl alcohol washingAnd dried in vacuum at 40 ° C to obtain 69 g of tenofovir dipivoxil fumarate. The overall yield was 83percent and the purity was 99.4percent.
83% at 10℃; for 4 h; To the concentrated solution was added 200 ml of isopropanol,Heated to 50 ° C with stirring,After being dissolved in the reaction flask,15 g of fumaric acid,After the addition of the reaction solution was cooled to 10 ° C for 4 hours,The filter cake was washed with a small amount of isopropanol and dried in vacuo at 40 ° C to obtain 69 g of tenofovir dipivoxil fumarate. The overall yield was 83percent and the purity was 99.4percent.
83% at 10℃; for 4 h; Add 200ml of isopropanol to the residue, and heat to 50 ° C with stirring. After dissolving in the reaction flask, add 15g of fumaric acid. After cooling, the reaction solution is cooled to 10 ° C and stirred for 4 hours. , Filter cake with a small amount of isopropyl alcohol washed by vacuum drying at 40 to get 69g fumarate tenofovir dipivoxil finished. The overall yield was 83percent and the purity was 99.4percent.
83% at 50℃; for 4 h; Add 200ml isopropanol to the concentrated solution and warm to 50 ° C with stirring. After dissolving in the reaction flask, add15g fumaric acid, add the finished solution cooled to 10 ° C insulation and stirring crystallization for 4 hours, filter, filter cake with a small amount of isopropyl alcohol washingAnd dried in vacuum at 40 ° C to obtain 69 g of tenofovir dipivoxil fumarate. The overall yield was 83percent and the purity was 99.4percent.
83% at 10 - 50℃; for 4 h; Large scale Step up concentrated residue was added 200ml of isopropanol was stirred and heated to 50 , the reaction flask until clear solution was added 15g of fumaric acid, completion of the addition the reaction was cooled to 10 insulation mixing crystallization 4 hours, filtered and the cake was washed with a small amount of isopropyl alcohol after 40 vacuum dried affording 69g tenofovir disoproxil fumarate finished.83percent overall yield, 99.4percent purity.
69% at 60℃; for 2.5 h; The resulting intermediate (V) (5. 54 g) and fumaric acid (1. 43 g) were dissolved in isopropanol (34 ml) and heated to 60 ° C for 2.5 h. After cooling to 0 ° C for 2 h , Filtered, washed with isopropanol, and dried in vacuo to give 4.69 g of 69percent yield of tenofovir dipivoxyl fumarate (VI).
55 g at 50 - 55℃; for 0.833333 h; To a clean 3 -necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket, addition funnel and dean-stark apparatus was charged cyclohexane (400 ml) and tenofovir (50 gms, obtained from example 1) and triethyl amine (34 gms) at temperature 20°C to 35°C. Heated to 80°C to 85°C and stirred for 2 hours and simultaneously removed water liberated. The solvent was removed completely from the reaction mixture by distillation under vacuum at below 65 °C and to the obtained residue N-methyl pyrrolidinone (150 ml) and triethyl amine (34 gms) were charged at 25°C to 30°C. Heated to 50°C to 55°C and chloromethyl isopropyl carbonate (125 gms) was added at same temperature and stirred for 4 hours. After completion of the reaction, the reaction mass was cooled to 20°C to 25°C and washed with cyclohexane (200 ml). Methylene chloride (500 ml) was charged into the organic layer and stirred for 1 hour at 10°C to 15°C. Filtered the salts formed and washed the filtrate with water (500 ml), separated the layers and charged water (500 ml) to the organic layer. Adjusted pH to 6.5 to 7.5 with 10percent ammonia solution and separated the organic layer from the aqueous layer. The solvent was removed from the organic layer under vacuum at below 35°C to obtain oily product and then the oily product was diluted with isopropanol (150 ml). In a clean another 3 -necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged isopropanol (350 ml) and Fumaric acid (19 gms). Heated to 50°C to 55°C and stirred for 20 minutes and above obtained oily product solution was added at 50°C to 55°C. Stirred for 30 minutes at this temperature and cooled to 0°C to 5°C. Filtered the product and washed with chilled isopropanol (75 ml). The wet product was dried at 35°C to 40°C under reduced pressure to provide the title compound as crude (80 gms). In another clean 3 -necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged ethyl acetate (450 ml) and crude product (80 gms) at temperature 10°C to 15°C. Stirred the slurry for 1 hour and filtered the product and washed with chilled ethyl acetate (50 ml). The wet product was dried at 35°C to 40°C for 6 hours under reduced pressure to provide the title compound. Yield: 55 gms. HPLC purity: 98.9percent.
