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[ CAS No. 33657-49-7 ] {[proInfo.proName]}

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Chemical Structure| 33657-49-7
Chemical Structure| 33657-49-7
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Product Citations

Raithatha, Sheetal A. ; Hagel, Jillian M. ; Matinkhoo, Kaveh , et al. DOI: PubMed ID:

Abstract: The psychedelic prodrug psilocybin has shown therapeutic benefits for the treatment of numerous psychiatric conditions. Despite pos. clin. end points targeting depression and anxiety, concerns regarding the duration of the psychedelic experience produced by psilocybin, associated with enduring systemic exposure to the active metabolite psilocin, pose a barrier to its therapeutic application. Our objective was to create a novel prodrug of psilocin with similar therapeutic benefits but a reduced duration of psychedelic effects compared with psilocybin. Here, we report the synthesis and functional screening of 28 new chem. entities. Our strategy was to introduce a diversity of cleavable groups at the 4-hydroxy position of the core indole moiety to modulate metabolic processing. We identified several novel prodrugs of psilocin with altered pharmacokinetic profiles and reduced pharmacol. exposure compared with psilocybin. These candidate prodrugs have the potential to maintain the long term benefits of psilocybin therapy while attenuating the duration of psychedelic effects.

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Product Details of [ 33657-49-7 ]

CAS No. :33657-49-7 MDL No. :MFCD00216961
Formula : C5H9ClO2 Boiling Point : -
Linear Structure Formula :- InChI Key :BDPZFQLKFUONAG-UHFFFAOYSA-N
M.W : 136.58 Pubchem ID :2725008
Synonyms :

Calculated chemistry of [ 33657-49-7 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.8
Num. rotatable bonds : 4
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 32.23
TPSA : 26.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.98 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.03
Log Po/w (XLOGP3) : 1.63
Log Po/w (WLOGP) : 1.53
Log Po/w (MLOGP) : 1.27
Log Po/w (SILICOS-IT) : 1.31
Consensus Log Po/w : 1.55

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.45
Solubility : 4.85 mg/ml ; 0.0355 mol/l
Class : Very soluble
Log S (Ali) : -1.79
Solubility : 2.19 mg/ml ; 0.016 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.76
Solubility : 2.4 mg/ml ; 0.0175 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.71

Safety of [ 33657-49-7 ]

Signal Word:Danger Class:3,8
Precautionary Statements:P210-P233-P240-P241+P242+P243-P260-P264-P280-P301+P330+P331+P310-P303+P361+P353+P310+P363-P304+P340+P310-P305+P351+P338+P310-P370+P378-P403+P235-P405-P501 UN#:2924
Hazard Statements:H226-H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 33657-49-7 ]

* 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.

  • Downstream synthetic route of [ 33657-49-7 ]

[ 33657-49-7 ] Synthesis Path-Downstream   1~97

  • 1
  • [ 50-00-0 ]
  • [ 141-75-3 ]
  • [ 33657-49-7 ]
YieldReaction ConditionsOperation in experiment
70% With zinc(II) chloride In acetonitrile at 0 - 90℃; for 16h; Inert atmosphere;
64% at 20 - 80℃;
63%
With zinc(II) chloride
With tin(IV) chloride In benzene at 70 - 80℃;
With zinc(II) chloride In chloroform at 0℃; Yield given;
With zinc(II) chloride
With zinc(II) chloride at 50 - 60℃; for 24h;
With thionyl chloride; zinc(II) chloride In dichloromethane at 60 - 70℃;

Reference: [1]Sanrame, Carlos N.; Remenar, Julius F.; Blumberg, Laura C.; Waters, Julie; Dean, Reginald L.; Dong, Nan; Kriksciukaite, Kristi; Cao, Peixin; Almarsson, Örn [Molecular Pharmaceutics, 2014, vol. 11, # 10, p. 3617 - 3623]
[2]Nudelman, Abraham; Gnizi, Elisheva; Katz, Yifat; Azulai, Revital; Cohen-Ohana, Mirit; Zhuk, Regina; Sampson, Sanford R; Langzam, Leah; Fibach, Eitan; Prus, Eugenia; Pugach, Victoria; Rephaeli, Ada [European Journal of Medicinal Chemistry, 2001, vol. 36, # 1, p. 63 - 74]
[3]Franssen, Maurice C.R.; Goetheer, Earl L.V.; Jongejan, Hugo; De Groot, Aede [Tetrahedron Letters, 1998, vol. 39, # 45, p. 8345 - 8348]
[4]Euranto [1959, # 31, p. 1,12,16][Chem.Abstr., 1959, p. 11204]
[5]Bedford; Harris III; Howd; Goff; Koolpe; Petesch; Miller; Nolen III; Musallam; Pick; Jones; Koplovitz; Sultan [Journal of Medicinal Chemistry, 1989, vol. 32, # 2, p. 493 - 503]
[6]Waranis; Sloan [Journal of Pharmaceutical Sciences, 1987, vol. 76, # 8, p. 587 - 595]
[7]Sum; Gilbert; Venkatesan; Lim; Wong; O'Dell; Francisco; Chen; Grosu; Baker; Ellingboe; Malamas; Gunawan; Primeau; Largis; Steiner [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 14, p. 1921 - 1926]
[8]Nielsen, Anders Bach; Buur, Anders; Larsen, Claus [European Journal of Pharmaceutical Sciences, 2005, vol. 24, # 5, p. 433 - 440]
[9]Location in patent: scheme or table Berkovitch, Gili; Doron, Dvir; Nudelman, Abraham; Malik, Zvi; Rephaeli, Ada [Journal of Medicinal Chemistry, 2008, vol. 51, # 23, p. 7356 - 7369]
  • 2
  • [ 623-42-7 ]
  • [ 26464-32-4 ]
  • [ 817-76-5 ]
  • [ 33657-49-7 ]
  • [ 3153-37-5 ]
  • 3
  • [ 33657-49-7 ]
  • [ 63379-59-9 ]
YieldReaction ConditionsOperation in experiment
80% With sodium iodide In dichloromethane; acetone 4 4.6 Preparation of cisapride carbonates To a solution of chloromethyl butyrate (920 mg, 5.9 mmol) in acetone (40 ml) was added sodium iodide (3.09 g). The mixture was stirred for 3 hours, concentrated invacuo, and dissolved in dichloromethane (50 ml). This solution was washed with saturated aqueous sodium chloride, aqueous sodium thiosulfate, and saturated aqueous sodium chloride, dried (sodium sulfate) and concentrated invacuo to yield iodomethyl butyrate (80%).
70% With sodium iodide In acetone at 20℃; Inert atmosphere; Darkness; 5 Intermediate 5A - Iodomethyl butyrate To a solution of chloromethyl butyrate (0.25 g, 1.83 mmol) in acetone (50 mL) in a 100 mL 1 neck round-bottom flask (under argon and protected from light by aluminumfoil) was added Nal (0.549 g, 3.66 mmol). The reaction mixture was stirred at roomtemperature overnight, then was filtered; the filter cake was washed with acetone (5 mL) and the combined filtrates were concentrated in vacuo to provide an orange oil which was triturated with Et20 (10 mL) and filtered. The remaining material was concentrated invacuo to provide Intermediate 5A (0.29 1 g, 70% yield) as a brown oil, which was used inthe next reaction without further purification.
55% With sodium iodide In acetonitrile at 25℃; for 15h; Darkness;
With sodium iodide In acetone for 4h; Yield given;
With 18-crown-6 ether; sodium iodide In benzene Heating;
With sodium iodide In acetone 6 6.21 Preparation of deprenyl-N-butyroyloxymethyl, iodide salt To a solution of chloromethyl butyrate (1.9 g, 0.014 mol) in acetone (15 ml) was added sodium iodide (6.3 g, 0.041 mol). The mixture was refluxed for 2 hours, cooled, diluted with dichloromethane, washed with saturated aqueous sodium chloride, aqueous sodium thiosulfate (5%), and saturated aqueous sodium chloride, dried (sodium sulfate) and concentrated invacuo to yield iodomethyl butyrate (3.2 g).

