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Chemical Structure| 80841-78-7 Chemical Structure| 80841-78-7

Structure of 80841-78-7

Chemical Structure| 80841-78-7

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Product Citations

Product Citations

Pooja V. Hegde ; Michael D. Howe ; Matthew D. Zimmerman ; Helena I.M. Boshoff ; Sachin Sharma ; Brianna Remache , et al.

Abstract: Tuberculosis (TB) is one of the world's most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. para-Aminosalicylic acid (PAS), an important second-line agent for treating drug-resistant Mycobacterium tuberculosis, has moderate bioavailability and rapid clearance that necessitate high daily doses of up to 12 g per day, which in turn causes severe gastrointestinal disturbances presumably by disruption of gut microbiota and host epithelial cells. We first synthesized a series of alkyl, acyloxy and alkyloxycarbonyloxyalkyl ester prodrugs to increase the oral bioavailability and thereby prevent intestinal accumulation as well as undesirable bioactivation by the gut microbiome to non-natural folate species that exhibit cytotoxicity. The pivoxyl prodrug of PAS was superior to all of the prodrugs examined and showed nearly quantitative absorption. While the conceptually simple prodrug approach improved the oral bioavailability of PAS, it did not address the intrinsic rapid clearance of PAS mediated by N-acetyltransferase-1 (NAT-1). Thus, we next modified the PAS scaffold to reduce NAT-1 catalyzed inactivation by introduction of groups to sterically block N-acetylation and fluorination of the aryl ring of PAS to attenuate N-acetylation by electronically deactivating the para-amino group. Among the mono-fluorinated analogs prepared, 5-fluoro-PAS, exhibited the best activity and an 11-fold decreased rate of inactivation by NAT-1 that translated to a 5-fold improved exposure as measured by area-under-the-curve (AUC) following oral dosing to CD-1 mice. The pivoxyl prodrug and fluorination at the 5-position of PAS address the primary limitations of PAS and have the potential to revitalize this second-line TB drug.

Keywords: Tuberculosis ; para-Aminosalicylic acid (PAS) ; Prodrug ; Fluorination ; Metabolism ; N-acetyltransferase

Purchased from AmBeed: ; ; ; ; ; ; ; ; 75-07-0 ; ; ; ; ; 75-30-9 ; 3282-30-2 ; ; ;

Alternative Products

Product Details of [ 80841-78-7 ]

CAS No. :80841-78-7
Formula : C5H5ClO3
M.W : 148.54
SMILES Code : O=C1OC(C)=C(CCl)O1
MDL No. :MFCD07787494
InChI Key :QCLFSYYUWPUWQR-UHFFFAOYSA-N
Pubchem ID :9855518

Safety of [ 80841-78-7 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H302-H314
Precautionary Statements:P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501
Class:8
UN#:3265
Packing Group:

Computational Chemistry of [ 80841-78-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 5
Fraction Csp3 0.4
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 31.97
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

43.35 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.65
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.07
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.13
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

0.16
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

2.24
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.25

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.78
Solubility 2.46 mg/ml ; 0.0166 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.57
Solubility 3.98 mg/ml ; 0.0268 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-2.54
Solubility 0.431 mg/ml ; 0.0029 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.45 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.67

Application In Synthesis of [ 80841-78-7 ]

* 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 [ 80841-78-7 ]
  • Downstream synthetic route of [ 80841-78-7 ]