69 g at 10 - 50℃; for 4 h; Add 200ml of isopropanol to the residue, and heat to 50 ° C with stirring. After dissolving in the reaction flask, add 15g of fumaric acid. After cooling, the reaction solution is cooled to 10 ° C and stirred for 4 hours. , The filter cake was washed with a small amount of isopropyl alcohol and dried at 40 ° C under vacuum to obtain 69 gTenofovir fumarateFinished products. The overall yield was 83percent and the purity was 99.4percent.
8.073 kg at 50 - 55℃; for 2 h; Large scale tenofovir diproxil was transferred to the reactor with 47 kg of isopropanol, Stirring to solution clarification, adding fumaric acid 4.735kg, heating to 50 ~ 55 reaction 2 hours;2) to stop heating, cooling to 30 ° C, the ice bath cooling to 5 ~ 10 crystallization 1 hour after the centrifugal filter1500r / min; that is, fenvalerate fenvalifol dipivoxil crude product 10.27kg.Finally, the purified fenofloxate fumarate is composed of the following steps:1) isopropyl alcohol recrystallization: the preparation of the obtained solution of tenofovir dipivoxil fumarate into the reactor, addInto 51.35L isopropyl alcohol, stirring heated to 50 ~ 55 , until the reaction solution is dissolved after stirring for 30 minutes, stop heating, cooling toRoom temperature, for use with ice water bath cooling to 5 ~ 10 , keep the temperature stirring crystallization 1 hour, centrifugal rejection filter obtained fumarate fumarateEneveritrile ester isopropyl alcohol recrystallization product 8.54kg.
3.45 kg at 50℃; Large scale 4. 10 L of TNF-3 and isopropyl alcohol were added to a three-necked flask, Stir for 5 minutes, Adding fumaric acid 1.1 kg, Heated to 50 ° C, The solution was turbid state, Stir the reaction for 2-3 hours. Stop heating, Slowly cooling, Cooling to about 20 when, There will be white solid precipitation, Cooled to 5 ° C, Slowly stir the crystal overnight. Filter, 40-45 ° C in vacuo to give a white solid 3.45 kg.