  • 4
  • [ 33657-49-7 ]
  • [ 302-79-4 ]
  • RN 1 [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% With triethylamine In N,N-dimethyl-formamide at 70℃; for 3h;
  • 5
  • [ 59-67-6 ]
  • [ 33657-49-7 ]
  • nicotinic acid butyryloxymethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
59% With triethylamine In N,N-dimethyl-formamide at 60℃;
  • 6
  • [ 598-02-7 ]
  • [ 33657-49-7 ]
  • butyroyloxymethyl diethyl phosphate [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% With triethylamine In N,N-dimethyl-formamide at 70℃; for 4h;
  • 7
  • [ 33657-49-7 ]
  • [ 16024-56-9 ]
  • 2-(2-methoxyethoxy)acetyloxymethyl butyrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
44% With triethylamine; In acetone; EXAMPLE 1 Synthesis of 2-(2-Methoxyethoxy)acetyloxymethyl Butyrate 2-(2-Methoxyethoxy)acetyloxymethyl butyrate (Compound C) has the following structure STR4 and was synthesised as follows. To a solution of chloromethyl butyrate (682 mg, 5 mmol) in acetone (10 mL), <strong>[16024-56-9]2-<strong>[16024-56-9](2-methoxyethoxy)acetic acid</strong></strong> (570 mg, 5 mmol) was added, followed by the dropwise addition of triethylamine (0.7 mL, 0.5 g, 1 eq). The mixture was heated at 40 C. for 20 h, until TLC (ethyl acetate:hexane 2:1, ninhydrin) indicated the total consumption of the starting materials. The precipitate was filtered and washed with acetone. The filtrate was evaporated and the residue (1.08 g) was chromatographed on silica gel (ethyl acetate:hexane, 2:1) to give the product as an oil, 520 mg (44% yield).
  • 8
  • [ 33657-49-7 ]
  • [ 16024-58-1 ]
  • Butyric acid 2-[2-(2-methoxy-ethoxy)-ethoxy]-acetoxymethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
53% With triethylamine In acetone at 40℃;
  • 9
  • [ 33657-49-7 ]
  • [ 99855-49-9 ]
  • 4-(butyramido)benzoyloxymethyl butyrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With triethylamine In N,N-dimethyl-formamide at 60℃;
  • 10
  • [ 33657-49-7 ]
  • [ 150-13-0 ]
  • 4-aminobenzoyloxymethyl butyrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
41% With triethylamine In N,N-dimethyl-formamide at 60℃;
  • 11
  • [ 33657-49-7 ]
  • [ 84978-05-2 ]
  • 6-(3-methyl-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-hexanoic acid butyryloxymethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% With triethylamine In N,N-dimethyl-formamide at 70℃; for 2h;
  • 12
  • [ 33657-49-7 ]
  • [ 103124-12-5 ]
  • 3-[(butyryloxy)methyl] 5-methyl 4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With potassium carbonate In N,N-dimethyl-formamide at 20℃;
  • 13
  • [ 33657-49-7 ]
  • [ 400884-05-1 ]
  • 3-[(butyryloxy)methyl] 5-(2-propoxyethyl) 4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With potassium carbonate In N,N-dimethyl-formamide at 20℃;
  • 14
  • [ 123-99-9 ]
  • [ 33657-49-7 ]
  • bis-[(butanoyloxy)methyl] nonanedioate [ No CAS ]
YieldReaction ConditionsOperation in experiment
49% With caesium carbonate; sodium iodide In N,N-dimethyl-formamide at 60℃; for 48h;
  • 15
  • [ 33657-49-7 ]
  • [ 636595-81-8 ]
  • 5-{4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolin-1-yl]but-2-ynyloxymethyl}-2-butyryloxymethoxybenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; potassium iodide In acetone for 4h; Heating;
Stage #1: 5-{4-[3-(4-cyano-3-trifluoromethyl-phenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]-but-2-ynyloxymethyl}-2-hydroxy-benzamide With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: chloromethyl n-butyrate With potassium iodide In acetone for 4h; Heating / reflux; 3 A mixture of 40 mg (0. 078 mmol) of 6a and 21 mg (0.15 mmol) of potassium carbonate was stirred for 30 min at room temperature in 5 mL of acetone. In a separate flask, 16 mg (0.12 mmol) of chloromethyl butyrate and 22 mg (0.13 mmol) of potassium iodide were stirred in 5 mL of acetone at room temperature. The two mixtures were then combined and refluxed for 4 h. The reaction was stopped by cooling to room temperature and filtering through a glass frit. The collected liquid was rotary evaporated at 30 °C and the residue was dissolved in 100 mL of ethyl acetate. After 3x washes with 50 mL saturated brine, the organic layer was collected, dried over anhydrous magnesium sulfate, and concentrated by rotary evaporation at 40 °C. The washed product was then dissolved in 3 mL of ethyl acetate and introduced to a silica gel flash column (2 cm x 30 cm) packed in 50% hexanes/50% ethyl acetate. The desired product was eluted with 25% hexanes/ 75% ethyl acetate. Concentration by rotary evaporation at 30 °C yielded approximately 80% conversion. The semi-pure product was characterized by the following spectral properties and was used without further purification for the preparation of 10
  • 16
  • [ 33657-49-7 ]
  • [ 14252-80-3 ]
  • N-butanoyloxymethyl bupivacaine chloride salt [ No CAS ]
  • 17
  • [ 33657-49-7 ]
  • [ 389-08-2 ]
  • 1-ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid butyryloxymethyl ester [ No CAS ]
  • 18
  • [ 33657-49-7 ]
  • [ 1623-08-1 ]
  • [ 1002109-24-1 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate In acetone at 20℃; 8.A Example 8[[[(Bis(butylcarbonyloxymethoxy)phosphoryl)amino](imino)methyl](methyl)amino]acetic acid (11)Step A: [(Benzyloxy)(hydroxy)phosphoryl]oxy}methyl butyrate (12); Dibenzyl phosphate (2.8 g) was dissolved in 30 mL acetone and 1.8 g of chloromethyl butyrate and 8 g of cesium carbonate was added to the solution. The reaction mixture was stirred overnight at r.t. The solvent was removed, 100 mL of EtOAc added to the residue, and the suspension was filtered to remove the solid. After concentration of the filtrate, the acyloxy dibenzylphosphate was purified by silica gel chromatography using 25-50% EtOAc in hexane as the eluent. The purified acyloxy dibenzylphosphate was hydrogenated under 40 psi hydrogen in the presence of 300 mg of Pd/C. After removing the catalyst, the filtrate was concentrated to provide [(benzyloxy)(hydroxy)phosphoryl]oxy}methyl butyrate (12).
  • 19
  • [ 1002719-90-5 ]
  • [ 33657-49-7 ]
  • C17H25O8P [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate In acetone at 20℃; 8.B Step B: Bis(butylcarbonyloxymethoxy)phosphoric acid (13); [(Benzyloxy)(hydroxy)phosphoryl]oxy}methyl butyrate (12) was dissolved in 50 mL of acetone and 4.9 g of cesium carbonate, and 980 mg of chloromethyl butyrate was added to the solution. The reaction mixture was stirred overnight at r.t. The reaction mixture was filtered, and the filtrate concentrated by silica gel chromatography using 50% EtOAc in hexane as the eluent to provide the benzyl ester of the title compound (13), which was then treated with 10% Pd/C in a PARR reaction bottle using MeOH as solvent under 65 psi hydrogen atmosphere to provide the title compound (13).
  • 20
  • [ CAS Unavailable ]
  • [ 33657-49-7 ]
  • [ CAS Unavailable ]
  • [ 167221-71-8 ]
  • 21
  • [ CAS Unavailable ]
  • [ 33657-49-7 ]
  • [ 167221-71-8 ]
YieldReaction ConditionsOperation in experiment
90% In acetonitrile for 3.5h; Heating / reflux;
76% With potassium hydrogencarbonate In acetonitrile for 4.5h; Heating / reflux;
  • 22
  • [ CAS Unavailable ]
  • [ 33657-49-7 ]
  • [ 167221-71-8 ]
YieldReaction ConditionsOperation in experiment
74% With sodium hydrogencarbonate In acetonitrile for 5h; Heating / reflux;
  • 23
  • [ 33657-49-7 ]
  • (butyryloxy)methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% Stage #1: 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylic acid With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) Stage #2: chloromethyl n-butyrate In DMF (N,N-dimethyl-formamide) at 20 - 50℃; for 52h; 17 EXAMPLE 17; (Butyryloxy)methyl l -ethyl-6-oxo.3-phenyl-5-(pyridin-3-ylamino)-1 ,6- dihydropyridazine-4-carboxylate; To a stirred mixture of the title product of Preparation 28 (30 mg, 0.09 mmol) in dry DMF (1 ml), diisopropylethylamine (18 µl, 0.107 mmol) was added dropwise and the resulting mixture was stirred for a while. Then, chloromethyl butyrate (10 µl, 0.10 mmol) was added dropwise and the final mixture was stirred at 50°C for 4 h and then at rt for 2 days. Solvent was removed under reduced pressure and the resulting residue was purified by flash column chromatography (Si02, hexane-ethyl acetate) to yield the title product (40 mg, 52% yield). LRMS: m/Z 437 (M+1)+. Retention Time: 15 min. No. (DMSO-d6): 0.86 (t, 3H), 1.35 (t, 3H), 1.46 (m, 2H), 2.14 (t, 2H), 4.16 (q, 2H), 4.86 (s, 2H), 7.26 (m, 2H), 7.36 (m, 4H), 7.50 (m, 1H), 8.36 (m, 2H), 9.35 (s, 1H).
  • 24
  • [ 33657-49-7 ]
  • [ 15687-27-1 ]
  • α-methyl-4-(2-methylpropyl)-benzeneacetyloxymethyl butyrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate; triethylamine In <i>N</i>-methyl-acetamide 1 Synthesis of α-methyl4-(2-methylpropyl)-benzeneacetyloxymethyl butyrate. EXAMPLE 1 Synthesis of α-methyl4-(2-methylpropyl)-benzeneacetyloxymethyl butyrate. (Compound 1) To a stirred solution of ibuprofen (10.16 g, 49 mmol) and chloromethyl butyrate (6.80 g, 1 eq.) in dry dimethylformamide (20 mL), under nitrogen, was dropwise added triethylamine (8.5 mL, 6 g, 1.2 eq). The mixture was heated at 70° C. for four hours, during which time a large amount of precipitate formed; thin layer chromatography (TLC: ethyl acetate:hexane 1:1) showed that all of the acid had reacted. The precipitate was filtered and washed with ethyl acetate. The filtrate was partitioned between water and ethyl acetate. The aqueous phase was washed with a small amount of ethyl acetate and the combined organic phase was washed with water (3 x), 5% solution of sodium bicarbonate (2 x), and brine (2 x), dried with magnesium sulfate and evaporated to give the crude product as a colorless oil (11.6 g). The crude product was distilled at 170° C./1 mm Hg. The pure product was obtained as a colorless oil (8.7 g, 58% yield).
  • 25
  • sodium carbonate (NaHCO3) [ No CAS ]
  • Triethylamine (Et3 N)(5 ml, 1.2 eq) [ No CAS ]
  • [ 598-02-7 ]
  • [ 33657-49-7 ]
  • butyroyloxymethyl diethyl phosphate [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% In dimethylformamide [DMF] 1 (COMPOUND 1) (COMPOUND 1) The synthesis of butyroyloxymethyl diethyl phosphate (BODP) was carried out as follows: Triethylamine (Et3 N)(5 ml, 1.2 eq) was added dropwise to a stirred solution of diethyl phosphate (4.1 g, 30 mmol) and chloromethyl butyrate (4.12 g, 1 eq) in dry dimethylformamide (DMF) (10 mL), at room temperature under nitrogen. The reaction mixture was heated at 65° C. for three hours whereby a large amount of precipitate formed and thin layer chromatography (TLC: CHCl3:MeOH 7:1, detection-vanillin) showed that most of the acid had reacted. The precipitate was filtered and washed with ethyl acetate. The filtrate was partitioned between water and ethyl acetate. The aqueous phase was extracted back with a small amount of ethyl acetate, and the combined organic phase was washed three times with water, three times with a 5% solution of sodium carbonate (NaHCO3) and twice with brine, dried with magnesium sulfate (MgSO4) and evaporated to give the crude product as a yellowish material (1.6 g, 65% yield) which was chromatographed on silica gel (60 g, ethyl acetate:hexane:isopropanol 8:8:1). The product was found in the second fraction. The pure product (1 g, 40% yield) was a colorless oil. Additional compounds of the invention are provided in Table I. These compounds are those of Formula I having the designated groups. These compounds may be synthesised in a manner analogous to the method of Example 1 or as provided in the Detailed Description of the Invention.
  • 26
  • [ 49715-04-0 ]
  • [ 2472-88-0 ]
  • [ 107-92-6 ]
  • [ 33657-49-7 ]
YieldReaction ConditionsOperation in experiment
With potassium hydrogencarbonate In dichloromethane; water 4 4.6 Preparation of cisapride carbonates 4.6 Preparation of cisapride carbonates To a solution of butyric acid (1.76 g, 20 mmol) in dichloromethane (35 ml) was added tetrabutylammonium sulfate (680 mg, 2 mmol) and potassium bicarbonate (8.2 g) in water. To this solution was then added a solution of chloromethyl chlorosulfate (3.63 g) in dichloromethane (5 ml). The mixture was stirred at room temperature for one hour and the aqueous layer was extracted with dichloromethane (30 ml). The dichloromethane solutions were combined, dried (sodium sulfate), and concentrated in vacuo to yield crude chloromethyl butyrate (2.8 mg) which was purified by column chromatography (10.62 mmol, 53.1%).
  • 27
  • [ 33657-49-7 ]
  • [ 50-91-9 ]
  • [ 161632-24-2 ]
YieldReaction ConditionsOperation in experiment
58.9% With sodium iodide; potassium carbonate R.5.a REFERENCE EXAMPLE 5 (a) In the same manner as described in Reference Example 1(a) except for using 2.2 g of 5-fluoro-2'-deoxyuridine, 6.67 g of anhydrous potassium carbonate, 4.82 g of sodium iodide and 2.44 g of chloromethyl n-butanoate, there was prepared 1.82 g of 3-n-butanoyloxymethyl-2'-deoxy-5-fluorouridine in the form of white powder (yield: 58.9%). The melting point of the obtained powder was 103.0° to 105.0° C.
58.9% With sodium iodide; potassium carbonate 25.a Preparation of the compound (I) wherein R1=CH3(CH2)2COO, R2=R3=CH3(CH2)6COO, R4=H, R=H, Y=F (a) The procedures of Example 1(a) were repeated except that 5-fluoro-2'-deoxyuridine (2.2 g, 8.94 mmol), anhydrous potassium carbonate (6.67 g), sodium iodide (4.82 g) and chloromethyl n-butyrate (2.44 g, 2 equivalents) were used to give 3-n-butyryloxymethyl-2'-deoxy-5-fluorouridine as white powder (1.82 g) (yield: 58.9 %) (melting point: 103.0 to 105.0°C).
  • 28
  • [ 49715-04-0 ]
  • [ 107-92-6 ]
  • [ 33657-49-7 ]
YieldReaction ConditionsOperation in experiment
100% With tetrabutylammomium bromide; sodium hydrogencarbonate; In dichloromethane; water; at 20℃; for 16h; Compound 9 was prepared by a procedure similar to that of Hursthouse and co-workers,24 and Binderup and co-workers.35 To a mixture of butyric acid (426 muL, 4.6 mmol), water (5 mL), dichloromethane (5 mL), sodium hydrogen carbonate (1.46 g, 17.5 mmol) and tetrabutylammonium bromide (148 mg, 0.46 mmol) was added dropwise <strong>[49715-04-0]chloromethyl chlorosulfate</strong> (534 muL, 5.28 mmol) in dichloromethane (1.5 mL). The reaction was stirred at room temperature for 16 h and the organic layer separated, dried over anhydrous sodium sulfate and the solvent removed in vacuo. The crude residue was taken up in dimethylformamide (1 mL) and added to a solution of NRB (500 mg, 0.98 mmol) in dimethylformamide (2 mL), followed by potassium carbonate (135 mg, 0.98 mmol). The mixture was stirred at room temperature for 16 h, taken up in dichloromethane/water (1:1) (30 mL), washed with water (2 × 20 mL), dried over anhydrous magnesium sulfate and the solvent removed in vacuo. Purification by flash chromatography (hexane/ethyl acetate 1:1) afforded 9 as a colourless solid (375 mg, 0.61 mmol, 62%).