[ 80841-78-7 ] Synthesis Path-Upstream   1~7

  • 1
  • [ 80841-78-7 ]
  • [ 112984-60-8 ]
  • [ 123447-62-1 ]
References: [1] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 11, p. 1872 - 1877.
  • 2
  • [ 936114-12-4 ]
  • [ 80841-78-7 ]
  • [ 144690-92-6 ]
YieldReaction ConditionsOperation in experiment
91% With potassium carbonate; potassium iodide In N,N-dimethyl acetamide at 0 - 45℃; for 3 h; In 130 ml of N,N-dimethyl acetamide, 14.5 g (20 mmol) of potassium 4-(2-hydroxypropan-2-yl)-2-propyl-1-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate, 3.0 g (2.2 mmol) of potassium carbonate powder and 1.4 g (8.4 mmol) of potassium iodide were added.
The mixture was cooled to 0 °C and 5.0 g (33 mmol) of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one was added at 0 to 5°C.
After the addition, the reaction mixture was warmed to 40-45 °C within one hour, then the mixture was stirred at this temperature for 2h.
The sample of reaction mixture was analysed (HPLC; tritylolmesartan medoxomil, 97.44percent, 4-(2-hydroxypropan-2-yl)-2-propyl-1-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate 0.06 percent).
The mixture was cooled to 10 to 20°C and then 250 ml of ethyl acetate was added.
The mixture was cooled again to 5-10 °C and then 200 ml of 10percent NaCl was added slowly.
The temperature should not be higher than 25 °C during the addition.
The phases were mixed separated and organic phase was washed with 100 ml of 10percent NaCl (2*) and dried over anhydrous sodium sulphate.
After the filtration filtrate was evaporated under reduced pressure at temperature under 45°C to oily residue.
To the residue 30 ml of acetonitrile was added at temperature not more than 45°C.
The mixture was stirred at this temperature for 10 minutes then was cooled to 20 to 25°C and stirred at this temperature for 0.5 h and after that 3h at 0 to 5°C.
The suspension was filtered, washed with cold acetonitrile and dried at 40 to 50°C.
Yield: 17.0 g (91percent)
HPLC: 99.64 percent of the product, all other impurities under 0.1percent.
IR: 3408, 1818, 1805, 1741, 1681, 1529, 1148, 1002, 699
86% With potassium iodide In butanone at 50℃; for 7.5 h; Example 3; Trityl olmesartan medoxomil (III); A solution of potassium salt 4 in methyl ethyl ketone from the preceding experiment (ca. 20 g of the salt) was diluted with methyl ethyl ketone (290 ml), and, after adding potassium iodide (2 g) and 4-chloromethyl-5-methyl-l,3-dioxol-2-one (7 g), the mixture was stirred at 50 0C for 7.5 h. After the reaction was completed, the mixture was filtered, and the filtrate was washed with methyl ethyl ketone (3 x 50 ml). After concentrating to ca. 160 ml in vacuo, ethanol (250 ml) was added, and the reaction mixture was again concentrated to ca. 300 ml in vacuo.The concentrated product in ethanol was inoculated and stirred at 50 0C for 0.5 h, and after getting thicker, diluted with ethanol (50 ml) and cooled to 20 °C. The precipitated product was sucked off, washed with ethanol (2 x 20 ml) and dried in a vacuum drier at 50 °C. 14.4 g (86 percent) of the product was obtained.
84.4% With potassium iodide In butanone at 50℃; for 20 h; Example 1-5 (0330) (0331) A mixture of BIC (0.6 g, 0.83 mmol), potassium iodide (0.069 g, 0.41 mmol), OXC (0.245 g, 1.65 mmol) and methyl ethyl ketone (9.0 mL, 15 vol) was stirred at 50° C. for 20 hr. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the obtained concentrated residue was purified by silica gel column chromatography (20-22percent ethyl acetate/hexane) to give TOLM (650 mg, yield 84.4percent). (0332) Mass: 801 [M+H]+, 824 [M+Na]+.
76 g
Stage #1: With sodium carbonate; potassium iodide In acetone at 25 - 30℃; for 0.166667 h;
Stage #2: at 45 - 50℃; for 12 h;
To BIC (110 g, 1 eq) was added acetone (385 mL, 3.5 vol) at 25°C - 30°C, and the mixture was dissolved by stirring for 5 min. Sodium carbonate (20.85 g, 1.3 eq) and potassium iodide (0.25 g, 0.01) were added, and the mixture was stirred for 10 min. A solution of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (31.456 g, 1.4 eq) in acetone (165 mL, 1.5 vol) was added thereto. The reaction mixture was heated to 45°C - 50°C, and stirred at the same temperature for 12 hr. Using TLC (thin layer chromatography) (TLC eluent: 10percent methanol/methylene chloride, detection method: UV), complete disappearance of BIC was confirmed. The reaction mixture was cooled to 25°C - 30°C. Then, the solvent contained in the reaction mixture was evaporated under reduced pressure at 40°C - 45°C. To the obtained residue were added 10percent brine (550 mL, 5 vol) and toluene (550 mL, 5 vol). Furthermore, the mixture was adjusted to pH 7 - 8 by adding 5percent hydrochloric acid (33 mL), stirred for 10 min, left standing for 5 min and partitioned. The aqueous layer was extracted with toluene (2x330 mL, 2x3 vol). The extracts were combined with the organic layer, 10percent brine (550 mL, 5 vol) was added, and the mixture was stirred for 5 min, left standing for 45 min, partitioned, and concentrated under reduced pressure at 40°C - 45°C to give TOLM (110 g, 90percent). [0306] To the obtained TOLM was added acetone (110 mL, 1 vol), and the mixture was stirred at 25°C - 30°C for 30 min. n-Heptane (440 mL, 4 vol) was added, and the mixture was cooled to 5°C - 10°C and stirred at 5°C - 10°C for 30 min, whereby precipitation of a solid was confirmed. The solid (80 g, 66percent) was collected by filtration, and blast dried. To the obtained solid was added isopropyl alcohol (400 mL, 5 vol), and the mixture was heated to 50°C - 55°C and stirred at 50°C - 55°C for 1 hr. Then, the mixture was cooled to 25°C - 30°C, and stirred at 25°C - 30°C for 1 hr. The resulting solid was filtered and suction-filtered for 10 min to give TOLM (76 g, 62percent).

