63746-12-3|Dimethyl 4-aminoisophthalate| Ambeed

CAS No. :	63746-12-3
Formula :	C₁₀H₁₁NO₄
M.W :	209.20
SMILES Code :	O=C(OC)C1=CC=C(N)C(C(OC)=O)=C1
MDL No. :	MFCD12674801
InChI Key :	QWENMFNFBJHLTE-UHFFFAOYSA-N
Pubchem ID :	11095854

Safety of [ 63746-12-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 63746-12-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	6
Fraction Csp3	0.2
Num. rotatable bonds	4
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	53.41
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	78.62 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.03
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.52
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.85
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.26
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.92
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.52

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.76
Solubility	0.366 mg/ml ; 0.00175 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.82
Solubility	0.0319 mg/ml ; 0.000152 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.2
Solubility	1.33 mg/ml ; 0.00634 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.79 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	2.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.63

Application In Synthesis of [ 63746-12-3 ]

* 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 [ 63746-12-3 ]

[ 63746-12-3 ] Synthesis Path-Downstream 1~55

1
[ 69048-70-0 ]
[ 63746-12-3 ]

Yield	Reaction Conditions	Operation in experiment
97%	With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 40℃; for 5h;	Dissolve 20 g of dimethyl 4-nitroisophthalate in 518 mL of ethyl acetate and add 1 g of 10 wt % of Pd/C under agitation. Input H2, slowly heat to 40 C., react for about 5 h, and track the reaction process by TLC until the raw materials disappear. Stop heating after the reaction, cool the product to room temperature and filter it, wash filter cakes with ethyl acetate, and carry out column chromatography, eluent:petroleum ether:ethyl acetate=3:1. 17 g of white crystalline solid is obtained and the yield is 97%; mp 127-129 C. 1H (400 MHz, CDCl3): delta 8.59 (d, J=1.6 Hz, 1H), 7.91 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 6.2 (brs, 2H), 3.90 (s, 3H), 3.88 (s, 3H).
95.4%	With palladium 10% on activated carbon; In methanol; at 45℃;	3. Add methanol (400 mL) and the product obtained in Step 2 (167.2 mmol) to a 1000 mL single-mouth bottle.The stirring was turned on, and palladium carbon (10% by weight) was added to the single-mouth bottle.After the completion of the exhaust, hydrogen was introduced into the reaction system, and the reaction system was slowly warmed to 45 C overnight, and the reaction was followed by HPLC.After the reaction was completed, the reaction solution was filtered while hot, and the filter cake was washed with hot methanol (50 C) and filtered.The filtrate is desolvated, and when the methanol is removed to 1/3,600 mL of ethyl acetate and 200 mL of saturated brine were added thereto, stirred, and allowed to stand for stratification.Dry the organic phase with anhydrous sodium sulfate,Desolvation gave a white solid with a purity of 97.8% and a yield of 95.4%.
95%	With palladium on activated charcoal; hydrogen; In ethyl acetate; at 45℃; for 6h;	Dimethyl 4-nitroisophthalate (6.54g, 27.3mmol) and palladium/carbon (0.65g) were dissolved in ethyl acetate (90mL) at room temperature, hydrogen was added, and the temperature was slowly raised to 45 C in an oil bath. After 6 hours, the reaction was stopped. Palladium-carbon removal by suction filtration,The solvent was removed to give a white solid of 5.43 g.Yield: 95%.

63.7%	With hydrogen;10% palladium charcoal; In methanol; at 20℃;	4-Amino-isophthalic acid dimethyl ester: To a suspension of 4-nitro-isophthalic acid dimethyl ester (3.5 g, 0.014 mol) in dry methanol (200 ml) was added Pd/C (7 g, 50 % w/w) in an autoclave. The suspension was stirred at RT under 3 kg H2 pressure. The solution was filtered through a celite bed and the filtrate concentrated to afford 4. Yield: 63.7 % (1.95 g).
	With hydrogen;palladium;	The intermediate compound of formula [(II)] which constitutes the starting material for the synthetic process illustrated by Schemes 22a and 22b above may be prepared in accordance with Scheme 24 below: Scheme 24.

