612501-52-7|4-((3-Chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol| Ambeed

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Quality Control of [ 612501-52-7 ] Purity: 97% SDS Specification

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Product Citations

Discovery of a Hydroxylamine-Based Brain-Penetrant EGFR Inhibitor for Metastatic Non-Small-Cell Lung Cancer

Hill, Jarvis ; Jones, Robert M. ; Crich, David ;

DOI: 10.1021/acs.jmedchem.3c01669 PubMed ID: 37934858 JMC,2023,66(22):15477-15492.

Abstract: Metastases to the brain remain a significant problem in lung cancer, as treatment by most small mol. targeted therapies is severely limited by efflux transporters at the blood-brain-barrier (BBB). Here, we report the discovery of a selective, orally bioavailable, epidermal growth factor receptor (EGFR) inhibitor, 9, that exhibits high brain penetration and potent activity in osimertinib-resistant cell lines bearing L858R/C797S and exon19del/C797S EGFR resistance mutations. In vivo, 9 induced tumor regression in an intracranial patient-derived xenograft (PDX) murine model suggesting it as a potential lead for the treatment of localized and metastatic nonsmall-cell lung cancer (NSCLC) driven by activating mutant bearing EGFR. Overall, we demonstrate that an underrepresented functional group in medicinal chem., the trisubstituted hydroxylamine moiety, can be incorporated into a drug scaffold without the toxicity commonly surmised to accompany these units, all while maintaining potent biol. activity and without the mol. weight creep common to drug optimization campaigns.

Purchased from AmBeed: 612501-52-7

Product Details of [ 612501-52-7 ]

CAS No. :	612501-52-7
Formula :	C₁₅H₁₁ClFN₃O₂
M.W :	319.72
SMILES Code :	OC1=CC2=C(NC3=CC=CC(Cl)=C3F)N=CN=C2C=C1OC
MDL No. :	MFCD26394834
InChI Key :	VZBZUFGPXJGXNJ-UHFFFAOYSA-N
Pubchem ID :	57476868

Safety of [ 612501-52-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 612501-52-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	22
Num. arom. heavy atoms	16
Fraction Csp3	0.07
Num. rotatable bonds	3
Num. H-bond acceptors	5.0
Num. H-bond donors	2.0
Molar Refractivity	82.56
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	67.27 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.86
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	3.76
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.3
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.	2.85
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	3.22
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.4

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.53
Solubility	0.00941 mg/ml ; 0.0000294 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-4.87
Solubility	0.00436 mg/ml ; 0.0000136 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	-6.32
Solubility	0.000152 mg/ml ; 0.000000474 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Poorly soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
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	Yes
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	Yes
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	Yes
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	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.58 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	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.55

Application In Synthesis of [ 612501-52-7 ]

* 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 [ 612501-52-7 ]

[ 612501-52-7 ] Synthesis Path-Downstream 1~35

1
[ 13220-33-2 ]
[ 612501-52-7 ]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(1-methylpyrrolidin-3-yl)oxy]quinazolinehydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%		Example 1; 4- (3-Chloro-2-fluoroanilino)-7-methoxy-6- [ (1-methylpyrrolidin-3-yl) oxy] quinazoline; To a suspension of 4- (3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (Reference Example 2,639 mg, 2.0 mmol) in DCM (30 ml) was added 1-methyl-3- pyrrolidinol (658 ul, 6.0 mmol) and triphenyl phosphine (1572 mg, 6.0 mmol). The suspension was cooled to 0°C under a nitrogen atmosphere. Di-tert-butyl azodicarboxylate (1380 mg, 6 mmol) was added as a solution in DCM (20 ml), dropwise over the course of 15 minutes. The resulting light brown solution was allowed to warm to room temperature and was stirred overnight. The solution was evaporated, and the residue purified by chromatography, eluting with 0 to 5percent methanol in DCM. The appropriate fractions were combined and evaporated, and the crude product (230 mg) re-dissolved in 1: 1 methanol/DCM (5 ml). Ethereal HC1 (1M, 1.14 ml) was added, and the mixture evaporated. Crystallisation from ethanol/diethyl ether gave the title product as a hydrochloride salt in the form of a white crystalline solid (154 mg, 16percent) ; 1H NMR (hydrochloride salt) : 2.30 (m, 1H), 2.65-2. 75 (m, 1H), 2.88 (s, 3H), 3.30-3. 80 (m, 3H), 3.85-4. 05 (m, 1H), 4.00 (s, 3H), 5.46 (m, 1H), 7.35 (dd, 1H), 7.45 (s, 1H), 7.51 (dd, 1H), 7.62 (dd, 1H), 8.53 (s, 1H), 8. 72 (s, 1H), 8. 81 (s, 1H) ; Mass Spectrum : 403.3, 405.3.