References: [1] Patent: EP2334668, 2011, A1, . Location in patent: Paragraph 0079-0080.
[2] Patent: WO2007/48361, 2007, A1, . Location in patent: Page/Page column 9; 10.
[3] Patent: US2015/239854, 2015, A1, . Location in patent: Page/Page column 40.
[4] Patent: EP2891650, 2015, A1, . Location in patent: Paragraph 0304-0306.
  • 3
  • [ 879097-59-3 ]
  • [ 80841-78-7 ]
  • [ 144690-92-6 ]
YieldReaction ConditionsOperation in experiment
93% With potassium carbonate In N,N-dimethyl acetamide at 5 - 10℃; for 4 h; Example 4; The reaction was carried out in the same manner as in Example 1 except that 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] -carboxylic acid sodium salt (Chemical Formula 5) and 50 mL of N, N-dimethylacetamide were added, the temperature was adjusted to 5 to 10 DEG C and 4 g of potassium carbonate was added. A solution of 6.2 g of 4- (chloromethyl) -5-methyl-1,3-dioxol-2-one (Formula 6) in 6 mL of N, N-dimethylacetamide was added dropwise to the reaction portion, For 4 hours. After the reaction was completed, the reaction solution was cooled to 20 to 25 ° C, and then 220 mL of ethyl acetate, 30 g of salt, and 170 mL of purified water were sequentially added to the reaction mixture, followed by separation of the organic layer, followed by the addition of 30 g of salt and 170 mL of purified water . & Lt; / RTI & gt; 1 g of activated carbon and 20 g of anhydrous sodium sulfate were added to the organic layer, followed by stirring for 30 minutes to 1 hour, followed by filtration. The filtrate was concentrated under reduced pressure, and 100 mL of acetonitrile was added to the residue, followed by stirring at 50 to 55 DEG C for 1 hour. The crystals were cooled to 0 to 5 ° C., stirred for 2 hours, filtered, washed with 50 mL of isopropyl alcohol and dried to obtain 21.7 g (yield: 93percent, purity: 99.96percent) of tritylolemethanemethoxysilane
45g With sodium iodide In N,N-dimethyl-formamide at 55℃; for 7.5 h; A solution containing about 46 g of compound 4 was taken, 3.5g sodium iodide was added, 280 mL N, N-dimethylformamide, 11.2g DMDO-Cl was slowly added dropwise, 30 Minute addition is completed. After dropping, Heated to 55 , Reaction for 7 hours, The reaction is completely over. filter, Remove insolubles, The filtrate was poured into 700mL of water, Extraction with ethyl acetate, The ethyl acetate layer was collected, dry, filter, The filtrate is concentrated. To the oily substance obtained after the concentration was added 200 mL of ethanol, Stirring, A white solid precipitation, Collect the solid, Washed with 50mL cyclohexane beating, 45.0 g of product was obtained, Two-step total yield of 80.6percent The purity of the product was 98percent by HPLC.
References: [1] Patent: KR101526249, 2015, B1, . Location in patent: Paragraph 0068; 0069.
[2] Synthetic Communications, 2009, vol. 39, # 2, p. 291 - 298.
[3] Patent: CN107311989, 2017, A, . Location in patent: Paragraph 0028; 0036; 0037.
[4] Patent: CN103012382, 2016, B, . Location in patent: Paragraph 0021; 0030-0031.
  • 4
  • [ 144690-33-5 ]
  • [ 80841-78-7 ]
  • [ 144690-92-6 ]
YieldReaction ConditionsOperation in experiment
88%
Stage #1: With sodium hydroxide In ethanol at 20 - 25℃;
Stage #2: With potassium carbonate In N,N-dimethyl acetamide at 45 - 50℃; for 4 h;