References: [1]Patent: US2016/264532,2016,A1 .Location in patent: Paragraph 0043.
[2]Patent: CN108164469,2018,A .Location in patent: Paragraph 0094; 0097.
[3]Patent: CN109503556,2019,A .Location in patent: Paragraph 0284; 0290; 0291.
[4]Patent: WO2008/152142,2008,A1 .Location in patent: Page/Page column 26.
[5]Monatshefte fur Chemie,1920,vol. 41,p. 155.
[6]Patent: WO2004/14384,2004,A2 .Location in patent: Page/Page column 157.
[7]Journal of Agricultural and Food Chemistry,2014,vol. 62,p. 11786 - 11796.
[8]Journal of the American Chemical Society,2015,vol. 137,p. 843 - 849.

2
[ 63746-12-3 ]
[ 66849-11-4 ]
[ 63746-15-6 ]

References: [1]European Journal of Medicinal Chemistry,1979,vol. 14,p. 247 - 251.

3
[ 25579-48-0 ]
[ 63746-12-3 ]
[ 85742-71-8 ]

References: [1]Journal of Medicinal Chemistry,1987,vol. 30,p. 1543 - 1549.

4
[ 60943-15-9 ]
[ 63746-12-3 ]
[ 85742-95-6 ]

References: [1]Journal of Medicinal Chemistry,1987,vol. 30,p. 1543 - 1549.

5
[ 141-30-0 ]
[ 63746-12-3 ]
8-(carboxymethyl)-2-chloro-10-oxo-10H-pyridazino<6,1-b>quinazoline [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1980,vol. 23,p. 964 - 966.

6
[ 63746-12-3 ]
[ 1488-42-2 ]
[ 100038-91-3 ]

References: [1]Synthesis,1985,p. 220 - 222.

7
[ 63746-12-3 ]
[ 33890-03-8 ]

References: [1]Journal of Medicinal Chemistry,1981,vol. 24,p. 735 - 742.

8
[ 63746-12-3 ]
[ 624-83-9 ]
4-(3-Methyl-ureido)-isophthalic acid dimethyl ester [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 2253 - 2258.

9
[ 63746-12-3 ]
[ 86945-39-3 ]
[ 108561-90-6 ]

References: [1]Journal of Medicinal Chemistry,1987,vol. 30,p. 1543 - 1549.

10
[ 52804-26-9 ]
[ 63746-12-3 ]
4-[2-(4-Adamantan-1-yl-phenoxy)acetyl-amino]-isophthalic acid dimethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.3%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	<Example 21> 4-[2-(4-Adamantan-l-yl-phenoxy)acetyl-amino]-isophtalic acid dimethyl esterTo a mixture of (4-adamantan-l-yl-phenoxy)-acetic acid (229 mg, 0.8 mmol) and <strong>[63746-12-3]4-aminoisophthalic acid dimethyl ester</strong> (301 mg, 1.4 mmol) were dissolved in DMF (5mL), and EDCHCl (140 mg, 0.75 mmol), HOAt (163 mg, 1.2 mmol) and DIPEA (0.21 ml, 1.2 mmol) was added. The mixture was stirred overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CHaCl2MeOH = 50:1) to give 4-[2-(4- Adamantan-l-yl-phenoxy)acetyl-amino]-isophtalic acid dimethyl ester as a white solid (281 mg, 76.3% yield).1H-NMR (CDCl3, 300Hz) 12.00(1H, s, NH), 9.40(1H, d, J=I .8 Hz, aromatic), 8.12(1H, d, J=7.8 Hz, aromatic), 7.78(1H, dd, J=8.1 & 1.8 Hz, aromatic), 7.33(2H, m, aromatic), 7.03(2H5 m, aromatic), 4.65(2H, s, <n="34"/>OCH2CO), 3.97(3H, s, OCH3), 3.95(3H, s, OCH3), 2.09(3H, m, adamantyl),. 1.89-1.90(6H, m, adamantyl), 1.72- 1.82(6H, m, adamanty).).
76.3%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	To a mixture of (4-adamantan-1-yl-phenoxy)-acetic acid (229 mg, 0.8 mmol) and <strong>[63746-12-3]4-aminoisophthalic acid dimethyl ester</strong> (301 mg, 1.4 mmol) were dissolved in DMF (5 mL), and EDCHCl (140 mg, 0.75 mmol), HOAt (163 mg, 1.2 mmol) and DIPEA (0.21 ml, 1.2 mmol) was added. The mixture was stirred overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=50:1) to give 4-[2-(4-Adamantan-1-yl-phenoxy)acetyl-amino]-isophthalic acid dimethyl ester as a white solid (281 mg, 76.3% yield). 1H-NMR (CDCl3, 300 Hz) 12.00 (1H, s, NH), 9.40 (1H, d, J=1.8 Hz, aromatic), 8.12 (1H, d, J=7.8 Hz, aromatic), 7.78 (1H, dd, J=8.1 & 1.8 Hz, aromatic), 7.33 (2H, m, aromatic), 7.03 (2H, m, aromatic), 4.65 (2H, s, OCH2CO), 3.97 (3H, s, OCH3), 3.95 (3H, s, OCH3), 2.09 (3H, m, adamantyl), 1.89-1.90 (6H, m, adamantyl), 1.72-1.82 (6H, m, adamantyl).

