Structure of Boc-D-cis-Hyp-OMe
CAS No.: 114676-69-6
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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.
Synonyms: (2R,4R)-1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate
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CAS No. : | 114676-69-6 |
Formula : | C11H19NO5 |
M.W : | 245.27 |
SMILES Code : | O=C(N1[C@@H](C(OC)=O)C[C@@H](O)C1)OC(C)(C)C |
Synonyms : |
(2R,4R)-1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate
|
MDL No. : | MFCD00797548 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 17 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.82 |
Num. rotatable bonds | 5 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 63.85 |
TPSA ? Topological Polar Surface Area: Calculated from |
76.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.41 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.58 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.15 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.22 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.11 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.65 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.4 |
Solubility | 9.85 mg/ml ; 0.0402 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.75 |
Solubility | 4.36 mg/ml ; 0.0178 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.27 |
Solubility | 131.0 mg/ml ; 0.535 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 |
No |
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 |
-7.38 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 |
0.0 |
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) |
3.36 |
* 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 |
---|---|---|
100% | With dmap; triethylamine; In water; acetone; | [0347] To a solution of <strong>[114676-59-4](2R,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride</strong> (4.4 g, 24.67 mmol) in Acetone and water (3:2, 30 mL) were added Et3N (6.8 mL , 49.28 mmol), DMAP (150 mg, 1.2 mmol). Then (Boc)20 (8.0 mL, 34.54 mmol) was added slowly and the reaction was stirred overnight. All the acetone was removed and diluted with EtOAc and washed with 0.5 N HC1, water, brine, dried and concentrated to yield 6.0 g of (2R,4R)-1- tert-butyl 2-methyl 4-hydroxypyrrolidine-l,2-dicarboxylate (quantitative). |
93.4% | At room temperature,(13.83 g, 76.38 mmol) was dissolved in a mixed solvent of 1,4-dioxane (50 mL) and water (20 mL), cooled to 0 ° C,Triethylamine (19.32 g, 190.95 mmol) was added and stirred for 10 min.Twenty-three butyl dicarbonate (21.67g, 99.29mmol)In dichloromethane (20 mL) was added dropwise to the reaction solution and reacted at room temperature overnight.Water (50 mL) was added to the reaction solution and extracted with dichloromethane (50 mL x 3).The organic phases were combined and washed with a hydrochloric acid solution (1 mol / L, 20 mL x 2) and a saturated aqueous saline solution (40 mL x 2).Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow liquid 3C (17.49 g, yield 93.4percent). | |
88% | With triethylamine; In dichloromethane; | Step A-2. Preparation of a Boc compound To a suspension of <strong>[114676-59-4](2R,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine hydrochloride</strong> (25.64 g: 125 mmole) in dichloromethane (125 ml), triethylamine (19.11 ml: 137.5 mmole) is added dropwise in a nitrogen atmosphere under ice cooling. The mixture is stirred for 5 minutes at room temperature. Then, a solution of di-t-butyl dicarbonate (34.11 g: 156.3 mmole) in dichloromethane (125 ml) is added dropwise, and the mixture is stirred for 40 minutes at room temperature to give (2R,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (26.85 g). Yield: 88percent. Colorless crystals. NMR delta(CDCl3) ppm: 1.46(d, J=8.4 Hz, 9H), 2.0 to 2.2(m, 1H), 2.2 to 2.5(m, 1H), 3.4 to 3.8(m, 2H), 3.79(d, J=3.0 Hz, 3H), 4.2 to 4.5(m, 2H). IR nu (KBr) cm-1: 3460, 1730, 1680. |