References: [1]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 100.

2
[ 612501-52-7 ]
[ 166815-96-9 ]
6-[(1-tert-butoxycarbonyl)piperidin-4-yl]methoxy}-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate; In N,N-dimethyl acetamide; at 80℃; for 4h;	Reference Example 4; 6-{ [(1-tert-Butoxycarbonyl) piperidin-4-yl] methoxy}-4- (3-chloro-2-fluoroanilino)-7- methoxyquinazoline; 4- (3-Chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (Reference Example 2,700 mg, 2.19 mmol) was dissolved in DMA (35 ml). Potassium carbonate (1209 mg, 8.76 mmol) and tert-butyl 4- (toluene-4-sulfonyloxymethyl) piperidine-l-carboxylate (prepared as described in Example 1 in WO 9427965; 808 mg, 2.19 mmol) were added, and the mixture was stirred at 80C for 4 hours. The solvent was evaporated, and the residue was partitioned between water (100 ml) and DCM (100 ml). The aqueous layer was extracted with DCM (3x 100 ml) and the extractions combined with the DCM layer. The combined DCM fractions were filtered through a silicone-treated filter paper, and evaporated, giving the product as a brown solid (1290 mg, 98%) ; 1H NMR : 1.20 (m, 2H), 1.39 (s, 9H), 1.82 (m, 2H), 2.03 (br. m, 1H), 2.70-2. 85 (br. m, 2H), 3.93 (s, 3H), 3.95-4. 05 (br. m, 2H), 3.98 (d, 2H), 7.19 (s, 1H), 7.26 (dd, 1H), 7.46 (dd, 1H), 7.50 (dd, 1H), 7.76 (s, 1H), 8.35 (s, 1H), 9.57 (s, 1H); Mass Spectrum : 517. 3, 519.3

References: [1]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 163.
[2]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4908 - 4912.

3
[ 612501-52-7 ]
[ 147699-19-2 ]
6-[2-(1-tert-butoxycarbonyl)piperidin-4-yl]ethoxy}-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In N,N-dimethyl acetamide; at 60℃; for 16h;	Reference Example 5; 6-[2-(1-tert-Butoxycarbonyl) piperidin-4-yl] ethoxy}-4-(3-chloro-2-fluoroanilino)-7- methoxyquinazoline; 4- (3-Chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (Reference Example 2,500 mg, 1.56 mmol) was dissolved in DMA (25 ml). Potassium carbonate (864 mg, 6.26 mmol) and tert-butyl 4- [2- (methanesulfonyloxy) ethyl] piperidine-l-carboxylate (prepared as described in Example 20 in US 5252586; 504 mg, 1.64 mmol) were added, and the mixture was stirred at 60C for 16 hours. The solvent was evaporated, and the residue was partitioned between water (100 ml) and DCM (100 ml). The aqueous layer was extracted with DCM (3x 100 ml) and the extractions combined with the DCM layer. The combined DCM fractions were filtered through a silicone-treated filter paper, and evaporated, giving the product as a brown foam (830 mg, 100%) ; 1H NMR : 1. 00-1. 18 (m, 2H), 1.38 (s, 9H), 1.65-1. 80 (m, 5H), 2.65-2. 75 (m, 2H), 3.92 (s, 3H), 3.93 (m, 2H), 4.15 (t, 2H), 7.18 (s, 1H), 7.26 (dd, 1H), 7.46 (dd, 1H), 7.51 (dd, 1H), 7.77 (s, 1H), 8.36 (s, 1H), 9.54 (s, 1H); Mass Spectrum: 531.6, 533. 6.