References: [1]Patent: WO2008/4798,2008,A1 .Location in patent: Page/Page column 31; 32.
[2]Patent: US2009/306078,2009,A1 .Location in patent: Page/Page column 27.

11
[ 463-71-8 ]
[ 63746-12-3 ]
[ 342803-20-7 ]

References: [1]Journal of Organic Chemistry,2007,vol. 72,p. 284 - 287.

12
[ 63746-12-3 ]
2-chloro-10-oxo-10H-pyridazino<6,1-b>quinazoline-8-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1980,vol. 23,p. 964 - 966.

13
[ 63746-12-3 ]
[ 118621-02-6 ]

References: [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 2253 - 2258.

14
[ 63746-12-3 ]
[ 118621-01-5 ]

References: [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 2253 - 2258.

15
[ 63746-12-3 ]
[ 118621-06-0 ]

References: [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 2253 - 2258.

16
[ 63746-12-3 ]
[ 118621-03-7 ]

References: [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 2253 - 2258.

17
[ 63746-12-3 ]
[ 77423-13-3 ]

References: [1]Journal of Medicinal Chemistry,1981,vol. 24,p. 735 - 742.

18
[ 95-63-6 ]
[ 63746-12-3 ]

References: [1]Monatshefte fur Chemie,1910,vol. 31,p. 1297.

19
[ 54699-35-3 ]
[ 63746-12-3 ]

References: [1]Monatshefte fur Chemie,1910,vol. 31,p. 1297.

20
[ 528-44-9 ]
[ 63746-12-3 ]

References: [1]Monatshefte fur Chemie,1910,vol. 31,p. 1297.

21
[ 2459-10-1 ]
[ 63746-12-3 ]

References: [1]Monatshefte fur Chemie,1910,vol. 31,p. 1297.

22
[ 478788-48-6 ]
[ 63746-12-3 ]

References: [1]Monatshefte fur Chemie,1910,vol. 31,p. 1297.

23
[ 13912-71-5 ]
[ 63746-12-3 ]

References: [1]Monatshefte fur Chemie,1910,vol. 31,p. 1297.

24
[ 63746-12-3 ]
[ 871886-64-5 ]

References: [1]Monatshefte fur Chemie,1918,vol. 39,p. 394,395.

25
[ 63746-12-3 ]
4-(6-methoxycarbonyl-2-methyl-4-oxo-4<i>H</i>-quinazolin-3-yl)-isophthalic acid dimethyl ester [ No CAS ]

References: [1]Monatshefte fur Chemie,1918,vol. 39,p. 394,395.

26
[ 7501-68-0 ]
[ 63746-12-3 ]

References: [1]Monatshefte fur Chemie,1918,vol. 39,p. 394,395.
[2]Monatshefte fur Chemie,1918,vol. 39,p. 394,395.

27
[ 89-87-2 ]
[ 63746-12-3 ]

References: [1]Monatshefte fur Chemie,1920,vol. 41,p. 155.
[2]Journal of the American Chemical Society,2015,vol. 137,p. 843 - 849.
[3]Patent: CN108164469,2018,A .
[4]Patent: WO2008/152142,2008,A1 .

28
[ 4315-09-7 ]
[ 63746-12-3 ]

References: [1]Monatshefte fur Chemie,1920,vol. 41,p. 155.
[2]Journal of Agricultural and Food Chemistry,2014,vol. 62,p. 11786 - 11796.
[3]Journal of the American Chemical Society,2015,vol. 137,p. 843 - 849.
[4]Patent: US2016/264532,2016,A1 .
[5]Patent: CN108164469,2018,A .
[6]Patent: WO2008/152142,2008,A1 .
[7]Patent: CN109503556,2019,A .

