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Structure of 2-(2-Bromoethyl)-1,3-dioxolane
CAS No.: 18742-02-4
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Tian, Gui-Long ; Hsieh, Chia-Ju ; Taylor, Michelle ; Lee, Ji Youn ; Riad, Aladdin A. ; Luedtke, Robert R. , et al.
Abstract: The difference in the secondary binding site (SBS) between the dopamine 2 receptor (D2R) and dopamine 3 receptor (D3R) has been used in the design of compounds displaying selectivity for the D3R versus D2R. In the current study, a series of bitopic ligands based on Fallypride were prepared with various secondary binding fragments (SBFs) as a means of improving the selectivity of this benzamide analog for D3R versus D2R. We observed that compounds having a small alkyl group with a heteroatom led to an improvement in D3R versus D2R selectivity. Increasing the steric bulk in the SBF increase the distance between the pyrrolidine N and Asp110, thereby reducing D3R affinity. The best-in-series compound was (2S,4R)-trans-27 which had a modest selectivity for D3R versus D2R and a high potency in the β-arrestin competition assay which provides a measure of the ability of the compound to compete with endogenous dopamine for binding to the D3R. The results of this study identified factors one should consider when designing bitopic ligands based on Fallypride displaying an improved affinity for D3R versus D2R.
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Keywords: Dopamine 2 receptor ; Dopamine 3 receptor ; Fallypride ; Bitopic ligands ; PET imaging
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Purchased from AmBeed: 89031-84-5 ; 40216-83-9 ; 88-13-1 ; 135042-17-0 ; 110-52-1 ; 488-93-7 ; 18742-02-4 ; 98-98-6 ; 86864-60-0 ; 62-23-7 ; 29886-64-4 ; 59741-04-7 ; 4385-62-0 ; 15268-31-2 ; 134441-72-8 ; 54751-01-8 ; 166173-78-0 ; 213131-32-9 ; 98-98-6 ; 69966-55-8 ; 154342-67-3
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CAS No. : | 18742-02-4 |
Formula : | C5H9BrO2 |
M.W : | 181.03 |
SMILES Code : | C(C1OCCO1)CBr |
MDL No. : | MFCD00003216 |
InChI Key : | GGZQLTVZPOGLCC-UHFFFAOYSA-N |
Pubchem ID : | 87776 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H227-H301-H315-H319-H335 |
Precautionary Statements: | P210-P261-P264-P270-P271-P280-P301+P310+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P370+P378-P403+P233-P403+P235-P405-P501 |
Class: | 6.1 |
UN#: | 2810 |
Packing Group: | Ⅲ |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 34.08 |
TPSA ? Topological Polar Surface Area: Calculated from |
18.46 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.1 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.99 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.14 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.8 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.9 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.39 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.45 |
Solubility | 6.36 mg/ml ; 0.0352 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.97 |
Solubility | 19.6 mg/ml ; 0.108 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.62 |
Solubility | 4.33 mg/ml ; 0.0239 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.7 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.65 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In ethanol; toluene; | A) 2-(2-Aminoethyl)-1,3-dioxolane A suspension of 50 g of 2-(2-bromoethyl)-1,3-dioxolane (product known in literature, CAS RN = 5754-35-8) (0.27 mL, 32.5 mol), 62.5 g of potassium phthalimide (0.34 mol), 9.16 g of Bu4N+HSO4- (0.027 mol) in 150 ml of toluene was heated to 100C and under N2 stream for 3 h. After cooling to room temperature, the mixture was filtered and evaporated to dryness. By crystallization of the residue from abs. EtOH the phthalimido derivative was obtained. A solution of 58.5 g of NH2NH2.H2O (1.17 ml; 56.8 mol), 64.36 g of phthalimido derivative (0.26 mol) in 2 l of abs. EtOH was heated to reflux under N2 stream for 2.5 h. After cooling to 0C, the precipitated phthalhydrazide was filtered through a sintered funnel. By evaporation of the filtrate to dryness, 23.26 g of the desired product (0.198 mol) were obtained. Yield: 73% The 1H-NMR, 13C-NMR, IR and MS spectra are consistent with the indicated structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dichloro bis(acetonitrile) palladium(II); potassium hydrogencarbonate; norbornene; In N,N-dimethyl acetamide; water; at 70℃; for 14h;Schlenk technique; Inert atmosphere; | General procedure: A 50-mL Schlenk flask equipped with a magnetic stirring bar and a rubber septum was charged with 1H-indole substrate 1 (1.00 mmol), norbornene (188 mg, 2.00 mmol), the base [K2CO3 (276 mg, 2.00mmol), KHCO3 (300 mg, 3.00 mmol), or K2HPO4 (522 mg, 3.00mmol) as indicated], and PdCl2(MeCN)2 (25.9 mg, 0.100 mmol). A 0.5 M solution of H2O in DMA (5 mL) was added. The alkyl bromide 2 (2.00 mmol) was then added from a syringe, and the resulting mixture was degassed by three freeze-pump-thaw cycles with liquid nitrogen under high vacuum. The flask was then placed in an oil bath preheated to 70 C or 90 C, as indicated, and the mixture was stirred vigorously under balloon pressure of argon. Upon completion of the reaction (TLC), the mixture was cooled to r.t., diluted with Et2O (30 mL), and filtered. The filtrate was concentrated in arotary evaporator (60 C water bath, 8-10 mbar) to remove the Et2O and most of the DMA. The residue was purified directly by flash column chromatography [silica gel (dry loading)] to give the alkylation product 3. |
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