References: [1]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 163-164.

4
[ 612501-52-7 ]
[ 612501-49-2 ]
4-(3-chloro-2-fluoroanilino)-6-(1-tert-butoxycarbonylpiperidin-3-yloxy)-7-methoxyquinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With cesium fluoride; In N,N-dimethyl-formamide; at 20℃; for 96h;	Dimethylformamide (23 ml) was added to 4- (3-chloro-2-fluoroanilino)-6-hydroxy-7- methoxyquinazoline, tert-butyl 3- [ (4-nitrophenyl) sulfonyloxy] piperidine-1-carboxylate (1.93 g) and cesium fluoride (2. 28 g). The reaction mixture was then stirred at room temperature for 4 days. The reaction mixture was evaporated under vacuum and partitioned between methylene chloride and water. The solutions were filtered to remove insoluble solids and the methylene chloride was washed with water and saturated brine and adsorbed onto silica. The product was then purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 94/6). The fractions containing the required product were combined and evaporated under vacuum to give 4- (3-chloro-2- fluoroanilino)-6- (l-tert-butoxycarbonylpiperidin-3-yloxy)-7-methoxyquinazoline as a yellow gum (0.67 g); Mass Spectrum : (M+H) + 503.

References: [1]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 115.

5
[ 2106-04-9 ]
[ 230955-75-6 ]
[ 612501-52-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogenchloride; In acetonitrile; for 1h;Heating / reflux;Product distribution / selectivity;	The 4- (3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline starting material used above was prepared as follows: 6-Acetoxy-4-chloro-7-methoxyquinazoline (Example 25-5 in W001/66099 ; 10. 0g, 39.6 mmole) was suspended in acetonitrile (400 ml) and 3-chloro-2-fluoroaniline (6. 05g, 41. 6 mmole) and hydrogen chloride (4. 0M solution in 1,4-dioxane) (10.4 ml, 41.6 mmole) were added. The reaction mixture was refluxed for one hour and then allowed to cool to ambient temperature. The resulting precipitate was filtered off, washed with acetonitrile and diethylether to give a white solid. This solid was added in portions to a stirred 7N methanolic ammonia solution (400 ml). The mixture was stirred for two hours and the precipitate filtered, washed with acetonitrile followed by diethylether and dried under vacuum to give 4- (3-chloro- 2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline as a white solid (12. 1g, 95%) ; lH NMR Spectrum: (DMSOd6) 3.95 (s, 3H) ; 7.18 (s, lH) ; 7.20-7. 25 (m, 1H); 7.39-7. 44 (m, lH) ; 7.47- 7.52 (m, 11-1) ; 7.65 (s, lH) ; 8.31 (s, 1H) ; 9.45 (br. s, lH) ; Mass Spectrum: (M+H) + 320.

References: [1]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 116.

6
[ 612501-52-7 ]
[ 612501-56-1 ]
4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(t-butoxycarbonyl)pyrrolidin-3-yloxy]-7-methoxyquinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With cesium fluoride; In N,N-dimethyl-formamide; at 20℃;	4- (3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (prepared as described in the starting materials used in Example 22; 4. 0g, 12.5 mmol) was mixed with tert-butyl (3S)- 3- [ (4-nitrophenyl) sulfonyloxy] pyrrolidine-1-carboxylate (4.7g, 12.6 mmol) and cesium fluoride (5.7g, 7.5 mmol). Dry N, N-dimethylformamide (60ml) was then added and the mixture stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, 50% aqueous brine then brine, dried over Na2S04, filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (98/2). The fractions containing the expected product were combined and evaporated to give 4- (3-chloro-2-fluoroanilino)-6- [(3R)-l-(t-butoxycarbonyl) pyrrolidin-3-yloxy] -7-methoxyquinazoline as a dry foam (2.35g, 38%) ; 1H NMR Spectrum : (DMSO d6) 1.39 (s, 9H) ; 2.10-2. 30 (m, 2H) ; 3.35-3. 50 (m, 3H) ; 3.64-3. 71 (m, lH); 3.92 (s, 3H); 5.12 (m, 1H) ; 7.21 (s, 1H) ; 7.23-7. 27 (m, 1H) ; 7.44-7. 55 (m, 2H) ; 7.80 (s, 1H) ; 8.37 (s, 1H) ; 9.61 (s, 1H) ; Mass Spectrum: (M+H) + 489.<

References: [1]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 125.