41% With sodium hydrogencarbonate; tetra(n-butyl)ammonium hydrogen sulfate; In dichloromethane; water; 6.21 Preparation of deprenyl-N-butyroyloxymethyl, iodide salt To a solution of butyric acid (3 g, 0.034 mol) in dichloromethane (34 ml) was added sodium bicarbonate (11 g, 0.13 mol), tetrabutylammonium hydrogen sulfate (1.15 g, 0.0034 mol) and water (34 ml). With rapid stirring, <strong>[49715-04-0]chloromethyl chlorosulfate</strong> (ClCH2 SO3 Cl, 6.4 g, 0.04 mol) was added. The mixture was stirred for one hour, diluted with dichloromethane (20 ml), washed with water, dried (sodium sulfate), and concentrated in vacuo to yield chloromethyl butyrate (2.1 g, 41%) which was purified by distillation.
31% With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate; In dichloromethane; water; at 0℃; for 1h; To a stirred solution of butyric acid (2 g, 22.70 mmol) in DCM (30 ml_) and water (30.0 ml_) was added sodium bicarbonate (7.63 g, 91 mmol) and tetrabutylammonium hydrogen sulfate (0.771 g, 2.270 mmol) followed by chloromethyl sulfurochloridate (5.62 g, 34.0 mmol) drop wise at 0 C. The reaction mixture was stirred at 0 C for 1 h. The progress of the reaction was monitored by TLC (Si02, 5% EtOAc/Pet., Rf = 0.8, KMn04- active). The reaction mixture was quenched with water (20 ml_) and extracted with DCM (2 x 25 ml_). The combined organic layers were washed with brine (2 c 50 ml_) and concentrated under reduced pressure to give the crude residue. The crude compound was dissolved in Et20 (50 ml_) and washed with cold water (4 x 30 mL), dried over Na2S04, filtered and concentrated under reduced pressure to afford chloromethyl butyrate (1 .0 g, Yield: 31 %, pale yellow liquid).. NMR (400 MHz, CDCI3) d = 5.70 (s, 2H), 2.37 (t, J = 7.5 Hz, 2H), 1 .74-1 .65 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). GCMS: RT = 1.646 mins, Purity = 98%.
  • 29
  • [ 51-21-8 ]
  • [ 33657-49-7 ]
  • [ 554-68-7 ]
  • [ 66542-37-8 ]
YieldReaction ConditionsOperation in experiment
86.9% With triethylamine; In N-methyl-acetamide; EXAMPLE 1 In a 300 cc 4-necked flask equipped with a stirrer, a thermometer and a dropping funnel were placed 80 ml of dimethylformamide. Then, 10.41 g (0.08 mol) of 5-fluorouracil was dissolved in the dimethylformamide and 24.29 g (0.24 mol) of triethylamine was added to this solution. To the mixture was added dropwise over 15 minutes 10.93 g (0.08 mol) of butyryloxymethyl chloride. The mixture was reacted together for 5 hours at room temperature and the reaction liquid was filtered to remove the precipitated triethylamine hydrochloride. The solvent was then distilled from the filtrate and the residue was subjected to a treatment using a column packed with silica gel and a mixture (1:1 in mixing ratio) of benzene and ethyl acetate whereby crude 1-butyryloxymethyl-5-fluorouracil was isolated. This crude product was recrystallized from benzene whereby 16.0 g of pure white crystals having a melting point of 96~98 C. were obtained in a yield of 86.9%.
  • 30
  • [ 33657-49-7 ]
  • [ 36322-90-4 ]
  • 4-(Butyryloxy)methoxy-2-methyl-N-(pyridin-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-Dioxide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In dichloromethane; water; acetone 32 4-(Butyryloxy)methoxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-Dioxide EXAMPLE 32 4-(Butyryloxy)methoxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-Dioxide To a round bottomed flask equipped with a reflux condenser and stirring bar were added piroxicam (1.00 g, 3.0 mmol), potassium carbonate (0.84 g, 6.1 mmol), chloromethyl butyrate (0.45 g, 3.3 mmol) and acetone (15 mL). The heterogenous reaction mixture was heated to reflux under a nitrogen atmosphere. After 24 hours the acetone was removed in vacuo leaving a yellow solid which was treated with water (100 mL) and methylene chloride (100 mL). The organic layer was separated and the aqueous layer extracted with additional methylene chloride (100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried (Na2 SO4) and concentrated in vacuo to a yellow oil. Column chromatography on silica gel (1:9 ethyl acetate/methylene chloride) afforded 260 mg of yellow oil which produced a white foam under vacuum (0.60 mmol, 20.2%). Attempted crystallization from toluene/hexane produced an oil, but with refrigeration the oil produced pure white crystals. Combined first and second crops yielded 86 mg white crystals; mp 202°-204° C.; IR (KBr) 1770, 1688 cm-1; 1 H NMR (CDCl3) delta 0.79 (t, J=7 Hz, 3H), 1.35-1.53 (m, 2H), 2.18 (t, J=7 Hz, 2H), 3.12 (s, 3H), 5.70 (s, 2H), 7.05-7.18 (m, 1H), 7.65-7.88 (m, 4H), 7.88-7.99 (m, 1H), 8.28-8.42 (m, 2H), 9.32 (br s, 1H); precise mass calcd for C20 H21 N3 O6 S m/e 431.1151, found 431.1106.
  • 31
  • [ 593-71-5 ]
  • [ 156-54-7 ]
  • [ 33657-49-7 ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate In chloroform; water; tetra(n-butyl)ammonium hydrogen sulfate; acetone 10 Chloromethyl Butyrate PREPARATION 10 Chloromethyl Butyrate In a one liter beaker tetrabutylammonium hydrogen sulfate (38.54 g, 113.5 mmol) and sodium bicarbonate (9.53 g, 113.5 mmol) were combined with water (225 mL). When all forming had ceased, the solution was stirred and chloroform (675 mL) was added, followed by sodium butyrate (12.50 g, 113.5 mmol). The two phase system was stirred vigorously for 15 minutes, at which time the organic layer was separated, the aqueous layer extracted with chloroform (325 mL) and the combined organic extracts dried (Na2 SO4) and evaporated in vacuo to a thick oil. To a stirring solution of the oil in acetone (650 mL) was rapidly added at room temperature a solution of iodochloromethane (20.0 g, 113.5 mmol) in acetone (25 mL). Stirring was continued 0.5 hour. The acetone was removed in vacuo to yield a white solid. Column chromatography on silica gel eluding with 9:1 methylene chloride:hexane and collecting the fractions containing the least polar spot by TLC (same eluant, Rf 0.60, visualization by bromocresol green spray aided by heat) afforded chloromethyl butyrate as a pale yellow oil (3.00 g, 22.0 mmol, 19.4%): 1 H NMR (CDCl3) delta 0.80 (t, J=7 Hz, 23H), 1.45 (sextet, J=7 Hz, 2H), 2.16 (t, J=7 Hz, 2H), 5.77 (s, 2H).
  • 32
  • (4S)-1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-carboxymethyl-3-pyridinecarboxylic acid [ No CAS ]
  • [ 108-20-3 ]
  • [ 33657-49-7 ]
  • [ 167356-40-3 ]
YieldReaction ConditionsOperation in experiment
42% With sodium hydrogencarbonate In 2,2,4-trimethylpentane; dichloromethane; ethyl acetate; N,N-dimethyl-formamide 5 Example 5 Example 5 (4R)-Butyroxymethyl methyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate To a stirred mixture of (4S)-1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-carboxymethyl-3-pyridinecarboxylic acid (2.0 g, 5.61 mmol) and sodium bicarbonate (0.96 g, 11.4 mmol) in DMF (100 ml) under nitrogen atmosphere was added chloromethyl butyrate (1.16 g, 8.5 mmol). The reaction mixture was heated at 80° C. for 23 h. Workup by filtration followed by evaporation of solvent. The crude residue was dissolved in dichloromethane and washed with sodium bicarbonatesolution. The organic phase was dried over sodium sulfate and evaporated. Recrystallization first from a mixture of 45% ethylacetate in isooctane followed by diisopropylether gave colorless crystals (1.08 g, 42%), mp. 128°-129° C. NMR spectral data are identical with the data of the racemate as shown in Example 3. [α]D20 =-21.50 (1 % in methanol).
  • 33
  • (4R)-1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-carboxymethyl-3-pyridinecarboxylic acid [ No CAS ]
  • [ 33657-49-7 ]
  • [ 167356-39-0 ]
YieldReaction ConditionsOperation in experiment
70% With sodium hydrogencarbonate In dichloromethane; N,N-dimethyl-formamide 4 Example 4 Example 4 (4S)-Butyroxymethyl methyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate To a stirred mixture of (4R)-1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-carboxymethyl-3-pyridinecarboxylic acid (2.93 g, 8.23 mmol) and sodium bicarbonate (1.38 g, 16.5 mmol) in DMF (150 ml) under nitrogen atmosphere was added chloromethyl butyrate (1.72 g, 12.6 mmol). The reaction mixture was heated at 80° C. for 17 h. Workup by filtration followed by evaporation of solvent. The crude residue was chromatographed on silica gel with 5% ethyl acetate in dichloromethane. Recrystallization from diisopropylether gave colorless crystals (2.62 g, 70%), mp. 128°-129° C. NMR spectral data are identical with the data of the racemate as shown in Example 3. [α]D20 =+17.5° (1% in methanol).
  • 34
  • [ 752222-83-6 ]
  • [ 33657-49-7 ]
  • [3-ethyl-2,6-dioxo-1-propyl-8-(1-[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurin-7-yl]methyl butanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 60℃; for 16h; 5 Example 5- Synthesis of Exemplary Compound E Compound E was synthesized according to the steps below. (0710) [00316] To a solution of compound 1 (400 mg, 0.897 mmol, 1.0 eq) in DMF (10 mL) was added K2CO3 (371 mg, 2.69 mmol, 3.0 eq) and KI (15 mg, 0.0897 mmol, 0.1 eq), followed by (0711) chloromethyl butyrate (366 mg, 2.69 mmol, 3.0 eq), and the mixture was stirred at 60 °C for 16 h. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using 30% ethyl acetate/hexane to afford Compound E (420 mg, 86%) as a white solid. (0712) [00317] LCMS: [M+1] = 547.45; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 2.1 Hz, 2H), 7.63- 7.44 (m, 4H), 6.33 (s, 2H), 5.41 (s, 2H), 4.17 (d, J = 7.1 Hz, 2H), 4.01- 3.90 (m, 2H), 2.30 (t, J = 7.4 Hz, 2H), 1.72- 1.57 (m, 4H), 1.34 (t, J = 7.1 Hz, 3H), 0.92 (dt, J = 19.0, 7.5 Hz, 6H).
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16h; 1.A EXAMPLE 1; Preparation of a Compound of Formula I Preparation of a Compound of Formula I where R1 is n-Propyl, R2 is Ethyl, R4 is 3-Trifluoromethylphenyl, X is Hydrogen, and Y is n-Butanoyl; To a solution of 3-ethyl-1-propyl-8-(1-[3-(trifluoromethyl)phenyl]methyl}-pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione (250 mg, 0.56 mmol) in N,N-dimethylformamide (10 ml) was added potassium carbonate (230 mg, 1.68 mmol), followed by chloromethylbutyrate (230 mg, 1.68 mmol), and the mixture was stirred at 60° C. for 16 hours. The solid was filtered off, and solvent removed from the filtrate under reduced pressure. The residue was chromatographed on silica gel, eluting with 30% ethyl acetate/hexane, yielding [3-ethyl-2,6-dioxo-1-propyl-8-(1-[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurin-7-yl]methyl butanoate (150 mg). 1H NMR (CDCl3): δ 7.98 (s, 1H), 7.97 (s, 1H), 7.65-7.45 (m, 4H), 6.35 (s, 2H), 5.44 (s, 2H), 4.19 (q, J=8 Hz, 2H), 3.98 (q, J=2 Hz, 2H), 2.33 (t, J=8 Hz, 2H), 1.75-1.60 (m, 4H), 1.36 (t, J=8 Hz, 3H), 0.96 (t, J=8 Hz, 3 H), 0.92 (t, J=8 Hz, 3 H).
  • 35
  • [ 916324-77-1 ]
  • [ 33657-49-7 ]
  • N-[4-chloro-2-(2,4-dichlorophenoxy)phenyl]-N-(butyryl)oxymethyl-1,1,1-trifluoromethanesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With potassium carbonate; sodium iodide In acetone for 3h; Heating / reflux; 5 Preparation of N-[4-chloro-2-(2,4-dichlorophenoxy)phenyl]-N-(butyryl)oxymethyl-1,1,1-trifluoromethanesulfonamide (Compound 73); A mixture of N-[4-chloro-2-(2,4-dichlorophenoxy)phenyl]-1,1,1-trifluoromethane sulfonamide (316 mg, 0.750 mmol), n-butanoic acid chloromethyl ester (205 mg, 0.750 mmol), potassium carbonate (311 mg, 1.50 mmol), sodium iodide (22mg, 0.150 mmol) and acetone (10 mL) was stirred at room temperature for 16h (no reaction observed) and then refluxed for 3h, after which the reaction was complete, as determined by thin-layer chromatography. The mixture was filtered and evaporated in vacuo and the residue partitioned between 1:1 concentrated NH3(aq.)/brine and dichloromethane. The organic phase was dried and evaporated in vacuo. The crude product was chromatographed through a plug of SiO2, eluting with a gradient of 1:4 to 1:1 dichloromethane in petroleum spirit. The major fraction gave N-[4-chloro-2-(2,4-dichlorophenoxy)phenyl]-N-(butyryl)oxymethyl-1,1,1-trifluoromethanesulfonamide (Compound 73) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=2.4 Hz, 1H); 7.34 (m, 2H); 7.13 (d, J=8.7Hz, 1H); 7.08 (dd J=8.3, 2.2 Hz, 1H,); 6.59 (d, J=2.2 Hz, 1H); 5.76 (brs, 2H); 2.33 (t, J=7.5 Hz, 2H); 1.63 (m, 2H); 0.93 (m, 3H). ES-MS 541 m/z (M+Na)+
  • 36
  • [ 33657-49-7 ]
  • [ 37076-68-9 ]
  • (5-fluoro-2,3-dihydro-3-((R)-tetrahydrofuran-2-yl)-2,6-dioxopyrimidin-1(6H)-yl)methyl butyrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 20h;
  • 37
  • [ 33657-49-7 ]
  • 4-dimethylcarbamoyl-1-{4-[5-(2-fluorobiphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]benzyl}piperidine-4-carboxylic acid tert-butylamine salt [ No CAS ]
  • [ 1093213-66-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-dimethylcarbamoyl-1-{4-[5-(2-fluorobiphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]benzyl}piperidine-4-carboxylic acid tert-butylamine salt With potassium carbonate In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: chloromethyl n-butyrate In tetrahydrofuran; N,N-dimethyl-formamide at 20 - 80℃; for 0.583333h; 140 Potassium carbonate (0.092 g, 0.0007 mol) is added to a solution of t-butyl amine salt of 4-dimethyl carbamoyl-1 -{4-[5-(2-fluorobiphenyl-4-yl)-[1 ,2,4]oxadiazol- 3-yl]-benzyl}-piperidine-4-carboxylic acid (0.200 g, 0.0003 mol) in tetrahydrofuran (10 ml_).This solution is stirred at room temperature for 10 minutes and then is concentrated under reduced pressure. The residue is dissolved in N,N-dimethyl formamide (5 ml_) and stirred at room temperature for 5 minutes. Chloromethyl butyrate (0.068 g, 0.0005 mol) is added to the solution, which is then heated at 800C for 30 minutes. Reaction mixture is concentrated under reduced, demineralized water (6 ml_) is added to the residue and the aqueous layer is extracted with ethyl acetate (2x10 ml_). Combined organic layer are concentrated under reduced pressure and the residue is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate 1.5:8.5) to furnish 4- dimethylcarbamoyl-1 -{4-[5-(2-fluorobiphenyl-4-yl)-[1 ,2,4]oxadiazol-3-yl]-benzyl}- piperidine-4-carboxylicacid butyryloxy methyl ester
  • 38
  • [ 33657-49-7 ]
  • [ 1132945-26-6 ]
  • [ 1132935-84-2 ]
YieldReaction ConditionsOperation in experiment
10% With potassium carbonate In dimethyl sulfoxide at 20℃; for 20h; 25 Example 25. Preparation of (N-(4-(3-tert-butyl-5-(3-(butyryloxymethyl)-2,4-dioxotetrahydro pyrimidin-l(2H)-yl)-2-methoxybenzamido)phenyl)methylsulfonamido)methyl butyrate (compound IA- L3-1.88).; [00970] The product from Example 22, Part G (0.098g, 0.20mmole) was dissolved in DMSO (2ml) and treated with potassium carbonate (0.166g, 1.20mmole) and chloromethyl butyrate (0.41 Ig, 3.0mmol). The mixture was stirred 2Oh at room temperature. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous solid sodium sulfate. The drying agent was filtered and the solvent evaporated under vacuum. The residue was purified with silica gel eluting with ethyl acetate/hexane (10% to 80%) to give two major fractions. The first fraction was purified with silica gel eluting with methanol/dichloromethane (1% to 3%) to give the title compound as a foam (0.014, 10%). 1H NMR (300 MHz, DMSO-D6) δ ppm 0.88 (m, 6 H) 1.38 (s, 9 H) 1.55 (m, 4 H) 2.26 (t, J=7.17 Hz, 2 H) 2.39 (t, J=7.17 Hz, 2 H) 2.95 (t, J=6.62 Hz, 2 H) 3.14 (s, 3 H) 3.77 (s, 3 H) 3.81 (t, J=6.62 Hz, 2 H) 5.57 (s, 2 H) 5.68 (s, 2 H) 7.35 (d, J=2.57 Hz, 1 H) 7.38 (d, J=2.94 Hz, 1 H) 7.42 (d, J=8.82 Hz, 2 H) 7.79 (d, J=8.82 Hz, 2 H) 10.60 (s, 1 H).