Reference: [1] Patent: CN106008603, 2016, A, . Location in patent: Paragraph 0052-0053; 0062-0063; 0067-0068; 0072-0073
[2] Patent: KR2016/13412, 2016, A, . Location in patent: Paragraph 0052; 0053
[3] Patent: KR2017/63471, 2017, A, . Location in patent: Paragraph 0146; 0147; 0152-0156
[4] Patent: KR2015/5818, 2015, A, . Location in patent: Paragraph 0056; 0057
[5] Patent: CN105566393, 2016, A, . Location in patent: Paragraph 0020
[6] Patent: CN105418684, 2016, A, . Location in patent: Paragraph 0019; 0021
[7] Patent: CN105418683, 2016, A, . Location in patent: Paragraph 0018; 0020
[8] Patent: CN105440077, 2016, A, . Location in patent: Paragraph 0018; 0020
[9] Patent: CN105481897, 2016, A, . Location in patent: Paragraph 0020
[10] Patent: CN105418682, 2016, A, . Location in patent: Paragraph 0018; 0020
[11] Patent: CN105481898, 2016, A, . Location in patent: Paragraph 0016; 0020
[12] Patent: CN103374038, 2016, B, . Location in patent: Paragraph 0062; 0063
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  • 24
  • [ 110-17-8 ]
  • [ 202138-50-9 ]
YieldReaction ConditionsOperation in experiment
83%
Stage #1: With triethylamine In dichloromethane; water at 25℃;
Stage #2: at 0 - 50℃;
The Orotate salt (purity: 99.4percent, S-isomer: 0.19percent, dimer:0.22percent) prepared in Example 2 was vacuum-dried at 100 ° C overnight to lower thecontent of S-isomer and dimer impurity S-isomer: 0.09percent, dimer: 0.07percent).10 g ofthe sample was put into a container,After adding 50 ml of water and 50 ml ofdichloromethane, put the 2.4 ml of triethylamine ,And completely dissolved bystirring at about 25 for5 to 10 minutes. After the solution was separated into layers, the organiclayer was washed with 50 ml of water and After drying over sodium sulfate andfiltration, The remaining filtrate was concentrated under reduced pressure togive terfenovir disoproxyl oil.In a terfenovirdisoproxyl oil,80 ml of isopropyl alcohol and 2.2 g offumaric acid were added and the temperature was raised to about 50 .Andcompletely dissolved by stirring for 30 to 60 minutes,The dissolved reactionsolution was gradually cooled to about 25 ,then Again it cooled to 0 ~ 5 bystirring for 2-3 hours.The resulting crystals were then filtered and Afterwashing with 30 ml of isopropyl alcohol,And dried under a warm air at about 40 to obtain the title compound (8.3 g, yield: 83percent).
Reference: [1] Patent: KR2015/5818, 2015, A, . Location in patent: Paragraph 0099; 0100
  • 25
  • [ 1215085-38-3 ]
  • [ 110-17-8 ]
  • [ 202138-50-9 ]
Reference: [1] Patent: WO2011/111074, 2011, A2, . Location in patent: Page/Page column 8; 9
  • 26
  • [ 1236549-06-6 ]
  • [ 110-17-8 ]
  • [ 173334-58-2 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With 10% palladium on activated carbon; Degussa type; hydrogen In isopropyl alcohol at 20℃;
Pd/C 10percent, 50percent wet w/w (0.06 g, 0.03 mmol) is added to a stirred solution of /V-Cbz-Aliskiren (6) (0.77 g, 1 .12 mmol) in isopropanol (7.0 ml_). The mixture is hydrogenated at atmospheric pressure and at room temperature up to complete conversion by HPLC.The catalyst is filtered and the solution is evaporated under vacuum maintaining the bath temperature under 30 °C to obtain Aliskiren (1 ) in quantitative yield.Fumaric acid (0.08 g, 0.69 mmol) is added to a stirred solution of the so obtained Aliskiren in EtOH (3.0 ml_).The solution is evaporated under vacuum maintaining the temperature bath under 30 °C. The residue is crystallized from a mixture acetonitrile/ethanol 95:5 (8.0 ml_). After drying at 60 °C Aliskiren hemifumarate salt is obtained (0.77g, quantitative yield) in a HPLC purity > 99.9percent
85%
Stage #1: With 10% palladium on activated carbon; Degussa type In isopropyl alcohol at 20℃;
Pd/C 10percent, 50percent wet w/w (0.06 g, 0.03 mmol) is added to a stirred solution of N-Cbz-Aliskiren (6) (0.77 g, 1.36 mmol) in isopropanol (7.0 mL). The mixture is hydrogenated at atmospheric pressure and at room temperature up to complete conversion by HPLC. The catalyst is filtered and the solution is evaporated under vacuum maintaining the bath temperature under 30 °C to obtain Aliskiren (1) in quantitative yield. Fumaric acid (0.08 g, 0.68 mmol) is added to a stirred solution of the so obtained Aliskiren in EtOH (3.0 mL). The solution is evaporated under vacuum maintaining the temperature bath under 30 °C. The residue is crystallized from a mixture acetonitrile/ethanol 95:5 (8.0 mL). After drying at 60 °C Aliskiren hemifumarate salt is obtained (0.77g, 85percent) in a HPLC purity ≥ 99.9percent.