29
[ 63746-12-3 ]
[ 622-78-6 ]
3-benzyl-6-(methoxycarbonyl)-2-thioxo-l,2,3,4-tetrahydroquinazolin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine;Heating / reflux;	In Scheme 28, methyl [4-AMINOISOPHTHALATE] (2a) is treated with benzyl isothiocyanate, in a solvent such as pyridine or acetic acid, to give 3-benzyl-6- [(METHOXYCARBONYL)-2-THIOXO-1,] 2,3, 4-tetrahydroquinazolin-4-one (2b). This compound is heated, in a refluxing alcohol, in the presence of hydrazine hydrate to give the corresponding hydrazine which is in turn cyclized by reaction with a carboxylic acid derivative RCOOH (such as an acid chloride or an ortho ester). The 4-benzyl-7- (methoxycarbonyl)-4, 5-dihydrotriazolo [4,3-a] quinazolin-5-one (2d) obtained is N4-debenzylated using aluminum chloride in benzene, and the intermediate secondary lactam is then substituted with a halide, in the presence of a base such as cesium carbonate, in a solvent such as dimethylformamide. The N- substituted analogue obtained [(2F)] is then hydrolyzed, preferably in acidic medium, to give the corresponding acid (2g) which may be subsequently subjected to a coupling reaction of peptide type. The order of the steps in the above process may be modified for the synthesis of certain compounds. For example, when R2 is [PARA-CYANOBENZYL,] step 5 will be carried out last since the para-cyanobenzyl group would not withstand the conditions of step 6.

References: [1]Patent: WO2004/14384,2004,A2 .Location in patent: Page/Page column 161.

30
[ 32315-10-9 ]
[ 63746-12-3 ]
C₁₁H₉NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		According to another aspect, the intermediate compound of formula (III) may be prepared, in accordance with the synthetic process illustrated in Scheme 26 above, according to Method B, as illustrated in Synthetic Scheme [26/METHOD B] below: Scheme 26/Method B. 0 0 0 0 0 Toluene I, 11 2 Tnphosgene NS 0 O O Toluene 0 0- R2NH2 NH O NH R2 MeOH 0 0 0 R3 MeONa-'-N 10 MeONa I N' O N 0 H 0 0 O O LiOH gp I N-R2 unto Dioxane/H20 H (III) wherein [R2] is as defined above for Formula [I.]

References: [1]Patent: WO2004/14384,2004,A2 .Location in patent: Page/Page column 15.

31
water+ice [ No CAS ]
[ 63746-12-3 ]
[ 3173-56-6 ]
[ 209604-61-5 ]

Yield	Reaction Conditions	Operation in experiment
62%	With pyridine; In ethanol;	4th Stage: Methyl 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate 4 g (19.1 mmol) of <strong>[63746-12-3]dimethyl 4-aminoisophthalate</strong> and 40 ml of pyridine are successively introduced into a 50 ml three-necked flask fitted with a reflux condenser and protected from moisture, followed by addition of 3.2 g (24 mmol) of benzyl isocyanate. The colourless solution is stirred and heated at 95-100 C. After 6 hours at this temperature, 1 ml of benzyl isocyanate is added and stirring is then continued at 100 C. overnight. The next day, the reaction medium is cooled and poured into 400 ml of a water+ice mixture, it is left stirring for about 30 minutes and the precipitate obtained is then filtered off. The product is re-slurried at reflux in 150 ml of ethanol. After cooling, the product is filtered off. The product is obtained as follows: Weight=3.7 g, yield=62% NMR: DMSO 1H delta (ppm): 3.75 (s,3H); 4.95 (s,2H); 7.1-7.2 (m,6H); 8.05 (d,1H); 8.35 (s,1H); 11.8 (bs,1H).

References: [1]Patent: US2003/78276,2003,A1 .