  • 39
  • [ 33657-49-7 ]
  • [ 72072-06-1 ]
  • [ 1088563-50-1 ]
  • 40
  • [ 33657-49-7 ]
  • [ 66-22-8 ]
  • (2,3-dihydro-2,6-dioxopyrimidin-1(6H)-yl)methyl butyrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% Stage #1: uracil With potassium carbonate In DMF (N,N-dimethyl-formamide); acetone Stage #2: chloromethyl n-butyrate In DMF (N,N-dimethyl-formamide); acetone at 20℃; for 20h; To a solution of uracil (0.21 gram, 1.83 mmol) in DMF (3 ml) and acetone (4 ml) was added K2C03 (0.51 gram, 3.66 mmol) and the mixture was stirred for a few minutes. Chloromethyl butyrate (0.5 ml, 3.66 mmol) in 1 ml of DMF was added over 15 minutes. The reaction mixture was stirred for 20 hours at room temperature and was then filtered. To the filtrate were added ethyl acetate and water. The organic layer was extracted with ml5 x 15 ml of water and the aqueous layer was extracted with ml5 x 15 ml of ethyl acetate. The organic layers were combined, dried over MgS04 and evaporated. The obtained crude white powder was purified by silica gel chromatography, using a mixture of hexane and ethyl acetate (1:1) to give the product (0.12 gram, 31% yield) as a white powder having a melting point of 121-122 °C. H-NMR (CDCl3) No. = 8.3 (bs, 1H, NH), 7.51 (d, J = 8.4 Hz, 1H, H-1), 5.71 (dd, J = 8.4,2.3 Hz, 1H, H-2), 5.67 (s, 2H, H-4), 2.37 (triplet, J = 7.3 Hz, 2H, H-5), 1.66 (sextet, 2H, H-6), 0.94 (triplet, J = 7.3 Hz, 3H, H-7) ppm. C-NMR (CDCl3) No. = 173.8 (C-7), 163.1 (C-8), 150.5 (C-9), 144.6 (C-2), 103.0 (C-1), 69.5 (C-3), 35.8 (C-4), 18.2 (C-5), 13.6 (C-6) ppm. MS (ES+): m/z (%) =235.0667 ([M+Na] (at), 100), 251.0351 ([M+K]+, 21.55), 213.0880 (MH+, 13.35).
  • 41
  • [ 33657-49-7 ]
  • [ 17902-23-7 ]
  • 5-fluoro-2,3-dihydro-3-(tetrahydrofuran-2-yl)-2,6-dioxopyrimidin-1(6H)-ylmethyl butyrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% To a solution of <strong>[17902-23-7]tegafur</strong> (0.26 gram, 1.31 mmol) in DMF (2 ml) was added K2C03 (0.18 gram, 1.31 mmol) and the mixture was stirred for a few minutes. Chloromethylbutyrate (0.16 ml, 1.31 mmol, 1 equivalent) in 1 ml of DMF was added over 15 minutes. The reaction mixture was stirred for 20 hours at room temperature and was then filtered. To the filtrate were added toluene, water and brine. The organic layer was extracted with 5 x 15 ml of brine and the aqueous layer was extracted with 5 x 15 ml of toluene. The organic layers were combined, dried over MgS04 and evaporated. The obtained oily residue was dissolved in a minimal amount of ethyl acetate and was then purified by silica gel chromatography, using a mixture of hexane and ethyl acetate (1: 3). The filtrate was evaporated and was left to crystallize in the freezer for several hours to give AN-420 (0.33 gram, 83 % yield) as off-white crystals having a melting point of 67-68 C. H-NMR (DMSO-d6): 8 = 8.05 (d, J = 6.9 Hz, 1H, HI), 5.98 (ddd, J = 6.7, 3.4, 1.6 Hz, 1H, H2), 5.82 (s, 2H, H6), 4.3 + 3.86 (dt, J = 8,6 Hz, 1H + q, J = 8 Hz, 1H, 2Hs), 2.12 + 2.01 (m, 1H + m, 1H, 2H4), 2.32 (t, J = 7.1 Hz, 2H, H7), 1:97 (m, 2H, H3), 1.56 (sext, J = 6.7 Hz, 2H, H8), 0.9 (t, J = 6.7 Hz, 3H, H9); C-NMR (DMSO-d6): No. = 171.8. (C13), 156.0 (d, J = 26.4 Hz, C11,148.3 (C12), 139.1 (d, J=228 Hz, Cio), 125.0 (d, J= 33.2 Hz, C1), 87.5 (C2), 69.6 (C6), 64.2 (C5), 34.9 (C7), 31.4 (C3), 23.4 (C4), 17.7 (C8), 13.1 (C9); 19F-NMR (DMSO-d6): No. = 166.7 (dd, J= 7.2, lHz) . (MS (CI+): m/z (%) = 301.124 (C13H18N2O5F, 100), 231.020 ([M-C4H7O] +, 62) ; HRMS: calculated for C13H18N2O5F ([M-1]+, DCI/CH4) 301.119975; found 301.123656. Elemental Analysis: calculated for C13H17N2O5F (300.11) C 52.00, H 5.71, N 9.33; found: C 51.84, H 5.72, N 9.33.
  • 42
  • [ 33657-49-7 ]
  • [ 50-35-1 ]
  • 2-(1-butyroyloxymethyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% To a solution of <strong>[50-35-1]thalidomide</strong> (0.44 g, 1.72mmol) in DMF (6 ml) was added Cs2C03 (0.56 g, 1.72 mmol) and the mixture was stirred for a few minutes until total dissolution. Chloromethyl butyrate (0.23 ml, 1.72 mmol) in 1 ml of DMF was added over 15 minutes. The reaction mixture was then stirred for 20 hours at room temperature. To the mixture were added toluene, water and brine. The organic layer was extracted with 5 x 15 ml of brine and the aqueous layer was extracted with 5 x 15 ml of toluene. The organic layers were combined, dried over MgS04 and evaporated. The crude white powder was purified by silica gel chromatography, using a mixture of hexane and ethyl acetate (2:1) to give an off-white powder. The powder was dried over P205 overnight to give AN-438 (0.48 gram, 74 % yield). melting point: 132-133 C. (at)H-NMR (DMSO-d6): 8 = 7.96-7.89 (m, 4H, AA'BB'), 5.65 (ABq, J = 9.8 Hz, 2H, H-4), 5.35 (dd, J = 13.2, 5.6 Hz, 1H, H-lax), 3.07 (ddd, J = 17.6, 13.2, 5.6 Hz, 1H, H-3ax), 2.84 (ddd, J = 17.6, 4.6, 2.9 Hz ,1H, H-3eq), 2.63 (qd, J = 13.2, 4.6 Hz, 1H, H- 2ax), 2.26 (triplet, J = 7.5 Hz, 2H, H-5), 2.12 (dtd, J = 13.2, 5.6, 2.9 Hz, 1H, H-2eq), 1.52 (sextet, J = 7.5 Hz, 2H, H-6), 0.87 (triplet, J = 7.5 Hz, 3H, H-7) ppm. C-NMR (DMSO-d6) 8 = 171.8 (C-8), 171.1 (C-10), 169.2 (C-9), 167.1 (C- 11), 135.0 (C-14), 131.1 (C-12), 123.5 (C-13), 62.9 (C-4), 49.5 (C-1), 35.0 (C-3), 31.0 (C-5), 20.8 (C-2), 17.8 (C-6), 13.3 (C-7) ppm. MS (ES+): m/z (%) =381 ([M+Na]+, 100), 359 (MH+, 7.45), 271 ([M- C4H7O2] +, 14.51).
  • 43
  • [ 921927-94-8 ]
  • [ 33657-49-7 ]
  • [ 1200041-15-1 ]
YieldReaction ConditionsOperation in experiment
52% Stage #1: methyl 2-{(1R,3R)-3-[(2S,3S)-2-azido-3-methylpentanoyl]amino}-4-methyl-1-[(triethylsilyl)oxy]pentyl}-1,3-thiazole-4-carboxylate With potassium hexamethylsilazane In tetrahydrofuran at -45℃; for 0.166667h; Stage #2: chloromethyl n-butyrate In tetrahydrofuran at -45 - 20℃; for 3h;
5.7 g Stage #1: methyl 2-{(1R,3R)-3-[(2S,3S)-2-azido-3-methylpentanoyl]amino}-4-methyl-1-[(triethylsilyl)oxy]pentyl}-1,3-thiazole-4-carboxylate With potassium hexamethylsilazane In tetrahydrofuran; toluene at -45℃; for 0.25h; Stage #2: chloromethyl n-butyrate In tetrahydrofuran; toluene The crude product 4 was co-evaporated with toluene again and used without further purification. TES protected dipeptide was dissolved in 38 mL THF (anhydrous, inhibitor- free) and cooled to -45 °C and stirred for 15 minutes before adding KHMDS (0.5 M in toluene, 25.5 mL, 12.8 mmol, 1.1 equiv) drop-wise. After the addition of KHMDS was complete, the reaction mixture was stirred at -45 °C for 15 minutes, and chloromethyl butyrate (1.8 mL, 1.2 equiv, 14 mmol) was added. The reaction mixture changed from light yellow to a bluish color. TLC (20% EtOAc/petroleum ether) showed the majority of starting material was converted. LC-MS showed about 7% starting material left. The reaction was quenched by adding 3 mL MeOH, the mixture was warmed to room temperature and concentrated under reduced pressure to an oily residue. The residue was dissolved in petroleum ether and passed through short silica plug to remove the potassium salt. The plug was washed with 13% EtOAc/petroleum ether, and the collected eluates were combined and concentrated under reduced pressure. The crude alkylated product was passed through an additional silica plug (product/silica = 1:50) and eluted with 13% EtOAc/petroleum ether to remove residual starting material to give 5.7 g of product 5 (two steps, yield 76%)
5.7 g Stage #1: methyl 2-{(1R,3R)-3-[(2S,3S)-2-azido-3-methylpentanoyl]amino}-4-methyl-1-[(triethylsilyl)oxy]pentyl}-1,3-thiazole-4-carboxylate With potassium hexamethylsilazane In tetrahydrofuran; toluene at -45℃; for 0.25h; Stage #2: chloromethyl n-butyrate In tetrahydrofuran; toluene Synthesis of Dipeptide 3 The crude product 2 was co-evaporated with toluene again and used without further purification. TES protected dipeptide was dissolved in 38 mE THF (anhydrous, inhibitor- free) and cooled to -45° C. and stirred for 15 minutes before adding KHMDS (0.5 Mintoluene, 25.5 mE, 12.8 mmol, 1.1 equiv) drop-wise. After the addition of KHMDS was complete, the reaction mixture was stirred at -45° C. for 15 minutes, and chloromethyl butyrate (1.8 mE, 1.2 equiv, 14 mmol) was added. The reaction mixture changed from light yellow to a blueish color. TEC (20% EtOAc/petroleum ether) showed the majority of starting material was converted. ECMS showed about 7% starting material lefi. The reaction was quenched by adding 3 mE MeOR, the mixture was warmed to room temperature and concentrated under reduced pressure to an oily residue. The residue was dissolved in petroleum ether and passed through short silica plug to remove the potassium salt. The plug was washed with 13% EtOAc/petroleum ether, and the collected eluates were combined and concentrated under reduced pressure. The crude alkylated product was passed through an additional silica plug (product/silica=1 :50) and eluted with 13% EtOAc/petroleum ether to remove residual starting material to give 5.7 g of product 3 (two steps, yield 76%)
With potassium hexamethylsilazane In tetrahydrofuran
12.1 g Stage #1: methyl 2-{(1R,3R)-3-[(2S,3S)-2-azido-3-methylpentanoyl]amino}-4-methyl-1-[(triethylsilyl)oxy]pentyl}-1,3-thiazole-4-carboxylate With potassium hexamethylsilazane In tetrahydrofuran; toluene at -45℃; for 0.25h; Stage #2: chloromethyl n-butyrate In tetrahydrofuran; toluene at -45℃; The crude product 2 was co-evaporated with toluene again and used without further purification. TES protected dipeptide was dissolved in 80 mL THF (anhydrous, inhibitor-free) and cooled to -45° C. and stirred for 15 minutes before adding KHMDS (0.5 M in toluene, 50 mL, 25.0 mmol, 1.05 equiv) drop-wise. After the addition of KHMDS was complete, the reaction mixture was stirred at -45° C. for 15 minutes, and chloromethyl butyrate (3.6 mL, 1.2 equiv, 28.3 mmol) was added. The reaction mixture changed from light yellow to a blueish color. TLC (20% EtOAc/petroleum ether) showed the reaction was complete. The reaction was quenched by adding 20 mL MeOH, the mixture was warmed to room temperature and concentrated under reduced pressure to an oily residue. The residue was dissolved in petroleum ether and passed through short silica plug to remove the potassium salt. The plug was washed with 13% EtOAc/petroleum ether, and the collected eluents were combined and concentrated under reduced pressure to give 12.1 g of product 3 (two steps, yield 76%)
With potassium hexamethylsilazane In tetrahydrofuran at -45℃; 1.a; 1.e e. EXAMPLE. EC1004 is re ared accordin to the followin rocess. Into a round bottomed flask equipped with magnetic stir bar and temperature probe dipeptide EC1458, imidazole, and methylene chloride is added. Once all the solids have dissolved, the solution is cooled using an ice bath. Chlorotriethylsilane (TESCl) is added drop wise and the ice bath is removed. The reaction is monitored for completion. A second portion of chlorotriethylsilane and/or imidazole is added if necessary. The imidazole HCl salt is removed by filtration and methylene chloride is added. The organics are washed with a saturated solution of sodium chloride (brine), the aqueous layer is back extracted once with methylene chloride, and the combined organic layers are washed with brine. The organic layer is dried over sodium sulfate and concentrated on a rotary evaporator. The residue is dissolved in tetrahydrofuran (THF) and cooled to approximately -45 oC. A solution of potassium bis(trimethylsilyl)amide (KHMDS) in toluene is added drop wise. With stirring, chloromethyl butyrate is added and the reaction is monitored. The reaction is quenched with methanol and then ethyl acetate and brine are added. The aqueous layer is discarded and the organics are washed once with brine. The organic layer is concentrated on a rotary evaporator and the oily residue is passed through a short plug of silica gel. The plug is washed with a 20% solution of ethyl acetate in petroleum ether. The combined organics are concentrated on a rotary evaporator until distillation ceases. The crude EC1004 oil is analyzed by LC and NMR and stored in a freezer until use.
16.5 g Stage #1: methyl 2-{(1R,3R)-3-[(2S,3S)-2-azido-3-methylpentanoyl]amino}-4-methyl-1-[(triethylsilyl)oxy]pentyl}-1,3-thiazole-4-carboxylate With potassium hexamethylsilazane In tetrahydrofuran at -45℃; for 0.333333h; Stage #2: chloromethyl n-butyrate In tetrahydrofuran at -45℃; for 0.333333h; 1.d 10.83 g of dipeptide 7 (27.25 mmol) (prepared according to the methods described in Peltier, H.M., et al., “The Total Synthesis of Tubulysin D”, J. Am. Chem. Soc., v. 128, pp. 16018-16019 (2006)) was dissolved in 100 mL dichloromethane and imidazole (2.05 g, 1.1 eq.)was added. The reaction mixture was stirred at room temperature to dissolve all solids andcooled in the ice bath for 10 mi TESC1 (4.8 mL, 1.05 eqiv.) was added drop-wise at 0 °C,stirred under argon, and warmed to room temperature over 1.5 h. TLC (3:1 hexanes/EtOAc)showed complete conversion. The reaction was filtered to remove the imidazole HC1 salt. 125mL dichloromethane was added to the filtrate, and the resulting solution was extracted with 250mL brine. The brine layer was extracted with 125 mL dichloromethane. The combined organicphase was washed with 250 mL brine, separated, dried over 45.2 g of Na2504, and filtered. Theresulting solution was concentrated under reduced pressure, co-evaporated with toluene (2 x 5mL) and dried over high-vacuum overnight to give 14.96 g of crude product 8.
With potassium hexamethylsilazane In tetrahydrofuran at -45℃;
16.5 g Stage #1: methyl 2-{(1R,3R)-3-[(2S,3S)-2-azido-3-methylpentanoyl]amino}-4-methyl-1-[(triethylsilyl)oxy]pentyl}-1,3-thiazole-4-carboxylate In tetrahydrofuran at -45℃; for 0.25h; Stage #2: With potassium hexamethylsilazane In tetrahydrofuran; toluene at -45℃; for 0.333333h; Stage #3: chloromethyl n-butyrate In tetrahydrofuran; toluene at -45℃; for 0.333333h; 1.d The crude product 8 was used without further purification. TES protected dipeptide was dissolved in 100 mL THF (anhydrous, inhibitor-free), cooled to -45° C., and stirred at -45° C. for 15 minutes before adding KHMDS (0.5 M in toluene, 61 mL, 1.05 equiv.), drop-wise. After the addition of KHMDS was finished, the reaction was stirred at -45° C. for 20 minutes, and chloromethyl butyrate (4.4 mL, 1.1 equiv.) was added. The reaction mixture was stirred at -45° C. for another 20 minutes. The reaction was quenched with 25 mL MeOH and warmed to room temperature. 250 mL EtOAc and 250 mL brine were added to the reaction mixture, and the organic phase was separated. The solvent was evaporated to reduce the volume of solution. The solution was passed through 76.5 g silica in a 350 mL sintered glass funnel. The silica plug was washed with 500 mL EtOAc/petroleum ether (1:4). The filtrate and the wash were concentrated to oily residue and dried under high vacuum to give 16.5 g product 9 as a light yellow wax.