7
[ 612501-52-7 ]
[ 1361054-84-3 ]
[ 612501-71-0 ]

Yield	Reaction Conditions	Operation in experiment
	With cesium fluoride; In N,N-dimethyl-formamide; at 20℃; for 16h;	Dimethylformamide (15 ml) was added to 4- (3-chloro-2-fluoroanilino)-7-methoxy-6- hydroxyquinazoline (0.66 g; prepared as described in Example 22-preparation of starting materials), 1-tert-butyl 2-methyl (2S, 4S)-4- [ (4-nitrophenyl) sulfonyloxy] pyrrolidine-1, 2- dicarboxylate (0. 889 g) and cesium fluoride (0.941 g). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was evaporated under vacuum and the residue partitioned between ethyl acetate and water. The organics were washed with water and saturated brine and dried over magnesium sulfate. The product was then purified by column chromatography eluting with increasingly polar mixtures of methylene chloride /methanol (100/0 to 95/5). The fractions containing the expected product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-[(2S, 4R)-l-(t- butoxycarbonyl)-2- (methoxycarbonyl) pyrrolidin-4-yloxy] -7-methoxyquinazoline as a colourless gum (0.36 g); Mass Spectrum: (M+H) + 547.

References: [1]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 140-141.

8
[ 612501-52-7 ]
[ 107-06-2 ]
[ 848440-10-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 48h;	1,2-Dichloroethane (5 ml) was added to a stirred suspension of 4- (3-chloro-2- FLUOROANILINO)-6-HYDROXY-7-METHOXYQUINAZOLINE 6 (2.0 g, 6.27 mmol, prepared as described in Reference Example 2 of W003/082831) and potassium carbonate (1.39 g, 10.0 mmol) in DMF (10 ml), and the resulting suspension was heated at 60C for 48 hours. The reaction mixture was diluted with methylene chloride (50 ml) and washed with water (3 x 20 ml), dried (MgS04) and evaporated to dryness to afford 5 (2.39 g, 100%) as a brown oil which was used without further purification

References: [1]Patent: WO2005/26150,2005,A1 .Location in patent: Page/Page column 113.

9
[ 612501-52-7 ]
[ 848440-15-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With pyridine hydrochloride; at 170℃; for 2.16667h;	Solid 4- (3-CHLORO-2-FLUOROANILINO)-6-HYDROXY-7-METHOXYQUINAZOLINE 6 (1.00 g, 3.13 mmol) was added to neat liquid pyridinium hydrochloride (3.62 g, 31.3 mmol) at 170C over a period of 10 minutes. The reaction mixture was stirred at 170C for 2 hours then cooled to room temperature. The mixture was then suspended in water (30 ml) and the resulting precipitate was collected by filtration, washed with acetonitrile (5 ml) diethyl ether (5 ml) and dried to a constant weight in a vacuum oven at 50C to afford 10 as a beige solid (0.71 g, 77%);

References: [1]Patent: WO2005/26150,2005,A1 .Location in patent: Page/Page column 115; 116.

10
[ 612501-52-7 ]
[ 141699-59-4 ]
[ 612501-81-2 ]