Example 5: The reaction part was charged with ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] 22 g of 5-carboxylate (Formula 4), 3.1 g of sodium hydroxide and 90 mL of ethanol were added and the mixture was stirred at 20 to 25 ° C for 4 to 5 hours. When the reaction was completed, the reaction solution was concentrated. To the residue were added 50 mL of ethyl acetate and 50 mL of purified water. The mixture was stirred for 1 hour and then layered. The separated organic layer was washed twice with an aqueous solution containing 30 g of salt and 170 mL of purified water. 1 g of activated carbon and 20 g of anhydrous sodium sulfate were added to the organic layer, followed by stirring for 30 minutes to 1 hour, followed by filtration Respectively. After the filtrate was concentrated under reduced pressure, 50 mL of N, N-dimethylacetamide was added to the residue, the temperature was adjusted to 5 to 10 DEG C 4 g of potassium carbonate was added and 6.2 g of 4- (chloromethyl) -5-methyl-1,3-dioxol-2-one (Formula 6) was dissolved in N, N-dimethylacetamide 6 ML was added dropwise, and the mixture was reacted at 45 to 50 ° C for 4 hours with stirring. When the reaction is completed, the reaction solution is cooled to 20 to 25 After cooling, 220 mL of ethyl acetate, 30 g of salt and 170 mL of purified water were added successively. The organic layer was separated And then washed once more with an aqueous solution containing 30 g of salt and 170 mL of purified water. The organic layer was washed with 1 g of activated carbon, 20 g of sodium was added and stirred for 30 minutes to 1 hour, followed by filtration. The filtrate was concentrated under reduced pressure, and then acetone 100 mL of i-tril was added, and the mixture was stirred at 50 to 55 ° C for 1 hour. The crystals were cooled to 0 to 5 [deg.] C and stirred for 2 hours. Followed by washing with 50 mL of isopropyl alcohol, followed by drying to obtain 21.6 g (yield: 88percent) of tritylolemecanemethoxysilane (formula 1a) Purity 99.97percent) was obtained
85.8%
Stage #1: With sodium hydroxide In acetone at 50 - 60℃; for 5 h; Green chemistry
Stage #2: With potassium iodide In acetone at 20 - 60℃; for 1 h; Green chemistry
1L glass reaction flask was added with 600ml of acetone, 114.8g of intermediate 1 was added with stirring, then 12.8g of sodium hydroxide was added, the temperature was raised to 50-60 °C, and the reaction was incubated for 5 hours, and the reaction was monitored by HPLC. To 20-30 °C, add 2.8g potassium iodide, 36.0g 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and increase the temperature to 50-60 °C after the addition After 1 hour of heat preservation reaction, the temperature was lowered to 20-30 ° C, filtered, and the filter cake was rinsed with 115 ml of acetone, and the filtrate was combined. The filtrate was concentrated under reduced pressure at 40-50 °C until no obvious solvent flowed out, and 320 ml of acetonitrile was added to cool down. The mixture was decanted to 20-30 °C for 1 hour, filtered, and the filter cake was rinsed with 320 ml of acetonitrile. The filter cake was blast dried at 40-50 °C for 12 hours to obtain a white solid 110.0 g (intermediate 2). The rate was 85.8percent, HPLC: 99.2percent.
309 g
Stage #1: Reflux
Stage #2: Reflux
To the flask was added 2000 g of acetone, 160 g of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate (II), 150 g of K2CO3, 460 g of 4- [2- (Trityltetrazol-5-yl) phenyl] benzyl bromide (III), 20g KI, the temperature was raised to reflux, the reaction was incubated for 34-38 hours under stirring.Then add 102g KOH, reflux reaction 6 ~ 8h. Cool to 10 ~ 20 , add 170g DMDO-Cl, incubated for 30 ~ 60min.Heating to reflux, the reaction 22 to 26 hours.After the reaction was added 40g of diatomaceous earth, stirring for 30 to 60 minutes, suction filtration, 200g acetone rinse cake. To the filtrate was added 800g of drinking water and 200g of refined hydrochloric acid, the reaction at room temperature for 2 to 4 hours, filtered to remove by-product triphenylcarbinol. Dropping 10percent K2CO3 aqueous solution, adjusting feedstock pH to 4, cooling to 10 ~ 20 , stirring crystallization 2h, filtration, the filter cake with a mixture of pre-cooled 45g acetone and 230g of drinking water washing and drying, to obtain Olmesartan Medoxomil 309 g, total yield 83.1percent (relative to ethyl-4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5- carboxylate (II)), purity: 99.27percent of the main peak, 0.08percent of the olmesartan acid, 0.14percent of the triphenylmethanol, and 0.13percent of the largest unidentified one.