  • 44
  • [ 33657-49-7 ]
  • [ 950173-68-9 ]
  • [ 1219813-32-7 ]
YieldReaction ConditionsOperation in experiment
26.3% Stage #1: (5S)-5-[(1,3-dihydro-6-methoxy-1-oxo-2H-isoindol-2-yl)methyl]-5-furo[3,2-c]pyridin-2-yl-2,4-imidazolidinedione With lithium hydride In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: chloromethyl n-butyrate In N,N-dimethyl-formamide at 0 - 20℃; 12 Compound 1d (120 mg, 0.306 mmol) was dissolved in DMF (3 mL) and cooled to 0 0C. LiH (4.8 mg, 0.62 mmol) was added. After the solution was stirred at 0 0C for 5 minutes, Chloromethyl butyrate xr (46 mg, 0.34 mmol) was added. The solution was stirred at 0 0C for three hours, then was allowed to warm up to room temperature and stirred overnight. AcOH (37 mg, 0.62 mmoi) was added. The solution was purified by C18 chromatography (CH3CNZH2O, 5% to 90%, containing 0.1% HCO2H) to give compound 81 (45.2 mg, 26,3%)
  • 45
  • [ 921196-96-5 ]
  • [ 33657-49-7 ]
  • C18H16ClNO10S [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With caesium carbonate; sodium iodide In N,N-dimethyl-formamide at 20℃; for 16h; Darkness;
  • 46
  • [ 33657-49-7 ]
  • [ 1257044-79-3 ]
  • [ 1257051-03-8 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In acetonitrile for 1h; Reflux; 368 Example 368 [4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)amino}methyl butyrate EXAMPLE 37E (500 mg) was dissolved in acetonitrile (3.7 mL) and chloromethyl butyrate (77 mg) and Hunig's base (73 mg) were added. The reaction was heated under reflux for one day. After cooling and dilution with dimethylsulfoxide (4 mL) the reaction was purified by preparative HPLC using a 250*50 mm C18 column and eluding with 20-100% CH3CN vs. 0.1% trifluoroacetic acid in water, giving the product as a trifluoroacetate salt. The trifluoroacetic acid salt was dissolved in dichloromethane (6 ml) and washed with 50% aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to provide the title compound. 1H NMR (400 MHz, dimethylsulfoxide-d6) δ 11.72 (s, 1H), 8.43 (d, 1H), 8.22 (dd, 1H), 8.01 (d, 1H), 7.55 (m, 3H), 7.36 (m, 3H), 7.03 (d, 2H), 6.68 (dd, 1H), 6.41 (m, 1H), 6.17 (d, 1H), 5.83 (s, 2H), 4.40 (d, 2H), 3.78 (m, 2H), 3.59 (m, 2H), 3.08 (br m, 4H), 2.73 (br s, 2H), 2.18 (m, 8H), 1.96 (s, 2H), 1.84 (m, 4H), 1.39 (m, 4H), 0.92 (s, 6H), 0.75 (t, 3H).
With N-ethyl-N,N-diisopropylamine In acetonitrile for 24h; Reflux; 368 [4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)amino}methyl butyrate (1163) Compound 37E (500 mg) was dissolved in acetonitrile (3.7 ml) and chloromethyl butyrate (77 mg) and Hunig's base (73 mg) were added. The reaction was heated under reflux for one day. After cooling and dilution with dimethylsulfoxide (4 ml) the reaction was purified by preparative HPLC using a 250×50 mm C18 column and eluting with 20-100% CH3CN vs. 0.1% trifluoroacetic acid in water, giving the product as a trifluoroacetate salt. The trifluoroacetic acid salt was dissolved in dichloromethane (6 ml) and washed with 50% aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to provide the title compound. 1H NMR (400 MHz, dimethylsulfoxide-d6) δ 11.72 (s, 1H), 8.43 (d, 1H), 8.22 (dd, 1H), 8.01 (d, 1H), 7.55 (m, 3H), 7.36 (m, 3H), 7.03 (d, 2H), 6.68 (dd, 1H), 6.41 (m, 1H), 6.17 (d, 1H), 5.83 (s, 2H), 4.40 (d, 2H), 3.78 (m, 2H), 3.59 (m, 2H), 3.08 (br m, 4H), 2.73 (br s, 2H), 2.18 (m, 8H), 1.96 (s, 2H), 1.84 (m, 4H), 1.39 (m, 4H), 0.92 (s, 6H), 0.75 (t, 3H).
  • 47
  • [ 33657-49-7 ]
  • [ 100986-85-4 ]
  • [ 55696-44-1 ]
  • [ 1261134-52-4 ]
YieldReaction ConditionsOperation in experiment
59% Stage #1: levofloxacin With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 0.333333h; Stage #2: chloromethyl n-butyrate In N,N-dimethyl-formamide at 90℃; for 1h;
  • 48
  • [ 33657-49-7 ]
  • [ 40554-92-5 ]
  • [ 1114367-10-0 ]
YieldReaction ConditionsOperation in experiment
42.73% With triethylamine In dichloromethane at 25 - 42℃; for 5.16667h; 2 Chloro methylbutyrate (0.28 gm, 2.0 mmol) was added drop wise to a suspension of 3,7-bis(benzyloxy)-2-(4-(benzyloxy)-3-hydroxyphenyl)-5-hydroxy-4H-chromen-4-one [(III, R1=benzyl) 1 g, 1.7 mmol], triethylamine (0.36 ml, 2.6 mmol) in methylene chloride (20 ml), at 25° C. The resulting mixture was stirred at 25° C. for ten minutes and further for 5 hour at 40-42° C. The reaction mixture was diluted with methylene chloride (25 ml) and water (50 ml). The organic layer was separated, washed with water, dried over anhydrous sodium sulphate and evaporated to give crude product. The crude product was purified by crystallization using methylene chloride/Hexane to furnish the required product.Yield 0.500 g (42.73%). Rf 0.73 (30% EtOAC/Pet.ether); 1HNMR (DMSO-d6): δ 0.85-0.90 (t, 3H), 1.57-1.64 (m, 2H), 2.55 (m, 2H), 5.08 (s, 2H), 5.23 (s, 2H), 5.25 (s, 2H), 6.48 (s, 1H), 6.89 (s, 1H), 7.31-7.46 (m, 19H), 7.79 (s, 1H), 7.92-7.95 (d, 1H); HPLC purity=94.9%.
  • 49
  • [ 33657-49-7 ]
  • [ 348-27-6 ]
  • [ 1296131-18-4 ]
YieldReaction ConditionsOperation in experiment
43% To a 500 mL dry round bottom flask a were added <strong>[348-27-6]2-fluoro-4-hydroxybenzaldehyde</strong> (5.60 g, 40 mmol), anhydrous K2CO3 (10.6 g, 76.9 mmol) and acetone (200 mL). The mixture was stirred at room temperature for 30 minutes. To another 500 mL dry round bottom flash b were added chloromethyl butyrate (9.33 g, 61.5 mmol), KI (14.2 g, 66.6 mmol) and acetone (150 mL). This mixture was also stirred at room temperature for 30 minutes. After the solid settled down on the glassware bottom, the top yellow acetone solution in flask b was decanted into the stirring solution in the round bottom flask a. The resulting mixture was refluxed for 4 hours. Most acetone was rotary evaporated, and the residual solid was triturated with methyl tert-butyl ether (MTBE) three times (100 mL, 50 mL, 50 mL). The MTBE extract was concentrated, and the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give (3-fluoro-4-formylphenoxy)methyl butyrate (6.40 g) as a colorless oil. Yield: 43%. 1H NMR (CDCl3, 300 MHz): delta=10.18 (s, 1H), 7.80 (t, J=8.7 Hz, 1H), 6.93-6.89 (m, 1H), 6.82 (dd, J=12.3, 2.1 Hz, 1H), 5.83 (s, 2H), 2.36 (t, J=7.5 Hz, 2H), 1.64 (sextet, J=7.5 Hz, 2H), 0.92 (t, J=7.5 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz): delta=185.5 (d, J=6.1 Hz), 169.7 (d, J=258.8 Hz), 162.8 (d, J=12.2 Hz), 130.2 (d, J=3.7 Hz), 119.1 (d, J=8.5 Hz), 112.4 (d, J=3.1 Hz), 103.5 (d, J=24.4 Hz), 84.1, 35.7, 18.0, 13.3.
  • 50
  • [ 33657-49-7 ]
  • [ 123853-39-4 ]
  • clevidipine [ No CAS ]
YieldReaction ConditionsOperation in experiment
87.2% With potassium carbonate; lithium iodide; In N,N-dimethyl-formamide; at 70℃; for 4h; <strong>[123853-39-4]4-(2',3'-dichlorophenyl)-2,6-dimethyl-5-(methoxycarbonyl)-1,4-dihydropyridin-3-carboxylic acid</strong> (20.0g, 56.2mmol), Potassium carbonate (32.lg, 232.5 mmol), lithium iodide (3.86 g, 23.2 mmol) was addedDMF (300 ml), and chloromethyl n-butyrate was added(31.6 g, 232.5 mmol) at 70 C for 4 h. The reaction solution was cooled to roomThe organic layer was separated, dried and the solvent was removed. A solid precipitated and a pale yellow solid was obtained by filtration. The filter cake was washed with 250 ml of methanol / water (100 ml)(1/1, volume ratio) to obtain 61.6 g of a solid, 87.2% yield.
66% With potassium carbonate; In 1,4-dioxane; water; for 4h;Reflux; Example 3 - Synthesis of 3-butanoyloxymethoxycarbonyl-5-methoxycarbonyl-4- (2,3-dichlorophenyl)-2,6-dimethyl-1 ,4-dihydropyridine [0022] Purified carboxylic acid 2 (5.00g, 14 mmol) and potassium carbonate (1 .94g, 14 mmol) were suspended in a mixture of 1 ,4-dioxane (25ml_) and water (1 .25ml_). Chloromethyl butyrate (3.26g, 24 mmol) was added and the reaction mixture was refluxed for 4h. The reaction mixture was cooled to room temperature, and heptane (17ml_) and silica gel were added. The solids were filtered off and washed with a mixture of 1 ,4-dioxane and heptane. Isopropanol (20ml_) and water (75ml_) were added to the combined filtrates. The resulting solution was stirred at room temperature and the formed solids were collected by filtration and washed with a mixture of water and isopropanol followed by heptane. Drying for 48h under high vacuum at 40C gave the title compound as an off-white powder (4.20g, 66% yield). Analysis by HPLC indicates a purity of 99.03%, with no impurity 6 being detected.
65% With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 80℃; for 4h; Compound 7 (300 mg, 0.83 mmol), NaHC03 (150 mg, 1.66 mmol) was dissolved in DMF (8 ml), compound 8 (170 mg, 1.24 mmol) was added under N2 and heated to 80 C reflux, 4 hours The organic layer was washed with saturated brine, dried over anhydrous NaS04 and separated by column chromatography to obtain clovipid butyrate (250 mg,65% yield)
The free acid form of compound 1 is suitably prepared by basic hydrolysis of cyanoethyl ester 2, described above. Then the free acid can be reacted with solid TMAH, optionally in the form of a hydrate, in dioxane solvent. It is also preferred to add a small amount of water, e.g. 2-10% v/v, to the reaction, so as to obtain crude material of suitable quality.[0009] This reaction to produce the tetramethylammonium salt of compound 1 can be conducted at room temperature, with stirring. After substantial completion of the reaction, the chloromethyl butyrate is preferably added to the same reaction vessel, without recovering the carboxylate. The alkylation process proceeds under reflux conditions. When the reaction is complete, the reaction mixture is allowed to cool to some degree, and the organic phase containing the desired solid product is subjected to filtration to recover the solids. After suitable washing and drying, crude clevidipine butyrate is obtained.[0010] It is preferred according to the invention to subject the crude product to crystallization from a solution in mixed dichloromethane/heptane solvent. This step not only eliminates most of the impurities, but also significantly improves the colour of the final product, so as to yield an off-white solid. Repeating this crystallization step will produce a white solid. A final crystallization from isopropanol/water is also preferably conducted, for further removal of impurities.[0011] The invention is further described, for illustrative purposes, in the following specific experimental example. Specific Description of the Most Preferred Embodiment[0012] To free acid compound 1 , 4-(2,3-dichlorophenyl)-1 ,4-dihydro-2,6- dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid (50. Og, 140 mmol) and solid Me4NOH»5H2O (30.5g, 168 mmol) were added dioxane (250ml_) and water (12.5ml_), and the resulting suspension was stirred at room temperature for 45 min. Chloromethyl butyrate (33. Og, 242 mmol) was added and the reaction mixture was refluxed for 5h. Once the reaction was complete, heptane (250ml_) was added.[0013] The aqueous layer was removed, and silica gel was added to the organic phase. The suspension was stirred for 30 min., after which the solids were removed by filtration and washed with a 1 : 1 mixture of heptane and dioxane. The filtrate and wash were combined, and isopropanol (250m L) and deionized water (750ml_) were added. After agitating for 18h, the solids were collected by filtration, washed with a mixture of isopropanol and deionized water, then with heptane. The crude clevidipine butyrate was dried under high vacuum at 40C until constant weight (54.0g, 1 18 mmol, 84% yield) was achieved.[0014] Crude clevidipine butyrate (50. Og, 1 10 mmol) was dissolved in dichloromethane (200ml_) and heptane (800ml_) was added to the solution. After stirring for 2h, the solids were collected by filtration and washed with a mixture of dichloromethane and heptane, followed by heptane. The clevidipine butyrate was then dried under high vacuum at 40C for 16h to give an off-white solid (40.5g, 89 mmol, 81 % yield).[0015] For the final crystallization, clevidipine butyrate (40. Og, 88 mmol) was dissolved in hot isopropanol (400ml_). With the solution still hot, deionized water (400ml_) was added and the mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with a mixture of deionized water and isopropanol, followed by heptane. Drying under high vacuum at 40C gave clevidipine butyrate as an off white solid (36.6g, 80 mmol, 91 % yield).
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;Inert atmosphere;Product distribution / selectivity; Example-5: Preparation of Clevidipine:100 gm of 1 ,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-methoxycarbonyl-3- pyridinecarboxylic acid and 35.4 gm of Sodium bicarbonate is stirred in DMF under nitrogen atmosphere. 49.9 gm of Chloromethyl butyrate was added and reaction mixture was heated at about 80C for 4 hrs. The solvent was distilled out and residue was treated with methylene chloride. The obtained reaction mass was washed with water and the methylene chloride layer was dried over sodium sulphate. Methylene chloride was distilled out under vacuum. Diisopropyl ether (800 ml) was added to the residual mass and stirred at 25-30C for one hour. The reaction mass was filtered, the wet cake was washed with diisopropyl ether to give crude clevidipine (Wt. = 97.5 gms HPLC Purity > 99%).