Yield	Reaction Conditions	Operation in experiment
95%		Step 2: Preparation OF TERT-BUTVL 4-R4- 3-CHLORO-2-FLUOROANILINO)-7-METHOXVQUINAZOLIN-6- YLOXVLPIPERIDINE-1-CARBOXYLATE; 4- (3-CHLORO-2-FLUOROANILINO)-6-HYDROXY-7-METHOXYQUINAZOLINE (116.7 g), tert-butyl 4-methylsulfonyloxypiperidine 1-carboxylate (153.1 g), potassium carbonate (75.7 g) and NMP (700 ml), were stirred at 100C to 105C, under nitrogen, for 24 hours. The mixture was cooled to 75C to 80C before water (1080 ml) was added whilst maintaining the temperature above 70C. The mixture was stirred at 70C to 75C for 90 minutes then cooled to 20C to 25C. The resulting solid was filtered, washed with water (2 x 175 ml), and then dried in the vacuum oven between 50C and 55C to give tert-butyl 4- [4- (3-CHLORO-2- FLUOROANILINO) -7-METHOXYQUINAZOLIN-6-YLOXY] PIPERIDINE-1-CARBOXYLATE ; (174.4 G; 95% YIELD); Melting point: 192-193. 5C ; NMR Spectrum: (DMSO d6) 1.40-1. 42 (d, 9H); 1.62-1. 72 (m, 2H); 1.99-2. 08 (m, 2H); 3.24-3. 33 (m, 2H); 3.65-7. 73 (m, 2H); 4.00 (s, 3H); 4.76 (m 1H) ; 7.28 (s; 1H); 7.37 (t, 3H); 7.56 (t, 1H) ; 7.63 (t, 1H); 8.01 (s, 1H); 8.72 (s 1H); Mass Spectrum: (M+H) + 503.
84%	With potassium carbonate; In ethanol; water; for 16.5h;Reflux;Product distribution / selectivity;	Step 1: 6-[(1-tert-Butoxycarbonyl)piperidin-4-yl]oxy}-4-(3-chloro-2-fluoroanilino)-7-methoxy quinazoline4-(3-Chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (prepared as described in Step 2 of Example A; 60.00 g, 0.1828 mol), tert-Butyl(4-methanesulfonyloxy)piperidine-1-carboxylate (88.04 g, 0.3107 mol) and potassium carbonate (30.31 g, 0.2193 mol) were suspended in ethanol (584 ml) and water (58 ml), and the mixture was heated to reflux with stirring. Heating was continued at reflux for 16.5 hours. The mixture was then cooled to 70 C. and water (234 ml) was added over 60 minutes.The batch was stirred at 65 C. for a further 2 hours to establish crystallisation. The slurry was cooled to 20 C. over 6 hours. The product was isolated by filtration. The filter cake was slurried with aqueous ethanol (ethanol 117 ml, water 58 ml) and then displacement washed with aqueous ethanol (ethanol 117 ml, water 58 ml). The filter cake was then slurried with water (175 ml) and then displacement washed with water (175 ml). The product was dried in vacuo at 40 C. to give the title compound (81.5 g, 84%); 1H NMR (500 MHz, DMSO-d6) delta ppm 1.42 (s, 9H) 1.60-1.70 (m, 2H) 1.96-2.04 (m, 2H) 3.23-3.30 (m, 2H) 3.65-3.75 (m, 2H) 3.95 (s, 3H) 4.68-4.75 (m, 1H) 7.24 (s, 1H) 7.29 (t, J=8.06 Hz, 1H) 7.49 (t, J=7.50 Hz, 1H) 7.54 (t, J=7.19 Hz, 1H) 7.88 (s, 1H) 8.39 (s, 1H) 9.57 (s, 1H); Mass Spectrum: 503.5, 505.5.
60%	With cesium fluoride; In N,N-dimethyl acetamide; at 85℃; for 12h;	To a solution of compound 7 (1.44 g, 4.51 mmol) in DMA (15 mL) was added compound 8 (378 mg, 1.35 mmol) and CsF (685 mg, 4.51 mmol). The reaction mixture was heated to 85 C and stirred. At intervals of 2 h, 4 h and 6 h, each time compound 8 (378 mg, 1.35 mmol) and CsF (685 mg, 4.51 mmol) were added. After the final addition,the reaction mixture was stirred at 85 C for further 6 h. The solvent was removed under vacuum and the residual was partitioned between CH2Cl2 and water. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography with MeOH/CH2Cl2 (1:25) to afford 9 (1.37 g, 60%) as a pale yellow solid, mp 200-201 C. 1H NMR (DMSO-d6): d 9.59 (s, 1H), 8.39 (s, 1H), 7.88 (s, 1H), 7.55-7.48 (m, 2H), 7.29 (t, J = 8.0 Hz, 1H), 7.24 (s, 1H), 4.71 (s, 1H), 3.95 (s, 3H), 3.71-3.69 (m, 2H), 3.29-3.26 (m, 2H), 2.01-1.99 (m, 2H), 1.68-1.62 (m, 2H), 1.42 (s, 9H). LC-MS (ESI, m/z): calcd for C25H29ClFN4O4 ([M+H]+) 503.2, found 503.1.