Yield	Reaction Conditions	Operation in experiment
		Step 1-4 Methyl 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline -6-carboxylate 4 g (19.1 mmol) of compound of preparation A and 40 ml of pyridine are successively introduced into a 50 ml three-necked flask fitted with a reflux condenser and protected from moisture, followed by addition of 3.2 g (24 mmol) of benzyl isocyanate. The colourless solution is stirred and heated at 95-100 C. After 6 hours at this temperature, 1 ml of benzyl isocyanate is added and stirring is then continued at 100 C. overnight. The next day, the reaction medium is cooled and poured into 400 ml of a water+ice mixture, it is left stirring for about 30 minutes and the precipitate obtained is then filtered off. The product is re-slurried at reflux in 150 ml of ethanol.
		Step 1 Methyl-2,4-dioxo-3-phenethyl-1,2,3,4-tetrahydroquinazoline-6-carboxylate 0.750 g (3.6 mmol) of compound of Preparation A and 7.5 ml of pyridine are introduced into a round-bottomed flask. 0.530 g (0.5 ml; 3.6 mmol) of phenethyl isocyanate is added. The mixture is maintained at 100 C. overnight. Since the reaction is incomplete, a second addition of phenethyl isocyanate, i.e. 2 equivalents, is carried out.

33
[ 102422-56-0 ]
[ 110-86-1 ]
[ 63746-12-3 ]

Yield	Reaction Conditions	Operation in experiment
	In water;	Step 1 Methyl 3-(3-fluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate 5.5 g (26.3 mmol) of compound of the Preparation A and 50 ml of pyridine are introduced into a round-bottomed flask. 5.0 g (33.1 mmol) of 3-fluorobenzyl isocyanate are added. The mixture is maintained at reflux for 6 hours and 0.8 g (5.3 mmol) of 3-fluorobenzyl isocyanate is added in one portion. The mixture is heated overnight at reflux. The mixture is cooled and the product is precipitated with the addition of water and filtered.

References: [1]Patent: US2002/193377,2002,A1 .

34
[ 63746-12-3 ]
[ 76143-03-8 ]

Yield	Reaction Conditions	Operation in experiment
	In water;	C.) to give methyl 1,2-dihydro-2-trichloromethyl-4H-benzo[d]-[1,3]-oxazine-6-carboxylate, m.p. 178-179 C. The methyl 4-amino-3-hydroxymethylbenzoate used as the starting material in the above process was obtained by reducing dimethyl 4-amino-iso-phthalate (5 g.) in ether (100 ml., dried over sodium) with lithium aluminium hydride (2 g.). The mixture was stirred at room temperature for 3.5 hours, then water (50 ml.) was added cautiously. The organic phase was separated and dried, the solvent was evaporated, and the residue was purified by silica gel chromatography, eluding with diethyl ether/petroleum ether (b.p. 60-80 C.), 4:1 by volume. The product thus obtained was crystallized from ethyl acetate/petroleum ether (b.p. 60-80 C.) to give the required starting material, m.p. 116-117 C. The process described above was repeated, using the appropriate o-aminobenzyl alcohol as starting material, to give the following analogous products:

References: [1]Patent: US4268510,1981,A .

35
[ 75680-92-1 ]
[ 63746-12-3 ]
2-ethyl 8-methyl 10-oxo-10H-pyridazino[6,1-b]quinazoline-2,8-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; chloroform;	Step C. A mixture of ethyl 6-chloro-3-pyridazinecarboxylate (0.29 g, 1.55 mmol, Example 1, Step A) and <strong>[63746-12-3]dimethyl 4-aminoisophthalate</strong> (0.36 g, 1.72 mmol, Example 1, Step B) was heated as a melt at 165-170 C. for 30 min. The oil was dissolved into chloroform, washed with 10% ammonium hydroxide solution, dried (MgSO4), filtered and concentrated. Medium pressure chromatography (silica gel, chloroform to 1% methanol in chloroform) of the crude oily-solid afforded 2-ethyl 8-methyl 10-oxo-10H-pyridazino[6,1-b]quinazoline-2,8-dicarboxylate as a yellow solid, mp 218-221 C. dec.

References: [1]Patent: US5340808,1994,A .

36
[ 33890-03-8 ]
[ 63746-12-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step B. A mixture of 4-aminoisophthalic acid [prepared according to the procedure of Hirsh, J. A. and Schwartzkopf, G. (J. Org. Chem. 1974, 39, 2044-2048)] was saturated with hydrogen chloride gas for 15 min. The mixture was refluxed for 12 h, cooled concentrated, dissolved into chloroform and washed with saturated sodium bicarbonate solution. The chloroform extract was dried (MgSO4), filtered and concentrated to give dimethyl-4-aminoisophthalate as an off-white solid, mp 127-130 C.

References: [1]Patent: US5340808,1994,A .