  • 51
  • [ 33657-49-7 ]
  • [ 404373-25-7 ]
  • [ 1346550-33-1 ]
  • trans-2-(2',3'-dichloro-benzylidene)-3-oxo-butyric acid butyryloxymethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In acetone at 25 - 58℃; Inert atmosphere; 7 Preparation of Benzylidine butyrate (2-(2',3'-Dichloro-benzylidene)-3-oxo-butyric acid butyryloxymethyl ester) (compound I) 5.0 g (0.0193 mol) of benzylidine acid, 2.92 g (0.0289 mol) of triethyl amine and 50 ml acetone were charged in a 250 ml flask fitted with a reflux condenser. 3.55 g (0.026 mol) of chloromethyl butyrate were slowly added at 25-30° C. under nitrogen atmosphere. The reaction mass was stirred at 55-58° C. for 15-20 hours, followed by cooling, down to 30° C., and filtering of the inorganic salts. Acetone was distilled out under reduce pressure at 45-50° C. The obtained mixture was diluted with 100 ml of ethyl acetate and washed with 100 ml of demineralized (DM) water twice. The organic layer was separated and the ethyl acetate distilled out under reduced pressure at 45-50° C. to yield a yellowish coloured liquid. Yield: 6.5 g, Molar yield: 93.8%, HPLC purity: 91.58% (Mixture of cis and trans isomers are present in ratio of 64.91 and 35.09% respectively).
  • 52
  • [ 33657-49-7 ]
  • [ 1346644-00-5 ]
  • [ 1346550-33-1 ]
  • trans-2-(2',3'-dichloro-benzylidene)-3-oxo-butyric acid butyryloxymethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 25 - 42℃; Inert atmosphere; 8 Preparation of Benzylidine butyrate (2-(2',3'-Dichloro-benzylidene)-3-oxo-butyric acid butyryloxymethyl ester) (compound I) 2.0 g (0.0067 mol) of potassium salt of benzylidine acid, 20 ml of dichloromethane and 0.4 g (0.004 mol) of triethyl amine were charged in a 100 ml flas. 1.37 g (0.010 moles) of chlomethyl butyrate were slowly added at 25-30° C. under nitrogen atmosphere. The reaction mass was stirred at 40-42° C. for 25-30 hours. Afterwards, the mixture was cooled down to 25° C. and washed twice with 25 ml of water. The organic and the aqueous layer were separated and the dichloromethane distilled out at 40-42° C. under reduced pressure. 2.2 g of a yellow coloured liquid were obtained. Molar yield: 91.46%, HPLC purity: 91.9% (Mixture of cis and trans isomers in the ratio of 60.94 and 39.06° A) respectively).
  • 53
  • [ 33657-49-7 ]
  • [ 1346644-00-5 ]
  • [ 1020718-27-7 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 25 - 42℃; for 30h; Inert atmosphere; 8 Example 8 Preparation of Benzylidine butyrate (2-(2', 3'-Dichloro-benzylidene)-3-oxo-butyric acid butyryloxymethyl ester) (compound I) 2.0 g (0.0067 mol) of potassium salt of benzylidine acid, 20 ml of dichloromethane and 0.4 g (0.004 mol) of triethyl amine were charged in a 100 ml flas. 1.37 g (0.010 moles) of chlomethyl butyrate were slowly added at 25-30 ºC under nitrogen atmosphere. The reaction mass was stirred at 40-42 ºC for 25-30 hours. Afterwards, the mixture was cooled down to 25 ºC and washed twice with 25 ml of water. The organic and the aqueous layer were separated and the dichloromethane distilled out at 40-42 ºC under reduced pressure. 2.2 g of a yellow coloured liquid were obtained. Molar yield: 91.46 %, HPLC purity: 91.9% (Mixture of cis and trans isomers in the ratio of 60.94 and 39.06 % respectively).
  • 54
  • [ 33657-49-7 ]
  • C11H16NO5P [ No CAS ]
  • [ 1400482-65-6 ]
YieldReaction ConditionsOperation in experiment
358 mg Stage #1: C11H16NO5P With triethylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: chloromethyl n-butyrate In N,N-dimethyl-formamide at 20 - 70℃; Inert atmosphere; 4.1.8. General procedure to introduce the acyloxyalkyl/phenyl group General procedure: To a solution of the diethyl phosphonate in CH2Cl2 (3 mL/mmol) was added dropwise at 0 °C bromotrimethylsilane (5 eq.). The reaction mixture was stirred at 0 °C for 1 h and then overnight at room temperature. The reaction was quenched by addition of H2O (0.3 mL/mmol), and the mixture was stirred for 5 min and evaporated to dryness. The residue was dissolved in DMF (6 mL/mmol), and after addition of Et3N (3 eq.), the reaction mixture was stirred at room temperature for 5 min. Acyloxymethyl chloride (10 eq.) was added, and the mixture was stirred at 70 °C for 5 h. Another 3 eq. of Et3N and 5 eq. of acyloxymethyl chloride were added and the mixture was stirred overnight at room temperature. Et2O was added to the reaction mixture and the solution was successively washed with H2O, with a saturated solution of NaHCO3 and again with H2O. The resulting organic layer was dried, filtered and evaporated to dryness and the residue purified by flash chromatography on silica gel (Et2O).
  • 55
  • [ 33657-49-7 ]
  • [ 1376377-44-4 ]
  • [ 1376377-48-8 ]
YieldReaction ConditionsOperation in experiment
75 mg Stage #1: C11H16NO5P With triethylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: chloromethyl n-butyrate In N,N-dimethyl-formamide at 20 - 70℃; Inert atmosphere; 4.1.8. General procedure to introduce the acyloxyalkyl/phenyl group General procedure: To a solution of the diethyl phosphonate in CH2Cl2 (3 mL/mmol) was added dropwise at 0 °C bromotrimethylsilane (5 eq.). The reaction mixture was stirred at 0 °C for 1 h and then overnight at room temperature. The reaction was quenched by addition of H2O (0.3 mL/mmol), and the mixture was stirred for 5 min and evaporated to dryness. The residue was dissolved in DMF (6 mL/mmol), and after addition of Et3N (3 eq.), the reaction mixture was stirred at room temperature for 5 min. Acyloxymethyl chloride (10 eq.) was added, and the mixture was stirred at 70 °C for 5 h. Another 3 eq. of Et3N and 5 eq. of acyloxymethyl chloride were added and the mixture was stirred overnight at room temperature. Et2O was added to the reaction mixture and the solution was successively washed with H2O, with a saturated solution of NaHCO3 and again with H2O. The resulting organic layer was dried, filtered and evaporated to dryness and the residue purified by flash chromatography on silica gel (Et2O).
  • 56
  • [ 33657-49-7 ]
  • [ 1376377-45-5 ]
  • [ 1376377-49-9 ]
YieldReaction ConditionsOperation in experiment
110 mg Stage #1: C12H18NO5P With triethylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: chloromethyl n-butyrate In N,N-dimethyl-formamide at 20 - 70℃; Inert atmosphere; 4.1.8. General procedure to introduce the acyloxyalkyl/phenyl group General procedure: To a solution of the diethyl phosphonate in CH2Cl2 (3 mL/mmol) was added dropwise at 0 °C bromotrimethylsilane (5 eq.). The reaction mixture was stirred at 0 °C for 1 h and then overnight at room temperature. The reaction was quenched by addition of H2O (0.3 mL/mmol), and the mixture was stirred for 5 min and evaporated to dryness. The residue was dissolved in DMF (6 mL/mmol), and after addition of Et3N (3 eq.), the reaction mixture was stirred at room temperature for 5 min. Acyloxymethyl chloride (10 eq.) was added, and the mixture was stirred at 70 °C for 5 h. Another 3 eq. of Et3N and 5 eq. of acyloxymethyl chloride were added and the mixture was stirred overnight at room temperature. Et2O was added to the reaction mixture and the solution was successively washed with H2O, with a saturated solution of NaHCO3 and again with H2O. The resulting organic layer was dried, filtered and evaporated to dryness and the residue purified by flash chromatography on silica gel (Et2O).
  • 57
  • [ 33657-49-7 ]
  • [ 581106-29-8 ]
  • [ 1400482-55-4 ]
YieldReaction ConditionsOperation in experiment
53 mg Stage #1: [3-[acetyl(phenylmethoxy)amino]propyl]phosphonic acid With triethylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: chloromethyl n-butyrate In N,N-dimethyl-formamide at 20 - 70℃; Inert atmosphere; 4.1.8. General procedure to introduce the acyloxyalkyl/phenyl group General procedure: To a solution of the diethyl phosphonate in CH2Cl2 (3 mL/mmol) was added dropwise at 0 °C bromotrimethylsilane (5 eq.). The reaction mixture was stirred at 0 °C for 1 h and then overnight at room temperature. The reaction was quenched by addition of H2O (0.3 mL/mmol), and the mixture was stirred for 5 min and evaporated to dryness. The residue was dissolved in DMF (6 mL/mmol), and after addition of Et3N (3 eq.), the reaction mixture was stirred at room temperature for 5 min. Acyloxymethyl chloride (10 eq.) was added, and the mixture was stirred at 70 °C for 5 h. Another 3 eq. of Et3N and 5 eq. of acyloxymethyl chloride were added and the mixture was stirred overnight at room temperature. Et2O was added to the reaction mixture and the solution was successively washed with H2O, with a saturated solution of NaHCO3 and again with H2O. The resulting organic layer was dried, filtered and evaporated to dryness and the residue purified by flash chromatography on silica gel (Et2O).
  • 58
  • [ 33657-49-7 ]
  • [ 1394050-24-8 ]
  • [ 1394050-55-5 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In acetone for 24h; Inert atmosphere; Reflux; 5.V V. (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid butyryloxymethyl ester (R4=H; R7=-CH2OC(O)(CH2)2CH3) Chloromethyl butyrate (49 μL, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid butyryloxymethyl ester.
  • 59
  • [ 33657-49-7 ]
  • [ 2321-07-5 ]
  • [ 1394821-39-6 ]
YieldReaction ConditionsOperation in experiment
35% Stage #1: chloromethyl n-butyrate With sodium iodide In acetone at 20℃; for 24h; Inert atmosphere; Stage #2: fluorescein With silver(l) oxide In acetonitrile at 20℃; for 48h; Inert atmosphere; Molecular sieve;
  • 60
  • [ 33657-49-7 ]
  • [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] [ No CAS ]
  • N-butanoyloxymethyl-5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; 4.1.6. N-Butanoyloxymethyl-5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide (9) Compound 9 was prepared by a procedure similar to that of Hursthouse and co-workers,24 and Binderup and co-workers.35 To a mixture of butyric acid (426 μL, 4.6 mmol), water (5 mL), dichloromethane (5 mL), sodium hydrogen carbonate (1.46 g, 17.5 mmol) and tetrabutylammonium bromide (148 mg, 0.46 mmol) was added dropwise chloromethyl chlorosulfate (534 μL, 5.28 mmol) in dichloromethane (1.5 mL). The reaction was stirred at room temperature for 16 h and the organic layer separated, dried over anhydrous sodium sulfate and the solvent removed in vacuo. The crude residue was taken up in dimethylformamide (1 mL) and added to a solution of NRB (500 mg, 0.98 mmol) in dimethylformamide (2 mL), followed by potassium carbonate (135 mg, 0.98 mmol). The mixture was stirred at room temperature for 16 h, taken up in dichloromethane/water (1:1) (30 mL), washed with water (2 × 20 mL), dried over anhydrous magnesium sulfate and the solvent removed in vacuo. Purification by flash chromatography (hexane/ethyl acetate 1:1) afforded 9 as a colourless solid (375 mg, 0.61 mmol, 62%). mp 68-79 °C; 1H NMR (300 MHz, CDCl3) δ 0.89-0.96 (3H, m, Me), 1.55-1.71 (2H, m, OCOCH2CH2), 2.25-2.35 (2H, m, OCOCH2CH2), 3.37-3.74 (2.2H, m, 0.2H U/H-2 and U/H-3, 0.6H V/H-2 and V/H-3, 0.6H W/H-2, W/H-3 and W/H-4, 0.8H Y/H-2 and Y/H-3), 3.86-3.93 (0.4H, m, 0.1H U/H-1 and 0.3H V/H-1), 3.96-4.02 (0.4H, m, Y/H-4), 4.19-4.24 (0.1H, m, U/H-1), 4.37-4.43 (0.3H, m, V/H-4), 4.50-4.59 (0.6H, m, 0.2H W/H-1 and 0.4H Y/H-1), 5.30-5.35 (0.7H, m, 0.3H V/H-6 and 0.4H Y/H-6), 5.44-5.64 (3H, m, 2H NCH2O and 1H OH), 6.03-6.08 (0.3H, m, 0.1H U/H-6 and 0.2H W/H-6), 6.75-7.58 (16H, m, Ar), 8.37-8.44 (0.8H, m, 0.2H 2U/αPyr and 0.6H 2V/αPyr), 8.49-8.51 (0.6H, m, 0.2H W/αPyr and 0.4H Y/αPyr), 8.58-8.63 (0.6H, m, 0.2H W/αPyr and 0.4H Y/αPyr); 13C NMR (75 MHz, CDCl3) δ 13.2 (CH3), 17.7 (CH2), 35.2 (CH2), 43.8-46.7 (CH), 48.8-49.3 (CH), 61.2-61.4 (CH2), 77.2 (C), 121.3-122.4 (CH), 123.6-124.0 (CH), 126.4-130.0 (CH), 132.8-133.5 (CH), 135.6-136.4 (CH), 138.0-138.3 (C), 141.7-142.9 (C), 147.4-147.8 (CH), 148.7-148.9 (CH), 152.4 (C), 153.7 (C), 155.2 (C), 157.7-158.0 (C), 160.3-160.7 (C), 172.0-172.1 (C), 174.3-175.1 (C); νmax/cm-1 1041 and 1208 (C-O ester), 1585 (CO imide), 1713 (CO ester); m/z (ESI) 612 (MH+, 100%); (Found: MH+ 612.2489, C38H34N3O5 requires 612.2493).
  • 61
  • [ 33657-49-7 ]
  • [ 1432502-67-4 ]
  • [ 1432502-80-1 ]
YieldReaction ConditionsOperation in experiment
With 2,6-dimethylpyridine; sodium iodide In N,N-dimethyl-formamide at 20℃; 14.K K. Butyric Acid (R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'oxalylhydrazino]-2-hydroxypropionyloxymethyl Ester A mixture of (R)-3-[N'-t-butoxyoxalyl-N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (300 mg, 430 μmol), chloromethyl butyrate (175 mg, 1.3 mmol), NaI (192 mg, 1.3 mmol) and 2,6-dimethylpyridine (680 mg, 6.4 mmol) in DMF (10 mL) was stirred at room temperature overnight. The mixture was poured into water (30 mL) and the mixture was then extracted with EtOAc (3*20 mL). The organic layer was separated, washed with saturated aqueous NaCl (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude Compound 1 (300 mg) was used without purification. LC-MS: 567[M+H]+.
  • 62
  • [ 33657-49-7 ]
  • [ 1432502-24-3 ]
  • C27H34ClNO7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
240 mg With N-ethyl-N,N-diisopropylamine; sodium iodide In N,N-dimethyl-formamide at 30℃; for 16h; (2R,4R)-4-Amino-5-(3'-chlorobiphenyl-4-yl)-2-hydroxypentanoic Acid Butyryloxymethyl Ester Preparation 17 (2R,4R)-4-Amino-5-(3'-chlorobiphenyl-4-yl)-2-hydroxypentanoic Acid Butyryloxymethyl Ester A solution of (2R,4R)-4-t-butoxycarbonylamino-5-(3'-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid (900 mg, 2.1 mmol), chloromethyl butyrate (350 mg, 2.6 mmol), sodium iodide (481 mg, 3.21 mmol) and DIPEA (828 mg, 6.42 mmol) in DMF (20 mL) was stirred for 16 hours at 30° C. The mixture was diluted with EtOAc (150 mL) and washed with water (50 mL) and saturated aqueous NaCl (50 mL). The organic layer was collected and concentrated and purified by column chromatography (hexanes/EtOAc=5:1) to yield a white solid (240 mg). LC-MS: 542 [M+Na]+. A solution of this solid (240 mg, 460 μmol) in 1.4 M HCl in 1,4-dixoane (15 mL) was stirred overnight, and then concentrated in vacuo. The residue was dispersed in EtOAc (10 mL), and the precipitated was collected by filtration to yield the title compound as an off-white solid HCl salt (140 mg). LC-MS: 420 [M+H]+. 1H NMR: (DMSO) 0.85 (t, J=7.5 Hz, 3H), 1.61-1.52 (m, 2H), 1.89-1.86 (m, 2H), 2.30 (t, J=7.5 Hz, 2H), 2.98 (br, 2H), 3.56 (br, 1H), 4.33-4.30 (m, 1H), 5.74-5.68 (m, 2H), 6.21 (s, 1H), 7.37-7.35 (m, 4H), 7.70-7.767 (m, 4H), 8.01 (brs, 3H).
240 mg With N-ethyl-N,N-diisopropylamine; sodium iodide In N,N-dimethyl-formamide at 30℃; for 16h; 8 Preparation 8 (2R,4R)-4-Amino-5-(3'-chlorobiphenyl-4-yl)-2-hydroxypentanoic Acid Butyryloxymethyl Ester A solution of (2R,4R)-4-t-butoxycarbonylamino-5-(3'-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid (900 mg, 2.1 mmol), chloromethyl butyrate (350 mg, 2.6 mmol), sodium iodide (481 mg, 3.21 mmol) and DIPEA (828 mg, 6.42 mmol) in DMF (20 mL) was stirred for 16 hours at 30° C. The mixture was diluted with EtOAc (150 mL) and washed with water (50 mL) and saturated aqueous NaCl (50 mL). The organic layer was collected and concentrated and purified by column chromatography (hexanes/EtOAc=5:1) to yield a white solid (240 mg). LC-MS: 542 [M+Na]+. A solution of this solid (240 mg, 460 μmol) in 1.4 M HCl in 1,4-dioxane (15 mL) was stirred overnight, and then concentrated in vacuo. The residue was dispersed in EtOAc (10 mL), and the precipitated was collected by filtration to yield the title compound as an off-white solid HCl salt (140 mg). LC-MS: 420 [M+H]+. 1H NMR: (DMSO) 0.85 (t, J=7.5 Hz, 3H), 1.61-1.52 (m, 2H), 1.89-1.86 (m, 2H), 2.30 (t, J=7.5 Hz, 2H), 2.98 (br, 2H), 3.56 (br, 1H), 4.33-4.30 (m, 1H), 5.74-5.68 (m, 2H), 6.21 (s, 1H), 7.37-7.35 (m, 4H), 7.70-7.767 (m, 4H), 8.01 (brs, 3H).
  • 63
  • [ 33657-49-7 ]
  • [ 1439393-38-0 ]
  • [ 1439395-45-5 ]
YieldReaction ConditionsOperation in experiment
0.15 g Stage #1: C26H26N6O2S With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: chloromethyl n-butyrate In N,N-dimethyl-formamide at 80℃; for 1.5h; Inert atmosphere; 1 To a flask was added K2CO3 (0.28 g, 2.06 mmol), compound 295 (0.5 g, 1.03 mmol) followed by 25 mL of DMF. The mixture was stirred for 15 minutes and chloromethyl butyrate (0.17 g, 1.23 mmol) was added and the reaction placed under an atmosphere of argon. The mixture was heated to 80°C for 1.5 hours, allowed to cool to room temperature and poured into 200 ml water. The mixture was transferred to a separatory funnel, extracted with EtOAc (3x100 mL), the organic layers separated and washed with water (3x50 mL), brine (2x50 ml) and dried over Na2S04. The Na2S04 was removed by filtration and the volatiles removed under reduced pressure. The crude material was purified by reverse-phase chromatography giving 0.15 g of compound 402
  • 64
  • [ 33657-49-7 ]
  • [ 314045-39-1 ]
  • [ 1439389-42-0 ]
  • [ 1439389-41-9 ]
YieldReaction ConditionsOperation in experiment
1: 0.235 g 2: 0.126 g With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 15h; 1 To a flask containing N,N'-(5,5'-(thiobis(ethane-2,l-diyl))bis(l,3,4-thiadiazole-5,2- diyl))bis(2-phenylacetamide) (1) (9.4 mmol, 5.0 g, 1.0 equiv.) was added 100 mL DMF, K2C03 (20.98 mmol, 2.89 g, 2.2 equiv.), and chloromethyl butyrate (20.98 mmol, 2.86 g, 2.62 mL, 2.2 equiv.). The mixture stirred at room temperature for 15 hours then diluted with 200 mL water and 200 mL EtOAc. The layers were separated and the aqueous layer extracted with EtOAc (2 x 100 mL) and the organic layers combined, washed with water, brine and dried over Na2S04. The Na2S04 was removed by filtration and the volatiles removed under reduced pressure. The compounds were purified by reverse phase chromatography (MeCN, H20) giving 0.235 g of compound 8 and 0.126 g of compound 7. 1HNMR (300 MHz, DMSO, d6) Compound 8: δ 7.31 (m, 10H), 6.18 (s, 4H), 3.82 (s, 4H), 3.17 (dd, 2H, J=6.8 Hz), 2.92 (dd, 2H, J=6.8 Hz), 2.93 (m, 4H), 2.32 (dd, 2H, J=7.2 Hz), 1.54 (dt, 2H, J =7.2, 7.4 Hz), 0.87 (t, 3H, J= 7.4Hz). 1HNMR (300 MHz, DMSO, d6) Compound 7: δ 12.68 (s, 1H), 7.32 (m, 10H), 6.18 (s, 2H), 3.82 (s, 4H), 3.26 (dd, 2H, J=7.0 Hz), 3.17 (dd, 2H, J=6.8 Hz), 2.93 (m, 4H), 2.32 (dd, 2H, J =7.2 Hz), 1.54 (dt, 2H, J =7.2, 7.4 Hz), 0.87 (t, 3H, J = 7.4Hz).