88% | Add triethylamine (265.9 g, 2.63 mol) to a solution of methyl ester hydrochloride in dry dichloromethane (2 L) at 0° C. and stir for 30 min. Then add N,N-dimethylaminopyridine (0.18 mol, 21.9 g) and di-tert-butyl dicarbonate (1.43 mol, 313.5 g) consecutively. Warm the reaction mixture to room temperature and stir for 18 h. Quench the reaction mixture with water, separate the organic layer and wash with water and NaHCO3 solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the title compound (260 g, 88percent) as a thick oil. 1H NMR (400 MHz, CDCl3) delta 1.43 (s, 9H), 1.46 (s, 9 H), 2.05-2.10 (m, 2H), 2.26-2.35 (m, 2H), 3.48-3.56 (m, 2H), 3.58-3.61 (m, 1H), 3.64-3.70 (m, 2H), 3.77 (s, 3H), 3.79 (s, 3H), 4.27-4.29 (m, 1H), 4.34-4.38 (m, 2H). | |
79% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 0 - 20℃; for 1h; | Add di-tert-butyl dicarbonate (10.4 g, 47.7 mmol) in 1,4-dioxane (10 mL) to a solution of 4- (R)-hydroxypyrrolidine-2-(R)-carboxylic methyl ester hydrochloride (6.66 g, 36.7 mmol) in 1,4-dioxane (80 mL). Cool in an ice bath and add N,N- diisopropylethylamine (11 mL, 62.4 mmol), then remove ice bath and stir 1 h at room temperature. Concentrate and dissolve in ethyl acetate and wash with aqueous citric acid solution (2 x 100 mL), water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), filter and concentrate to give the title compound as a white solid (7.1 g, 79percent). MS (ES): m/z = 246.1 [M+H]. |
77% | With silica gel; triethylamine; In dichloromethane; at 23℃; for 5h; | To a stirred suspension [OF 4R-HYDROXYPYRROLIDINE-2R-CARBOXYLIC] acid methyl ester hydrochloride salt (15.9 g, 76.3 mmol, 1 eq. ) in [CH2C12] (200 mL) at [23 °C] was added Et3N (21.3 mL, 153 mmol, 2 eq.) followed by Boc20 (21.1 mL, 91.6 mmol, 1.2 eq. ). The resulting mixture was stirred for 5 h, then treated with silica gel (20 g). The volatiles were removed in vacuo to give a free-flowing powder, which was dry-loaded onto a pre-packed silica gel column. The product was purified via flash column chromatography (100percent EtOAc as an eluent) to give [4R-HYDROXYPYRROLIDINE-1,] 2R-dicarboxylic acid [1-TERT-BUTYL] ester 2-methyl ester (14.4 g, 58.9 mmol, 77percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 25℃; for 2h; | Example 1 (4S)-4- ({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N- cyclopropyl-1-methyl-D-prolinamide Example 1 HATU (0.23g) was added to an agitated solution of (4Y)-4- ( {4- [ (3-CHLORO-2- fluorophenyl) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-D-PROLINE (7) (0.18g), cyclopropylamine (34.4mg) and DIPEA (156mg) IN METHYLENE CHLORIDE (5M1). After 16hrs the reaction mixture was reduced in vacuo. The residues were re-dissolved in methylene chloride and washed with sodium hydroxide solution (2M) and water. The organic phase was then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE CHLORIDE (0/100-10/90). THE fractions containing the desired product were combined and evaporated to a foam which was triturated with diethylether to give the title compound as a white solid. (0. 15G). LH NMR Spectrum : (DMSO d6) 0.40-0. 48 (m, 2H), 0.57-0. 64 (M, 2H), 2.05-2. 14 (M, 1H), 2.28 (s, 3H), 2.33-2. 45 (M, 1H), 2.48-2. 56 (M, 1H + DMSO), 2. 61-2. 70 (M, 1H), 3.08 (t, 1H), 3.64 (dd, 1H), 3.94 (s, 3H), 5.06 (M, 1H), 7.20 (s, 1H), 7.28 (t, 1H), 7.44-7. 56 (M, 2H), 7.65 (s, 1H), 7.87 (d, 1H), 8.35 (s, 1H), 9.63 (s, 1H); Mass SPECTRUM : (M+H) + 486. 