References: [1] Patent: KR101526249, 2015, B1, . Location in patent: Paragraph 0071; 0072.
[2] Patent: CN108341804, 2018, A, . Location in patent: Paragraph 0015; 0033; 0034.
[3] Patent: WO2008/43996, 2008, A2, . Location in patent: Page/Page column 16-17; 18.
[4] Patent: WO2008/43996, 2008, A2, . Location in patent: Page/Page column 17-18.
[5] Patent: WO2008/43996, 2008, A2, . Location in patent: Page/Page column 18-19.
[6] Patent: US2009/131680, 2009, A1, . Location in patent: Page/Page column 8.
[7] Patent: WO2007/17135, 2007, A2, . Location in patent: Page/Page column 5; 21-22.
[8] Patent: EP1816131, 2007, A1, . Location in patent: Page/Page column 12.
[9] Patent: WO2011/14611, 2011, A2, . Location in patent: Page/Page column 11.
[10] Patent: WO2012/55994, 2012, A1, . Location in patent: Page/Page column 19.
[11] Patent: CN107311990, 2017, A, . Location in patent: Paragraph 0043; 0044; 0045; 0046.
  • 5
  • [ 761404-85-7 ]
  • [ 80841-78-7 ]
  • [ 144690-92-6 ]
YieldReaction ConditionsOperation in experiment
94% With potassium carbonate; potassium iodide In N,N-dimethyl acetamide at 0 - 45℃; for 3 h; Inert atmosphere 130 ml of N,N-dimethylacetamide, 14.0 g (20 mmol) of ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate and 2.2 g (16 mmol) of KOH were charged into reaction vessel at room temperature under inert atmosphere.
The mixture was stirred at room temperature for 2 h, and then the sample of reaction mixture was analysed (HPLC; starting material 0.2 percent, hydrolysed starting material 98.11 percent).
Then 3.0 g (2.2 mmol) of potassium carbonate powder and 1.4 g (8.4 mmol) of potassium iodide were added.
The reaction mixture was cooled to 0 °C and 5.0 g (33 mmol) of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one was added at 0 to 5°C.
After the addition, the reaction mixture was warmed to 40-45 °C within one hour, then the mixture was stirred at this temperature for 2h.
The sample of reaction mixture was analysed (HPLC; tritylolmesartan medoxomil 97.22 percent, 4-(2-hydroxypropan-2-yl)-2-propyl-1-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate 0.09 percent).
The mixture was cooled to 10 to 20 °C and then 250 ml of ethyl acetate was added.
The mixture was cooled again to 5-10 °C and then 200 ml of 10 percent NaCl was added slowly.
The temperature should not be higher than 25 °C during the addition.
The phases were mixed separated and organic phase was washed with 100 ml of 10 percent NaCl (2*) and dried over anhydrous sodium sulphate.
After the filtration filtrate was evaporated under reduced pressure at temperature under 45°C to oily residue.
To the residue 30 ml of acetonitrile was added at temperature not more than 45°C.
The mixture was stirred at this temperature for 10 minutes then was cooled to 20 to 25°C and stirred at this temperature for 0.5 h and after that 3h at 0 to 5°C.
The suspension was filtered, the cake washed with cold acetonitrile and dried at 40 to 50°C.
Yield: 17.0 g (94percent)
HPLC: 99.72 percent of the product, all impurities are under 0.1percent.
IR: 3408, 1818, 1805, 1741, 1681, 1529, 1147, 1003, 699
XRD:
91.6%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; Autoclave
Stage #2: With potassium iodide In N,N-dimethyl-formamide at 20℃;