37
[ 63746-12-3 ]
[ 29671-92-9 ]
[ 1289557-30-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With dimethylsulfone; at 150℃; for 2h;	3,5-dichlorophenyl-2-amino-4-oxo-3,4-dihydroquinazoline-6-carboxylate (or 2-Amino-4- oxo-3,4-dihydro-quinazoline-6-carboxylic acid methyl ester): The diester 4-Amino- isophthalic acid dimethyl ester (2.4 g, 0.011 mol) was added to a mixture containing dimethyl sulfone (12 g) and chloroformamidine hydrochloride (2.64 g 0.022 mol). The reaction content was heated at 150 0C for 2h and cooled to RT. The solid mass was added with water (50 ml) and stirred for 30 min. On adding aqueous ammonia to this suspension, the solid was precipitated out and filtered off. The solid was washed with water and dried to obtain 5 as off- white solid. Yield: 85 % (2.1 g)

References: [1]Patent: WO2008/152142,2008,A1 .Location in patent: Page/Page column 26.

38
[ 1002965-95-8 ]
[ 63746-12-3 ]

References: [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 2880 - 2894.

39
[ 857088-63-2 ]
[ 63746-12-3 ]
[ 1312919-68-8 ]

Yield	Reaction Conditions	Operation in experiment
62%	With pyridine; triethylamine; In dichloromethane; at 50℃; for 48h;Inert atmosphere;	Sulfonyl chloride 27 or 28 (1.00 mmol) was dissolved in CH2Cl2 (5 mL) and slowly added to a solution of amine 12i (1.20 mmol) in CH2Cl2 (5 mL), followed by the addition of Py (2.50 mmol) after 10 min. The reaction mixture was stirred for 2 days at 50 C. After the reaction was complete (monitored by TLC), 1 M HCl (15 mL) was added and the product extracted with CH2Cl2 (3 × 30 mL). The combined organic phases were washed with brine (2 × 30 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude products were purified by column chromatography, to yield compounds 29i and 30i.

References: [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 2880 - 2894.

40
[ 857088-63-2 ]
[ 63746-12-3 ]
[ 1312919-86-0 ]

References: [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 2880 - 2894.

41
[ 1092117-57-1 ]
[ 63746-12-3 ]
[ 1312919-77-9 ]

Yield	Reaction Conditions	Operation in experiment
52%	With pyridine; triethylamine; In dichloromethane; at 50℃; for 48h;Inert atmosphere;	Sulfonyl chloride 27 or 28 (1.00 mmol) was dissolved in CH2Cl2 (5 mL) and slowly added to a solution of amine 12i (1.20 mmol) in CH2Cl2 (5 mL), followed by the addition of Py (2.50 mmol) after 10 min. The reaction mixture was stirred for 2 days at 50 C. After the reaction was complete (monitored by TLC), 1 M HCl (15 mL) was added and the product extracted with CH2Cl2 (3 × 30 mL). The combined organic phases were washed with brine (2 × 30 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude products were purified by column chromatography, to yield compounds 29i and 30i.

References: [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 2880 - 2894.

42
[ 1092117-57-1 ]
[ 63746-12-3 ]
[ 1312919-95-1 ]

References: [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 2880 - 2894.

43
[ 1312919-57-5 ]
[ 63746-12-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 10h;	To a solution of compound 19 (300 mg, 1.00 mmol) in MeOH (15 mL), 10% Pd-C (30 mg) was added, and the mixture was hydrogenated for 10 h at room temperature. The suspension was then filtered through a pad of celite and washed with MeOH (20 mL). The solvent was evaporated under reduced pressure, yielding the pure product 12i as a white solid (178 mg, 85%). Mp: 126.5-127.0 C (lit. [40] 127-128 C); 1H NMR (300 MHz, CDCl3): delta 3.87 (s, 3H, CH3), 3.89 (s, 3H, CH3), 6.20 (br s, 2H, NH2), 6.64 (d, J = 8.7 Hz, 1H, Ar-H), 7.90 (dd, J = 8.7, 2.1 Hz, 1H, Ar-H), 8.58 (d, J = 2.1 Hz, 1H, Ar-H); HRMS (ESI) m/z calcd for C10H12NO4 [M + H]+ 210.0766, found 210.0769.

References: [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 2880 - 2894.

44
[ 6939-93-1 ]
[ 63746-12-3 ]