44 The starting material 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-, 1- (1, 1-DIMETHYLETHYL) 2- methyl ester, (2R, 4R) (2) was prepared as follows: 1- [3- (DIMETHYLAMINO) PROPYL]-3-ETLIYLCARBODIIMIDE hydrochloride (14.73 g) was added to a stirred suspension of 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-, l- (l, l-dimethylethyl) ester, (2R, 4R) (1) (13.65 g), DIMETHYLAMINOPYRIDINE (21.65 g) and methanol (5.67 g) in methylene chloride (400 ml) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with citric acid (1.0 M), saturated aqueous sodium bicarbonate solution and saturated brine, dried over MgSO4, filtered and evaporated. The residues were then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (1/99-5/95). The desired product fractions were combined and evaporated to give 1, 2-PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy-, L- (L, L-DIMETHYLETHYL) 2- methyl ester, (2R, 4R) (2) as a white crystalline solid, (5.9 g). 1H NMR Spectrum : (DMSO d6) 1.32 + 1.38 (2s, 9H), 1.76-1. 87 (M, 1H), 2.24-2. 28 (M, 1H), 3.06-3. 15 (M, 1H), 3.42- 3. 51 (m, 1H), 3.60 + 3.63 (2s, 3H), 4.15-4. 24 (M, 2H), 4.92-5. 00 (M, 1H). Starting material 1, 2-Pyrrolidinedicarboxylic acid, 4-hydroxy-1- (1, 1-dimethylethyl) ester, (2R, 4R), (1), (Boc-D-cis-hyp-OH) is commercially available Starting material (3) was prepared as follows: 6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 of in W001/66099 ; 10. 0g, 39.6 MMOLE) was added in portions to a stirred 7N methanolic ammonia solution (220 ML) cooled to 10C in an ice/water bath. After stirring for one hour the precipitate was filtered, washed with diethylether and dried thoroughly under high vacuum to give 4-chloro-7- METHOXYQUINAZOLIN-6-OL (3) (5.65g, 67.8%) ; 1H NMR Spectrum : (DMSO d6) 3.96 (s, 3H); 7.25 (s, 1H); 7.31 (s, 1H); 8.68 (s, 1H) ; Mass Spectrum: (M+H) + 211. The starting material (4) was prepared as follows: Di-ethyl azodicarboxylate (5.71g) was added slowly to a stirred suspension of 1,2- PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy-, L- (L, L-DIMETHYLETHYL) 2-methyl ester, (2R, 4R) (2) (5.9g), 4-CHLORO-7-METHOXYQUINAZOLIN-6-OL (3) (4.6g) AND TRIPHENYLPHOSPHINE (8.6g) in methylene chloride (400 ML) at 25C under an atmosphere of nitrogen and the reaction mixture was stirred for 2 hours. The reaction mixture was then evaporated to ½ volume and purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (1/99-3/97). The desired product fractions were combined and evaporated to give 1-tert-butyl 2-methyl (2R, 4S)-4-[(4-chloro-7-methoxyquinazolin-6- yl) oxy] pyrrolidine-1, 2-dicarboxylate (4) as a pale yellow gum. This was used in the preparation of (5) without further purification. The starting material methyl (4S)-4-({4-[(3-CHLORO-2-FLUOROPHENYL) AMINO]-7- METHOXYQUINAZOLIN-6-YL} OXY)-D-PROLINATE HYDROCHLORIDE (5) was prepared as follows: 4. 0M HCl in Dioxane (15 ml) was added to a suspension of 1-tert-butyl 2-methyl (2R, 4S)-4- [(4-chloro-7-methoxyquinazolin-6-yl0 oxy] pyrrolidine-1, 2-dicarboxylate (4) AND 3-CHLORO-2- fluoroaniline (2.89g) in acetonitrile (400 ML) and the reaction mixture was stirred and heated at 70C for 3 hours. The resulting precipitate was filtered hot and washed with acetonitrile and diethylether and dried under vacuum to give methyl (4S)-4- (14- [ (3-CLILORO-2- FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-D-PROLINATE HYDROCHLORIDE (S) as an off- white solid, (6. 3G). TH NMR Spectrum : (DMSO D6) 2.46-2. 60 (M, 2H), 3.37-3. 46 (M, 1H), 3.71 (s, 3H), 3.89-3. 98 (m, 4H), 4.53 (t, 1H), 5.42 (M, 1H), 7.29 (t, 1H), 7.38-7. 48 (M, 2H), 7.55 (t, 1H), 8.64 (s, 1H), 8.75 (s, 1H)... |