Reference: [1] Patent: WO2013/14191, 2013, A1, . Location in patent: Page/Page column 19; 20
[2] Patent: EP2551260, 2013, A1, . Location in patent: Paragraph 0106; 0107; 0108; 0109; 0110
  • 27
  • [ 173338-07-3 ]
  • [ 110-17-8 ]
  • [ 173334-58-2 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: With hydrogenchloride In dichloromethane at 0℃; for 3 h;
A stirred solution of N-Boc-Aliskiren (3) (1.00 g, 1.53 mmol) in dichloromethane (10.0 mL) at -10 °C is saturated with HCI gas and maintained under magnetic stirring for 3 hours at 0 °C monitoring by HPLC. When the reaction is complete, the mixture is poured in a cold (5-10 °C) aqueous solution of Na2CO3 and the two layers are separated. The organic phase is evaporated under vacuum to obtain Aliskiren (1) in quantitative yield. Fumaric acid (0.08 g, 0.76 mmol) is added to a stirred solution of the so obtained Aliskiren in EtOH (4.0 mL). The solution is evaporated under vacuum maintaining the bath temperature under 30°C. The residue is crystallized from a mixture acetonitrile/ethanol 95:5 (10.0 mL). After drying at 60°C Aliskiren Hemifumarate salt is obtained (0.87g, 85percent) in a HPLC purity ≥ 99.9percent.
85%
Stage #1: With hydrogenchloride In dichloromethane at 0℃; for 3 h;
A stirred solution of /V-Boc-Aliskiren (3) (1 .00 g, 1 .53 mmol) in dichloromethane (10.0 mL) at -10 °C is saturated with HCI gas and maintained under magnetic stirring for 3 hours at 0 °C monitoring by HPLC.When the reaction is complete, the mixture is poured in a cold (5-10 °C) aqueous solution of Na2CO3 and the two layers are separated. The organic phase is evaporated under vacuum to obtain Aliskiren (1 ) in quantitative yield. Fumaric acid (0.08 g, 0.69 mmol) is added to a stirred solution of the so obtained Aliskiren in EtOH (4.0 mL).The solution is evaporated under vacuum maintaining the bath temperature under 30 °C. The residue is crystallized from a mixture acetonitrile/ethanol 95:5 (10.0 mL). After drying at 60 °C Aliskiren Hemifumarate salt is obtained (0.87g, 85percent) in a HPLC purity > 99.9percent.