  • 65
  • [ 33657-49-7 ]
  • C29H45N5O4SSi [ No CAS ]
  • C34H53N5O6SSi [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% Stage #1: C29H45N5O4SSi With potassium hexamethylsilazane In tetrahydrofuran; toluene at -45℃; for 0.5h; Stage #2: chloromethyl n-butyrate In tetrahydrofuran; toluene for 2h; EXAMPLE. Compound 111. EXAMPLE. Compound 111. 746 mg (1.27 mmole) of TES protected dipeptide benzyl ester 110 was dissolved in 8 mL of THF (anhydrous, inhibitor-free) and cooled to - 45 ° C. After 15 minutes of cooling, 2.8 mL of 0.5 M KHMDS (1.1 eq., 1.4 mmole) in toluene solution was added dropwise. After an additional 15 mins, 175 μ^ of chloromethyl butyrate (1.1 eq., 1.4 mmole) was added dropwise. After 30 mins, TLC showed only a trace amount of starting material left. After 2 hours, the reaction mixture was quenched 1 mL MeOH, and allowed to warm to room temperature. The reaction was extracted with EtO Ac/brine. The organic layer was washed with brine and then concentrated to give 759 mg (87%) of crude product 111. LCMS: [M+Na]+ m/z = 710.57. 1H NMR (CDC13, δ in ppm) 8.10 (s, 1 H), 7.44- 7.40 (m, 2 H), 7.39-7.30 (m, 3 H), 5.43(d, J = 12.3 Hz, 1 H), 5.37(d, J = 12.3 Hz, 1 H), 5.35 (s, 2 H), 4.98 (t, J = 5.1 Hz, 1 H), 4.40-4.20 (br, 1 H), 3.52 (d, J = 16.0 Hz, 1 H), 2.42-2.38 (t, J = 6.7 Hz, 2 H), 2.25-2.05 (m, 2 H), 1.78-1.72 (m, 2 H), 1.68-1.55 (m, 3 H), 1.30- 1.20 (m, 1 H), 1.00-0.85 (m, 24 H), 0.65 (t, 6 H). 13C NMR (CDC13, δ in ppm) 177.6, 173.0, 171.0, 161.1, 146.6, 135.7, 128.6, 128.42, 128.36, 127.6, 77.2, 70.8, 66.8, 63.5, 40.9, 35.9, 34.9, 31.1, 25.0, 20.1, 19.5, 18.1, 15.7, 13
Stage #1: C29H45N5O4SSi With potassium hexamethylsilazane In tetrahydrofuran; toluene at -45℃; for 0.25h; Stage #2: chloromethyl n-butyrate In tetrahydrofuran; toluene for 2.5h; 746 mg (1.27 mmole) of TES protected dipeptide benzyl ester 19 was dissolved in 8 mE of THF (anhydrous, inhibitor-free) and cooled to -45° C. Afier 15 minutes of cooling, 2.8 mE of 0.5 M KHMDS (1.1 eq., 1.4 mmole) in toluene solution was added dropwise. Afier an additional 15 mins, 175 jtE of chloromethyl butyrate (1.1 eq., 1.4 mmole) was added dropwise. After 30 mins, TEC showed only a trace amount of starting material lefi. Afier 2 hours, the reaction mixture was quenched 1 mE MeOH, and allowed to warm to room temperature. The reaction was extracted with EtOAc/ brine. The organic layer was washed with brine and then concentrated to give 759 mg (87%) of crude product 20. LCMS: [M+Na] mlz=710.57. ‘H NMR (CDC13, ö in ppm)8.10 (s, 1H), 7.44-7.40 (m, 2H), 7.39-7.30 (m, 3H), 5.43 (d,J=12.3 Hz, 1H), 5.37 (d, J=12.3 Hz, 1H), 5.35 (s, 2H), 4.98 (t,J=5.1 Hz, 1H), 4.40-4.20 (br, 1H), 3.52 (d, J=16.0 Hz, 1H),2.42-2.38 (t, J=6.7 Hz, 2H), 2.25-2.05 (m, 2H), 1.78-1.72 (m,2H), 1.68-1.55 (m, 3H), 1.30-1.20 (m, 1H), 1.00-0.85 (m,24H), 0.65 (t, 6H). ‘3C NMR (CDC13, ö inppm) 177.6, 173.0,171.0, 161.1, 146.6, 135.7, 128.6, 128.42, 128.36, 127.6,77.2,70.8,66.8,63.5,40.9,35.9,34.9,31.1,25.0,20.1, 19.5,18.1, 15.7, 13.6, 10.5, 6.8, 4.7.
  • 66
  • [ 33657-49-7 ]
  • [ 1383023-80-0 ]
  • (2R,4R)-4-[(1-butyryloxymethoxy-1H-[1,2,3]triazole-4-carbonyl)amino]-5-(5'-chloro-2'-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
6 mg With triethylamine In acetone at 65℃; for 2h; 8E (2R,4R)-4-[(1-Butyryloxymethoxy-1H-[1,2,3]triazole-4-carbonyl)amino]-5-(5'-chloro-2'-fluorobiphenyl-4-yl)-2-hydroxypentanoic Acid Example 8E (2R,4R)-4-[(1-Butyryloxymethoxy-1H-[1,2,3]triazole-4-carbonyl)amino]-5-(5'-chloro-2'-fluorobiphenyl-4-yl)-2-hydroxypentanoic Acid Chloromethyl butyrate (13.7 mg, 100 μmol) was added to a solution of (2R,4R)-5-(5'-chloro-2'-fluorobiphenyl-4-yl)-2-hydroxy-4-[(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (30.0 mg, 66.8 μmol) in acetone (0.5 mL, 6.8 mmol). Et3N (18.6 μL, 134 μmol) was added and the resulting mixture was stirred at 65° C. for 2 hours. The mixture was then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (6.0 mg). MS m/z [M+H]+ calc'd for C25H26ClFN4O7, 549.15; found 549.1.
  • 67
  • [ 33657-49-7 ]
  • (R)-3-[N'-(1-allyloxy-1H-[1,2,3]-triazole-4-carbonyl)-N-(2',5'-dichlorobiphenyl-4-ylmethyl)-hydrazino]-2-hydroxypropionic acid [ No CAS ]
  • C27H29Cl2N5O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
220 mg With 2,6-dimethylpyridine; sodium iodide at 50℃; for 5h; 9J Example 9J Butyric Acid (R)-3-[N-(2',5'-Dichlorobiphenyl-4-ylmethyl)-N'-(1-hydroxy-1H-[1,2,3]triazole-4-carbonyl)hydrazino]-2-hydroxypropionyloxymethyl Ester To a mixture of (R)-3-[N'-(1-allyloxy-1H-[1,2,3]triazole-4-carbonyl)-N-(2',5'-dichlorobiphenyl-4-ylmethyl)-hydrazino]-2-hydroxypropionic acid (300 mg, 590 μmol) and chloromethyl butyrate (1.5 mL) were added NaI (178 mg, 1.2 mmol) and lutidine (124 mg, 1.2 mmol). The mixture was stirred at 50° C. for 5 hours. After cooling to room temperature, the mixture was diluted with water (15 mL) and extracted with EtOAc (2*15 mL). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (silica gel: 200-300 mesh; elute with PE:EtOAc=5:1 to 2:1) to yield Compound 1 as a light yellow solid (220 mg). LC-MS: 606 [M+H]+, 608 [(M+2)+H]+.
  • 68
  • [ 33657-49-7 ]
  • [ 1382976-53-5 ]
  • butyric acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino]-2-hydroxypropionyloxymethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: chloromethyl n-butyrate With sodium iodide In acetone at 65℃; for 1h; Stage #2: (R)-3-{N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]-hydrazino}-2-hydroxypropionic acid With triethylamine In acetone at 20℃; for 0.416667h; 3G Butyric acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino]-2-hydroxypropionyloxymethyl Ester Example 3G Butyric acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino]-2-hydroxypropionyloxymethyl Ester Chloromethyl butyrate (11.4 μL, 0.1 mmol) and NaI (13.6 mg, 0.1 mmol) were combined in acetone (0.7 mL, 10 mmol) and heated at 65° C. for 1 hour. The mixture was then cooled to room temperature. A mixture of (R)-3-{N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (16.0 mg, 30 μmol) dissolved in acetone (0.2 mL) and treated with Et3N (8.5 μL, 61 μmol) was added and the resulting mixture was stirred at room temperature for 25 minutes. The mixture was concentrated and the residue was dissolved in AcOH (2.0 mL), filtered and purified by reverse phase preparative HPLC. The desired fractions were combined and freeze dried to yield a yellowish solid. This solid was dissolved in AcOH (1.5 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and freeze dried to yield the title compound (5.7 mg, purity 100%) as a TFA salt white solid. MS m/z [M+H]+ calc'd for C31H28ClF2N3O2, 628.16. found 628.
  • 69
  • [ 33657-49-7 ]
  • [ 1382976-35-3 ]
  • butyric acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionyloxymethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
6.5 mg Stage #1: chloromethyl n-butyrate With sodium iodide In acetone at 65℃; for 1h; Stage #2: (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid With N-ethyl-N,N-diisopropylamine In acetone at 20℃; for 1h; 4F Butyric acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionyloxymethyl Ester Example 4F Butyric acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionyloxymethyl Ester A mixture of chloromethyl butyrate (16.2 μL, 129 μmol) and NaI (19.4 mg, 129 μmol) in acetone (0.7 mL, 10 mmol) was heated at 65° C. for 1 hour. The mixture was then cooled to room temperature and a mixture of (R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (20.0 mg) and DIPEA (15.0 mL, 0.1 mmol) in acetone (0.3 mL) was added. The resulting mixture was stirred at room temperature for 1 hour then concentrated. The residue was dissolved in AcOH (2.0 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and freeze dried to yield a white solid. The solid was dissolved in acetic acid (1.5 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound (6.5 mg, purity 100%). MS m/z [M+H]+ calc'd for C26H27ClFN3O8, 564.15. found. 564.
  • 70
  • [ 33657-49-7 ]
  • [ 1382977-45-8 ]
  • butyric acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)-hydrazino]-2-hydroxypropionyloxymethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 2,6-dimethylpyridine; sodium iodide In N,N-dimethyl-formamide at 20℃; for 8h; 5G Butyric acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)-hydrazino]-2-hydroxypropionyloxymethyl Ester Example 5G Butyric acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)-hydrazino]-2-hydroxypropionyloxymethyl Ester To a solution of (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 335 μmol) in dry DMF (6 mL) was added chloromethyl butyrate (68 mg, 503 mmol), NaI (101 mg, 670 mmol), and 2,6-dimethylpyridine (143 mg, 1.3 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 8 hours. Water (12 mL) was added and the mixture was extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=3:1) to yield the title compound as a white solid (21 mg). LC-MS: 625.9 [M+H]+. 1H NMR (DMSO-d6, 400 MHz) δ 0.84 (t, J=7.4 Hz, 3H), 1.45-1.56 (m, 2H), 2.29 (t, J=7.3 Hz, 2H), 3.31-3.17 (m, 2H), 4.18-4.35 (m, 2H), 4.35 (t, J=5.3 Hz, 1H), 5.68-5.79 (m, 2H), 7.28 (t, J=7.4 Hz, 1H), 7.34-7.40 (m, 1H), 7.43-7.55 (m, 7H), 7.58 (dd, J=6.8, 2.6 Hz, 1H), 7.90 (d, J=7.6 Hz, 2H), 9.98 (s, 1H), 12.76 (s, 1H).
  • 71
  • [ 33657-49-7 ]
  • [ 1382976-11-5 ]
  • C24H25Cl2N5O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
6.1 mg With triethylamine In acetone at 65℃; for 2h; 9C Butyric Acid 4-[N'4(R)-2-carboxy-2-hydroxyethyl)-N'-(2',5'-dichlorobiphenyl-4-ylmethyl)hydrazinocarbonyl]-[1,2,3]triazol-1-yloxymethyl Ester Example 9C Butyric Acid 4-[N'4(R)-2-carboxy-2-hydroxyethyl)-N'-(2',5'-dichlorobiphenyl-4-ylmethyl)hydrazinocarbonyl]-[1,2,3]triazol-1-yloxymethyl Ester Chloromethyl butyrate (13.7 mg, 100 μmol) was added to a solution of (R)-3-[N-(2',5'-dichlorobiphenyl-4-ylmethyl)-N'-(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)hydrazino]-2-hydroxypropionic acid (31.2 mg, 66.8 μmol) in acetone (0.5 mL, 6.8 mmol) followed by Et3N (18.6 μL, 134 μmol). The resulting mixture was stirred at 65° C. for 2 hours. The mixture was then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield to yield the title compound (6.1 mg, purity 99%) as a white solid. MS m/z [M+H]+ calc'd for C24H25Cl2N5O7, 566.11. found 566.1.
  • 72
  • [ 33657-49-7 ]
  • (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(2-trityl-2H-tetrazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid [ No CAS ]
  • C42H38ClFN6O6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: chloromethyl n-butyrate With sodium iodide In acetone at 60℃; for 1h; Stage #2: (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(2-trityl-2H-tetrazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid With N-ethyl-N,N-diisopropylamine In acetone at 40℃; for 2h; 7D Example 7D Butyric Acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(2H-tetrazole-5-carbonyl)hydrazino]-2-hydroxypropionyloxymethyl Ester A mixture of chloromethyl butyrate (6.8 μL, 54.5 μmol) and NaI (8.2 mg, 54.5 μmol) in acetone (0.5 mL, 7 mmol) was stirred at 60° C. for 1 hour, then it was added to a mixture of (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(2-trityl-2H-tetrazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (12.3 mg, 18.2 μmol) and DIPEA (4.8 μL, 27.2 μmol) in acetone (0.5 mL). The resulting mixture was stirred at 40° C. for 2 hours, concentrated and partitioned between EtOAc (10 mL) and water (2 mL). The organic layer was dried over MgSO4, filtered, and concentrated. 4.0 M HCl in 1,4-dioxane (40.0 μL, 160 μmol) in MeCN (0.2 mL, 4 mmol) was added and the resulting mixture was stirred at room temperature for 20 minutes. The mixture was concentrated and the residue was dissolved in AcOH (1.5 mL), filtered, and purified by reverse phase preparative HPLC to yield the title compound (1.3 mg). MS m/z [M+H]+ calc'd for C23H24ClFN6O6, 535.14. found 535.1.
  • 73
  • [ 33657-49-7 ]
  • (R)-3-[N-(3'-chlorobiphenyl-4-ylmethyl)-N'-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid 2-oxo-2-phenylethyl ester [ No CAS ]
  • C33H32ClN3O9 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: chloromethyl n-butyrate With sodium iodide In acetone at 60℃; for 1h; Stage #2: (R)-3-[N-(3'-chlorobiphenyl-4-ylmethyl)-N'-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid 2-oxo-2-phenylethyl ester With triethylamine In acetic acid at 20℃; for 2h; 8D Example 8D Butyric acid 5-[N'-((R)-2-carboxy-2-hydroxyethyl)-N'-(3'-chlorobiphenyl-4-ylmethyl)hydrazinocarbonyl]isoxazol-3-yloxymethyl Ester A mixture of chloromethyl butyrate (20.5 μL, 164 μmol) and NaI (24.5 mg, 164 μmol) in acetone (2.0 mL, 27 mmol) was stirred at 60° C. for 1 hour, then cooled to room temperature and added to a mixture of (R)-3-[N-(3'-chlorobiphenyl-4-ylmethyl)-N'-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid 2-oxo-2-phenylethyl ester (30.0 mg, 54.5 μmol) and Et3N (38.0 μL, 273 μmol) in acetone (1 mL). The resulting mixture was stirred at room temperature for 2 hours, concentrated, dissolved in AcOH (2 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and lyophilized. Zinc (178 mg, 2.7 mmol) and AcOH (1.0 mL, 18 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was filtered and purified by reverse phase preparative HPLC to yield the title compound (2.5 mg). MS m/z [M+H]+ calc'd for C25H26ClN3O8, 532.14. found 532.2.
  • 74
  • [ 33657-49-7 ]
  • (2R,4R)-5-(3'-chlorobiphenyl-4-yl)-2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl)amino]pentanoic acid [ No CAS ]
  • (2R,4R)-4-[(3-butyryloxymethoxy)-3H-benzotriazole-5-carbonylamino]-5-(3'-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
3.3 mg With triethylamine In acetone at 65℃; for 5h; Sealed tube; 1M (2R,4R)-4-[(3-Butyryloxymethoxy-3H-benzotriazole-5-carbonylamino]-5-(3'-chlorobiphenyl-4-yl)-2-hydroxypentanoic Acid (2R,4R)-4-[(3-Butyryloxymethoxy-3H-benzotriazole-5-carbonylamino]-5-(3'-chlorobiphenyl-4-yl)-2-hydroxypentanoic Acid Et3N (7.0 μL, 50 μmol) was added to a solution of [(2R,4R)-5-(3'-chlorobiphenyl-4-yl)-2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl)amino]pentanoic acid (20.0 mg, 42 μmol and chloromethyl butyrate (8.3 μL, 67 μmol) in acetone (1.3 mL, 17.2 mmol), and the resulting mixture was stirred in a sealed vial at 65° C. for 5 hours. The mixture was then concentrated to yield a yellow liquid. The crude liquid was purified by preparative HPLC (C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (3.3 mg, purity 94%). MS m/z [M+H]+ calc'd for C29H29ClN4O7, 581.17; found 581.1.
  • 75
  • [ 33657-49-7 ]
  • (2R,4R)-4-[(5-allyloxy-1-methyl-1H-pyrazole-3-carbonyl)amino]-5-(3'-chlorobiphenyl-4-yl)-2-hydroxy-pentanoic acid [ No CAS ]
  • C30H34ClN3O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
200 mg With 2,6-dimethylpyridine; sodium iodide at 50℃; for 5h; 2H A suspension of Compound 4 (400 mg, 830 μmol), NaI (248 mg, 1.7 mmol) and lutidine (173 mg, 1.7 mmol) in chloromethyl butyrate (2 mL) was stirred at 50° C. for 5 hours. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with saturated aqueous NaCl (40 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (silica gel: 200-300 mesh; elute with PE:EtOAc from 5:1 to 2:1) to yield Compound 5 as a light yellow solid (200 mg). LC-MS: 584 [M+H]+.
  • 76
  • [ 33657-49-7 ]
  • C23H41N5O4SSi [ No CAS ]
  • C28H49N5O6SSi [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium hexamethylsilazane In tetrahydrofuran; toluene Cooling; EC1004 is prepared according to the following process. Into a round bottomed flask equipped with magnetic stir bar and temperature probe dipeptide EC1458, imidazole, and methylene chloride is added. Once all the solids have dissolved, the solution is cooled using an ice bath. Chlorotriethylsilane (TESC1) is added drop wise and the ice bath is removed. The reaction is monitored for completion. A second portion of chlorotriethylsilane and/or imidazole is added if necessary. The imidazole HCl salt is removed by filtration and methylene chloride is added. The organics are washed with a saturated solution of sodium chloride (brine), the aqueous layer is back extracted once with methylene chloride, and the combined organic layers are washed with brine. The organic layer is dried over sodium sulfate and concentrated on a rotary evaporator. The residue is dissolved in tetrahydrofuran (THF) and cooled to approximately -45° C. A solution of potassium bis(trimethylsilyl)amide (KHMDS) in toluene is added drop wise. With stirring, chloromethyl butyrate is added and the reaction is monitored. The reaction is quenched with methanol and then ethyl acetate and brine are added. The aqueous layer is discarded and the organics are washed once with brine. The organic layer is concentrated on a rotary evaporator and the oily residue is passed through a short plug of silica gel. The plug is washed with a 20% solution of ethyl acetate in petroleum ether. The combined organics are concentrated on a rotary evaporator until distillation ceases. The crude EC1004 oil is analyzed by LC and NMR and stored in a freezer until use.