10L autoclave, 520g (0.75mol) Compound 5, DMF3kg, potassium carbonate and 215.3g (1.6mol), stirred at room temperature 1.5-2.5h added to the system after 63.0g (0.38mol) of potassium iodide was added dropwise while - Chloromethyl -5-methyl-1,3-dioxol-2-one 40.0g (0.94mol). Dropping was completed, the reaction at room temperature after 3-4h TLC or HPLC in control, raw reaction was complete. To the system was added ethyl acetate and 3L 3L water and 200g of sodium chloride, stirring separated and the aqueous layer was washed with 3X1L ethyl acetate, the combined organic layers, the organic layer was dried, filtered and the solvent was evaporated cooling is added 0-10 , methanol was added 1600g beating 30min, filtered, then the filter cake was slurried at room temperature in acetonitrile 1600g 30min, filtered to afford intermediate 6 about 553.8g,
23.2 g With potassium bromide In N,N-dimethyl acetamide at 15 - 50℃; for 8.6 h; Green chemistry 123.2g of compound and 2.5g of potassium hydroxide solid were added to a 500ml four-necked flask.DMAC76g, heated to 50 ° C, stirred for about 6h,The TLC dot plate showed that the compound 1 point disappeared, that is, the end of the hydrolysis reaction was judged.Cool to 15 ± 5 ° C, add KBr 0.64g, add DMDO-C16.5g, DMAC 10g,After about 40 minutes, the temperature was raised to 25±5°C for 2h, then the temperature was raised to 50°C, the reaction was about 6h, and the temperature was lowered again to 20±5°C for 5h. The reaction solution was added with 324g water and 208g of dichloromethane.Shake well and let the layers separate. The aqueous layer was extracted with 70 g of dichloromethane and combined with several layers.It was washed twice with 206 g of water, and the last aqueous layer was extracted with 100 g of dichloromethane.The organic layers were combined and dried under reduced pressure at 45 ° C.After adding 100g of the upper batch of crystallization, the mother liquid is heated and refluxed for 25±5 minutes, and then naturally cooled.Then crystallization at 0 ° C for 6 h,Drying by suction filtration to obtain 23.2 g of trityl olmesartan medoxomil white solid powder.The yield was 93.4percent. HPLC analysis, purity 99.7percent, acid miscellaneous <0.05percent,The olefinic impurity is <0.1percent, and the other unknown single impurities are <0.1percent.
References: [1] Patent: EP2334668, 2011, A1, . Location in patent: Paragraph 0077-0078.
[2] Patent: CN105481842, 2016, A, . Location in patent: Paragraph 0050; 0053; 0054.
[3] Patent: US2009/281327, 2009, A1, . Location in patent: Page/Page column 5-6.
[4] Patent: US2012/59172, 2012, A1, . Location in patent: Page/Page column 5.
[5] Patent: CN103880825, 2019, B, . Location in patent: Paragraph 0020; 0039-0044.
  • 6
  • [ 1114761-92-0 ]
  • [ 80841-78-7 ]
  • [ 144690-92-6 ]
YieldReaction ConditionsOperation in experiment
683.2 g With potassium carbonate In acetonitrile for 2 h; Reflux The reaction flask was charged with 697.5 g of compound V obtained in the previous step,414 g of anhydrous potassium carbonate (3.00 mol)163.4 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one (Compound VI) (1.10 mol)And 2500 ml of acetonitrile were refluxed for 2 hours,After the reaction,filter,The filtrate was concentrated to dryness,The residue was stirred in 1500 ml of ethyl acetate and 500 ml of water for 15 minutes,Layered, organic layer and then washed with water,Dried over anhydrous sodium sulfate,filter,The filtrate was concentrated to dryness,To give the crude product of compound VII,Recrystallization from toluene and petroleum ether,To obtain pure product 683.2 grams; two-step yield:85.40percent (calculated as compound II).
References: [1] Patent: CN103304550, 2016, B, . Location in patent: Paragraph 0051-0052.
  • 7
  • [ 80841-78-7 ]
  • [ 124750-51-2 ]
  • [ 144689-93-0 ]
  • [ 144690-92-6 ]
References: [1] Patent: WO2011/14611, 2011, A2, . Location in patent: Page/Page column 12; 13.
 

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