Reference: [1] Patent: EP2551260, 2013, A1, . Location in patent: Paragraph 0101; 0102; 0103; 0104; 0105
[2] Patent: WO2013/14191, 2013, A1, . Location in patent: Page/Page column 19
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YieldReaction ConditionsOperation in experiment
74.25% at 35℃; for 1 h; Example 12: Crystallization of Aliskiren hemifumarate.[00100] Fumaric acid (2.14 g) was added to a solution of Aliskiren base (22.64 g) in methanol (226 mL) at 35 °C and the mixture was stirred for about 1 h to a complete dissolution and evaporated. Then, the Aliskiren hemifumarate crude foam (4.97 g) was dissolved in methanol, and the obtained solution was evaporated to the weight 14.91 g. This residual solution was heated to 35 °C, and acetonitrile (112 mL) was added to the solution at 35 °C. The solution was seeded at 35 °C with Aliskiren Hemifumarate (Form VIII, 5 mg), the mixture was cooled to 25 °C (during 2 h), while theprecipitation started at 29 °C. The mixture was stirred at room temperature overnight. The white precipitate was separated by filtration; the cake was washed with a mixture of methanol and acetonitrile (2:22.5, 10 mL) to give Form VIII. The product was dried at 40 °C in a vacuum oven overnight to give Aliskiren hemifumarate, Form VIII, as white solid (3.69 g,
30 g at 40℃; In a clean single-necked flask, 40 g of aliskiren free base and 4.2 g of fumaric acid and 320mL of isopropanol was added and heated to 40 °C and dissolved, filtered while hot, The filtrate was slowly cooled to 3 °C for static crystallization, and after about 10 hours a large amount of solid precipitated. Filtered, the solid was washed twice with a small amount of isopropyl alcohol, The solid was dried to give 30.0 g of a white powdery solid with an HPLC purity of 99.2percent
Reference: [1] Patent: WO2013/61224, 2013, A1, . Location in patent: Page/Page column 25
[2] Patent: WO2012/34065, 2012, A1, . Location in patent: Page/Page column 24
[3] Patent: WO2009/64479, 2009, A1, . Location in patent: Page/Page column 19
[4] Patent: WO2009/64479, 2009, A1, . Location in patent: Page/Page column 28
[5] Patent: WO2009/64479, 2009, A1, . Location in patent: Page/Page column 24
[6] Patent: WO2009/64479, 2009, A1, . Location in patent: Page/Page column 26
[7] Patent: WO2009/64479, 2009, A1, . Location in patent: Page/Page column 33
[8] Patent: WO2009/64479, 2009, A1, . Location in patent: Page/Page column 32
[9] Patent: WO2009/64479, 2009, A1, . Location in patent: Page/Page column 24
[10] Patent: WO2009/64479, 2009, A1, . Location in patent: Page/Page column 28
[11] Patent: EP2062874, 2009, A1, . Location in patent: Page/Page column 15-16
[12] Patent: EP2189442, 2010, A1, . Location in patent: Page/Page column 21; 22
[13] Patent: WO2011/148392, 2011, A1, . Location in patent: Page/Page column 56
[14] Patent: WO2013/144979, 2013, A1, . Location in patent: Page/Page column 11
[15] Angewandte Chemie - International Edition, 2013, vol. 52, # 47, p. 12359 - 12363[16] Angew. Chem., 2013, vol. 125, # 47, p. 12585 - 12589,5
[17] Organic Process Research and Development, 2016, vol. 20, # 2, p. 270 - 283
[18] Patent: CN103172533, 2016, B, . Location in patent: Paragraph 0032; 0033
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Reference: [1] Patent: WO2003/103653, 2003, A1, . Location in patent: Page 196
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Reference: [1] Patent: WO2012/52829, 2012, A1, . Location in patent: Page/Page column 16-17
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YieldReaction ConditionsOperation in experiment
93 %Chromat. at 40℃; EXAMPLE 59Purification of compound according to formula 13, obtained in example 58, by crystallization with fumaric acid.A solution of the compound according to formula 13, as obtained in example 58 (1.48 g), and fumaric acid (155.4 mg) in EtOH (15 ml.) were heated to4O0C and subsequently the ethanol removed by distillation under reduced pressure to a total weight of 3.21 g. The concentrated ethanol solution was dissolved in CH3CN (37 ml.) at 370C. The solution slowly was cooled to room temperature and seeded by a few crystals of aliskiren fumarate salt and the mixture was allowed to stir for 19 hours. The precipitated aliskiren fumarate salt was filtrated and dried giving the product.According to 1H NMR the compound is pure besides a trace of acetonitril left, see Figure 1.The all (S) purity of the aliskiren fumarate-salt (2.8 g) obtained as such was 93 area percent according to HPLC.
Reference: [1] Patent: WO2010/10165, 2010, A1, . Location in patent: Page/Page column 50
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