With potassium hexamethylsilazane In tetrahydrofuran; toluene at -45℃; 1.e e. Example. EC1004 ss Prepared According to theFollowing Process Into a round bottomed flask equipped with magnetic stir bar and temperature probe dipeptide EC1458, imidazole, and methylene chloride is added. Once all the solids have dissolved, the solution is cooled using an ice bath. Chlorotriethylsilane (TESC1) is added drop wise and the ice bath is removed. The reaction is monitored for completion. A second portion of chlorotriethylsilane and/or imidazole is added if necessary. The imidazole HC1 salt is removed by filtration and methylene chloride is added. The organics are washed with a saturated solution of sodium chloride (brine), the aqueous layer is back extracted once with methylene chloride, and the combined organic layers are washed with brine. The organic layer is dried over sodium sulfate and concentrated on a rotary evaporatot The residue is dissolved in tetrahydroffiran (THF) and cooled to approximately -45° C. A solution of potassium bis(trimethylsilyl)amide (KHMDS) in toluene is added drop wise. With stuffing, chloromethyl butyrate is added and the reaction is monitored. The reaction is quenched with methanol and then ethyl acetate and brine are added. The aqueous layer is discarded and the organics are washed once with brine. The organic layer is concentrated on a rotary evaporator and the oily residue is passed through a short plug of silica gel. The plug is washed with a 20% solution of ethyl acetate in petroleum ether. The combined organics are concentrated on a rotary evaporator until distillation ceases. The crude EC1004 oil is analyzed by LC and NMR and stored in a freezer until use.
  • 77
  • [ 33657-49-7 ]
  • C23H41N5O4SSi [ No CAS ]
  • C28H49N5O6SSi [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: C23H41N5O4SSi With potassium hexamethylsilazane In tetrahydrofuran; toluene at -45℃; for 0.333333h; Stage #2: chloromethyl n-butyrate In tetrahydrofuran; toluene at -45℃; for 0.333333h; EXAMPLE. Synthesis of azido methylbutyrate dipeptide 9. The crude product 8 was used without further purification. TES protected dipeptide was dissolved in 100 mL THF (anhydrous, inhibitor-free), cooled to -45°C, and stirred at -45°C for 15 minutes before adding KHMDS (0.5 M in toluene, 61 mL, 1.05 equiv.), drop-wise. After the addition of KHMDS was finished, the reaction was stirred at -45°C for 20 minutes, and chloromethyl butyrate (4.4 mL, 1.1 equiv.) was added. The reaction mixture was stirred at -45 °C for another 20 minutes. The reaction was quenched with 25 mL MeOH and warmed to room temperature. 250 mL EtOAc and 250 mL brine were added to the reaction mixture, and the organic phase was separated. The solvent was evaporated to reduce the volume of solution. The solution was passed through 76.5 g silica in a 350 mL sintered glass funnel. The silica plug was washed with 500 mL EtO Ac/petroleum ether (1:4). The filtrate and the wash were concentrated to oily residue and dried under high vacuum to give 16.5 g product 9 as a light yellow wax.
  • 78
  • [ 33657-49-7 ]
  • [ 252898-13-8 ]
  • ((2-((3-amino-3-oxopropyl)carbamoyl)phenyl)thio)methyl butyrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In N,N-dimethyl-formamide at 20℃; for 24h; 1 EXAMPLE 1 This example demonstrates the synthesis of ((2-((3-amino-3- oxopropyl)carbamoyl)phenyl)thio)methyl butyrate 1. The reaction scheme is depicted in FIG. 1. Thiosalicylic acid (10 g, 65 mmole) and HBTU (25.8 g, 68 mmole) were dissolved in -200 mL DMF. DIEA (39.52 mL, 227 mmole) was then added and the solution was allowed to stir for 15 minutes, β-alaninamide HC1 (8.48 g, 96.2 mmole) was then added and the solution was allowed to stir at room temperature for 24 hours. Chloromethyl butyrate (8.12 mL, 64 mmole) was then added at room temperature and the solution was again allowed to stir 24 hours. The solvent was removed under reduced pressure (at ~65°C) and then the residue was allowed to solidify at 4°C. The white semi-solid was recrystallized from a mixture of 9: 1 ethyl acetate/hexanes adding slightly more EtOAc as needed. Overall yield with two recrystallizations was 43%. NMR (CDC13) 5 7.589 (d, I H), 7.489 (d, I H), 7.406 (t, I H), 7.303 (t, I H), 6.905 (s, IH), 5.979 (s, I H), 5.585 (s, I H), 5.408 (s, 2H), 3.722 (q, 2H), 2.599 (t, 2H), 2.346 (t, 2H), 1.660 (m, 2H), 0.950 (t, 2H).
  • 79
  • [ 33657-49-7 ]
  • (R)-7-fluoro-2-hydroxy-3-(2-(methylthio)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid [ No CAS ]
  • (R)-butyryloxymethyl 7-fluoro-2-hydroxy-3-(2-(methylthio)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
82 mg With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 18h; 13 Example 13: (i?)-butyryloxymethyl 7-fluoro-2-hydroxy-3-(2-(methylthio)acetamido)-3,4- dih dro-2H-benzo[el [L21oxaborinine-8-carboxylate (13) Example 13: (i?)-butyryloxymethyl 7-fluoro-2-hydroxy-3-(2-(methylthio)acetamido)-3,4- dih dro-2H-benzo[el [L21oxaborinine-8-carboxylate (13) [0260] To the solution of Compound 1 (156 mg, 0.5 mmol) in DMF (5 mL) was added chloromethyl butanoate (136 mg, 1 mmol), followed by K2C03 (103 mg, 0.75 mmol). The resulting mixture was stirred at 50 °C for 18 hours before it was diluted with 25 mL MeOH. After stirred at room temperature for 24 hours, the solution was concentrated to ~ 6 mL. The residue was purified by purified by prep-HPLC (CI 8, acetonitrile and water as mobile phases, 0.1% formic acid) to obtain the titled compound 13 (82 mg) as white solid. 1H-NMR(300 MHz, CD3OD) δ 10.20 (bs, 1H), 7.08 (dd, 1H), 6.56 (dd, 1H), 5.92 (s, 2H), 3.22 (s, 2H), 3.12 (m, 1H), 2.84 (d, 2H), 2.39 (t, 2H), 1.80 (s, 3H), 1.66 (m, 2H), 0.97 (t, 3H). MS calcd for (C17H2iBFN07S): 413 MS (ESI, positive) found: (M+l): 414 MS (ESI, negative) found: (M-l): 412
  • 80
  • [ 33657-49-7 ]
  • 4-(2-[diethylamino]-2-oxoethoxy)-3-methoxy-benzeneacetic acid [ No CAS ]
  • C20H29NO7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% With potassium hydrogencarbonate In acetone at 75 - 85℃; for 6h; 6 Example 6 Example 6Compound 5 may be prepared by the following reaction schemeThe intermediate compound B (3.3g, 0.011mol) was dissolved in acetone (40ml). Add potassium bicarbonate (2.3g, 0.023mol) and chloromethyl n-butanoate (2.4g,0.018mol). The temperature was adjusted to 75-85 deg.C stirred for 6 hours. inorganic salts were removed by filtration, the organic phase was concentrated at atmospheric pressure to a pale yellow liquid, was purified by column chromatography (ethylacetate: n-hexane = 1; 5) to give a yellow liquid 2.0g, 46% yield.
  • 81
  • [ 33657-49-7 ]
  • C16H23NO5 [ No CAS ]
  • C21H31NO7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
27.4% With potassium carbonate In acetonitrile at 80 - 85℃; for 8h; 3 Example 3 Example 3Compound 6 may be prepared by the following reaction scheme The intermediate compound A (12.6g, 0.041mol) was dissolved in acetonitrile(120ml). Add potassium carbonate (11.3g, 0.082 mol) and chloromethyl n-butanoate (8.4g, 0.062mol). The temperature was adjusted to 80-85 deg.C. The reaction was stirred for 8 hours. filtered,and placed in a rotary evaporator and the solvent removed to give an oil which was purified by column chromatography (ethyl acetate: n-hexane = 1; 6) to givea pale yellow liquid 4.6g, yield 27.4%.
  • 82
  • [ 33657-49-7 ]
  • [ 745-65-3 ]
  • butyryloxy-methyl-7-(1R,2R,3R,)-3-hydroxy-2(E)-3(S)-3-hydroxy-1-octenyl-5-oxo-cyclopentane heptanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
89.5% The 25mg alprostadil and 21mul of triethylamine were added to 10ml of ethanol, the ice bath was stirred for half an hour chloro butyrate with an appropriate amount of ethanol was dissolved 21 l of methyl chloride, was slowly added dropwise to the reaction solution, and stirring was continued at room temperature the reaction conditions 10h. It was added to the reaction solution, 50ml ethyl acetate, and the organic phase was transferred to a separatory funnel, washed with a concentration of 3% aqueous citric acid until slightly acidic, then with saturated aqueous sodium bicarbonate solution once, brine to neutral. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oily liquid as alprostadil derivative (III), chemical name: butyryloxy-methyl -7- (1R, 2R, 3R,) - 3-hydroxy -2 (E) -3 (S) -3- hydroxy-1-octene-5-oxo-cyclopentane enanthate, the raw material of alprostadil yield was 89.5%.
  • 83
  • [ 571190-30-2 ]
  • [ 33657-49-7 ]
  • (4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl butyrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
80 mg With triethylamine In dichloromethane Reflux; 19 Preparation example 19 compound 1E-3 preparation of General procedure: Apart from with bromine acetic acid ethyl ester instead of cyanopentanoyl acetyl chloride, the reaction temperature increased to the reflux temperature, with the preparation example 1 compound synthesis of 1A-1 the same method for synthesizing compound 1D-1 (70 mg).Except using butyric acid other than replaces the bromine chloro-ethyl ester of acetic acid, with the preparation example 13 synthesis of compound 1D-1 the same method for synthesizing compound 1E-3 (80 mg).1HNMR (CDCl3, 400MHz) δ: 8.92 (s, 1H), 8.25 (d, 1H), 8.12 (d, 1H), 7.36 (dd, 1H), 5.89 (m, 1H), 3.83 (t, 2H), 3.69 (t, 2H), 3.18 (m, 4H), 2.56 (s, 3H), 2.38 (m, 7H), 2.08 (m, 2H), 1.89 (m, 4H), 1.72 (m, 4H), 1.01 (t, 3H)
  • 84
  • [ 33657-49-7 ]
  • [ 64017-81-8 ]
  • [ 147-93-3 ]
  • ((2-((3-amino-3-oxopropyl)carbamoyl)phenyl)thio)methyl butyrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% To a round bottom flask was added thiosalicylic acid (0.250 g,1.62 mmol, 1.00 eq), HBTU (0.645 g, 1.70 mmol, 1.05 eq) and balanineamide hydrochloride (0.212 g, 1.70 mmol, 1.05 eq). DMF(4 mL) was added, followed by Huenig's base (0.988 mL, 5.67 mmol,3.5 eq). The mixture was stirred at RT for 12 h. Then, chloromethylbutyrate (0.203 mL, 1.62 mmol, 1.0 eq) was injected, and the reactionstirred for 4 h at RT. The reaction was quenched with water(5 mL) and extracted 4 with 5 mL of CH2Cl2. The combined organicswere washed with saturated NaHCO3 and brine before beingdried over Na2SO4. The organics were evaporated, and the residuewas purified by flash chromatography over silica gel in MeOH/DCMto yield 0.270 g (52% yield) of a white solid. 1H NMR (400 MHz,CDCl3) delta 7.56-7.53 (dd, 1H), 7.45-7.43 (dd, 1H), 7.38-7.34 (td, 1H),7.27-7.23 (td, 1H), 7.02-6.99 (bt, 1H), 6.21, (bs, 1H), 5.78 (bs, 1H),5.36 (s, 2H), 3.68-3.63 (m, 2H), 2.56-2.53 (m, 2H), 2.32-2.29 (t,2H), 1.67-1.57 (sext, 2H), 0.93-0.89 (t, 3H); 13C NMR (125 MHz,CDCl3) HRMS (ESI) m/z calculated for C15H20N2O4S [MNa]:347.1041, found 347.1042.
  • 85
  • [ 33657-49-7 ]
  • [ 123853-39-4 ]
  • 4-(2,3-dichlorophenyl)-2,6-dimethyl dihydropyridine-3,5-dicarboxylic acid methyl(butyryloxymethyl) ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
92.89% With potassium carbonate; In acetonitrile; for 4 - 6h;Reflux; Large scale; Step 1 preparation of intermediate 2.0 kg (5.61mol) inputs 10L in acetonitrile, inputs under stirring chloro-butyrate 850g (6.22mol) and potassium carbonate 860g (6.22mol), heating to reflux reaction 4-6h, cooling to room temperature, filter, filtrates in 40-50 C concentrated under reduced pressure to dry, subsequently joined 4L ethyl acetate, reflux is dissolved, and 45g activated carbon decolourizations 5-15min, hot filtering, filtrates in 30-40 C dropwise 7L-hexane crystallization, filtration, 40-50 C decompression drying to obtain the butyric acid clevidipine 2.38 kg, yield 92.89%.
  • 86
  • [ 16252-90-7 ]
  • [ 33657-49-7 ]
  • [ 16807-37-7 ]
  • C17H24N2O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
13% Stage #1: chloromethyl n-butyrate; 5-methoxy-2-sulfanyl-benzoic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Stage #2: 2-amino-2-methylpropanamide In N,N-dimethyl-formamide at 20℃;
  • 87
  • [ 16252-90-7 ]
  • [ 33657-49-7 ]
  • C8H5F3O3S [ No CAS ]
  • C17H21F3N2O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% Stage #1: C8H5F3O3S With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 2-amino-2-methylpropanamide In N,N-dimethyl-formamide at 20℃; Stage #3: chloromethyl n-butyrate In N,N-dimethyl-formamide at 20℃;
  • 88
  • [ 16252-90-7 ]
  • [ 33657-49-7 ]
  • [ 147-93-3 ]
  • C16H22N2O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
39% Stage #1: Thiosalicylic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 2-amino-2-methylpropanamide In N,N-dimethyl-formamide at 20℃; Stage #3: chloromethyl n-butyrate In N,N-dimethyl-formamide at 20℃;
  • 89
  • [ 33657-49-7 ]
  • [ 137360-55-5 ]
  • [ 147-93-3 ]
  • C16H20N2O4S [ No CAS ]
  • 90
  • [ 33657-49-7 ]
  • [ 17193-28-1 ]
  • [ 147-93-3 ]
  • C18H24N2O4S [ No CAS ]
  • 91
  • [ 33657-49-7 ]
  • 4’-(hydroxymethyl)-2,2’:6’,2”-terpyridine-6,6”-dicarboxylic acid [ No CAS ]
  • bis(butyryloxymethyl) 4’-(hydroxymethyl)-2,2’:6’,2”-terpyridine-6,6”-dicarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
36% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 50℃; for 15h;
36% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 15h; Inert atmosphere; 8.4 (Step 4) To a solution of 4’-(hydroxymethyl)-2,2’:6’,2”-terpyri-dine-6,6”-dicarboxylic acid (18 mg, 0.05 mmol) in DMF (1.0 mE) were added diisopropylethylamine (0.05 mE, 0.29 mmol) and chloromethylbutyrate (0.03 mE, 0.24 mmol). The reaction mixture was heated to 50° C. After stirring for 15 hr, the mixture was cooled to room temperature, and washed with saturated aqueous ammonium chloride solution (2.0 mE). The aqueous layer was extracted with ethyl acetate (3x5.0 mE). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel colunm chromatography (eluent: n-hexane:ethyl acetate=2: 1-1:1) to give bis(butyryloxymethyl) 4’-(hy-droxymethyl)-2,2’:6’,2”-terpyridine-6,6”-dicarboxylate (10 mg, yield 36%) as a white wax substance.‘H NMR (500 MHz, CDC13) ö 0.98 (t, J=7.5 Hz, 6H),1.71 (sext., J=8.0 Hz, 4H), 2.41 (t, J=7.5 Hz, 4H), 2.45 (bit,J=6.0 Hz, 1H), 4.9 (bt d, J=6.0 Hz, 2H), 6.12 (s, 4H), 8.01(t, J=7.5 Hz, 2H), 8.17 (dd, J=1.0, 7.5 Hz, 2H), 8.61 (s, 2H),8.80 (dd, J=1.0, 7.5 Hz, 2H); ‘3C NMR (125 MHz, CDC13) ö 13.5, 18.1, 35.8, 63.9, 80.2, 119.7, 124.9, 125.6, 137.9, 146.5, 152.6, 154.5, 156.5, 163.9, 172.3.
  • 92
  • [ 33657-49-7 ]
  • [ 1262117-93-0 ]
  • C30H27N3O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
46.2% With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 30℃; Inert atmosphere;
  • 93
  • [ 33657-49-7 ]
  • [ 1187594-09-7 ]
  • C21H25N7O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% Compound 1 (150 mg, 0.40 mmol, 1 equiv) was dissolved in a mixed solvent of dichloromethane and acetonitrile, and then triethylamine (140 mL, 2.5 equiv). The reaction was allowed to react for 15 minutes in an ice-water bath. NaH (0.1 equiv) was added slowly and the mixture stirred at low temperature for half an hour. Chloromethyl butyrate (0.077 mL, 0.60 mmol, 1.5 equiv) slowly warmed to room temperature and stirred overnight. The filtrate was concentrated, mixed with silica gel and subjected to direct column chromatography (methylene chloride: methanol = 50: 1) to give Compound C-1 (129 mg) in a yield of 68%.
  • 94
  • [ 33657-49-7 ]
  • 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate sodium salt [ No CAS ]
  • (Z)-1-((butyryloxy)methoxy)-3,3-diethyltriaz-1-ene 2-oxide [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.8% With sodium carbonate In acetonitrile at 0 - 20℃; for 18h; 5 General procedure General procedure: A slurry of NONOate salt I (1 eq.) in acetonitrile was cooled to 0°C in an ice bath, anhydrous sodium carbonate (1.4 eq.) was added followed by chloromethyl derivative (1.2 eq.). The concentration of the substrate should be 0.25 M in acetonitrile. The reaction mixture was allowed to warm up to room temperature and stirred for 18 h. The solids were removed using suction filtration and concentrated on a rotary evaporator. The resulting mixture was dissolved in a minimum amount of dichloromethane and purified using column chromatography (biotage, SiO2, ethyl acetate/hexane gradient) (0163) The above general procedure was used to prepare the following examples. In all cases the structure of the compound was confirmed using 1HNMR. Example 5: (Z)-1-((butyryloxy)methoxy)-3,3-diethyltriaz-1-ene 2-oxide (Compound 6) (0164) (0165) Yield: 0.8%
  • 95
  • [ 33657-49-7 ]
  • [ 1354745-52-0 ]
  • (6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yloxy)methyl butyrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate In N,N-dimethyl-formamide at 80℃; 1 General procedure: 6-Chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4( 1H)-one (1 equiv), Cs2CO3 (3 equiv), and anhydrous DMF (0.1 M) were added to a vial followed by the appropriate chloromethylester (3 equiv). The mixture was allowed to stir at 80 °C overnight. After that, the reaction was quenched with saturated aqueous NH4C1 solution, extracted with EtOAc, and washed with brine. The organic layers were combined, dried under Na2SO4, filtered, and concentrated under reduced pressure. The crude material was submitted to silica gel column chromatography to afford the desired products (eluent hexanes -* hexanes:EtOAc = 4:1) as white solids.
  • 96
  • [ 33657-49-7 ]
  • C25H25FN4O3 [ No CAS ]
  • (4-(4-fluoro-3-(1-(3-methyl-2-butenoyl)piperazin-4-ylcarbonyl)benzyl)-1-oxophthalazin-2(1H)-yl)methanol butanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
56% Stage #1: C25H25FN4O3 With sodium hydride In tetrahydrofuran at 1 - 10℃; for 0.5h; Stage #2: chloromethyl n-butyrate In tetrahydrofuran for 0.5h; 14 Example 14: Synthesis of (4-(4-Fluoro-3-(1-(3-methyl-2-butenoyl)piperazin-4-yl-carbonyl)-benzyl)-1-oxophthalazin2(1H)yl)methanol butyrate (Compound 27) 4-(4-Fluoro-3-(1-(3-methyl-2-butenoyl)piperazin-4-yl-carbonyl)-benzyl)pyridazine-1(2H)one (11) 600mg, 1.34mmol) was added to the 25ml double-mouth bottle.Add anhydrous THF (6 ml), cool to 1-10 ° C, then add sodium hydride (60%, 105 mg, 2.63 mmol), stir for 30 minutes,Methyl chlorobutyrate (220 mg, 1.61 mmol) was added and stirring was continued for 30 min.The reaction was completely monitored by TLC, and the silica gel column was purified by column.The foamy solid product (410 mg) was obtained in a yield of 56%.
  • 97
  • [ 33657-49-7 ]
  • [ 80382-23-6 ]
  • C20H26O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In toluene 2 Finally, 1-bromoethyl acetate was added to the suspension of loxoprofen sodium in toluene. It is made alkaline by using triethylamine (step g), and the reaction produces the target compound 1.
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