58%	With cesium fluoride; In N,N-dimethyl acetamide; at 85℃; for 18h;	4- (3-CHLORO-2-FLUOROANILINO)-6-HYDROXY-7-METHOXYQUINAZOLINE from Step 2 (1870 mg, 5.85 mmol) was dissolved in DMA (50 ml). tert-Butyl (4-methanesulfonyloxy) piperidine-1- carboxylate (prepared as in Chemical & Pharmaceutical Bulletin 2001,49 (7), 822-829; 490 mg, 1.76 mmol) and cesium fluoride (890 mg, 5.85 mmol) were added, and the mixture was heated to 85C with stirring. At intervals of 2 hours, 4 hours and 6 hours, tert-butyl 4- METHANESULFONYLOXYPIPERIDINE-1-CARBOXYLATE and cesium fluoride were added in the above quantities to the reaction mixture. Heating was continued at 85C for a further 6 hours after the final addition. The solvent was evaporated, and the residue was partitioned between DCM (150 ml) and H20 (150 ML). The aqueous layer was extracted with DCM (4x 100 ml), and the extractions combined with the DCM layer. The combined DCM fractions were dried over MGS04 and evaporated. The residue was purified by chromatography, eluting with 0 to 2.5% (7: 1 MEOH/CONCENTRATED aqueous NH4OH) in DCM. The appropriate fractions were combined and evaporated, giving the product as a light brown foam (2.40 g, 58%, allowing for 2.3 equivalents of residual DMA).'H NMR : 1.40 (s, 9H), 1.60-1. 65 (m, 2H), 1.95-2. 00 (m, 2H), 3.20-3. 25 (m, 2H), 3.65-3. 70 (m, 2H), 3.92 (s, 3H), 4.68 (m, 1H), 7.21 (s, 1H), 7.27 (dd, 1H), 7.47 (ddd, 1H), 7.51 (dd, 1H), 7.85 (s, 1H), 8.36 (s, 1H), 9.53 (s, 1H) ; Mass Spectrum: 503.5, 505.5.
58%	With cesium fluoride; In N,N-dimethyl acetamide; at 85℃; for 18h;	4- (3-CHLORO-2-FLUOROANILINO)-6-HYDROXY-7-METHOXYQUINAZOLINE from Step 2 (1870 mg, 5.85 mmol) was dissolved in DMA (50 ml). tert-Butyl (4-methanesulfonyloxy) PIPERIDINE-1-CARBOXYLATE (prepared as in Chemical & Pharmaceutical Bulletin 2001,49 (7), 822-829; 490 mg, 1.76 mmol) and cesium fluoride (890 mg, 5.85 mmol) were added, and the mixture was heated to 85C with stirring. At intervals of 2 hours, 4 hours and 6 hours, tert-butyl 4-METHANESULFONYLOXYPIPERIDINE-1-CARBOXYLATE and cesium fluoride were added in the above quantities to the reaction mixture. Heating was continued at 85C for a further 6 hours after the final addition. The solvent was evaporated, and the residue was partitioned between DCM (150 ml) and H20 (150 ml). The aqueous layer was extracted with DCM (4x 100 ml), and the extractions combined with the DCM layer. The combined DCM fractions were dried over MGS04 and evaporated. The residue was purified by chromatography, eluting with 0 to 2.5% (7: 1 MEOH/CONCENTRATED aqueous NH40H) in DCM. The appropriate fractions were combined and evaporated, giving the product as a light brown foam (2.40 g, 58%, allowing for 2.3 equivalents of residual DMA); HNMR : 1.40 (s, 9H), 1.60-1. 65 (m, 2H), 1.95-2. 00 (m, 2H), 3.20-3. 25 (m, 2H), 3.65-3. 70 (m, 2H), 3.92 (s, 3H), 4.68 (m, 1H), 7.21 (s, 1H), 7.27 (dd, 1H), 7.47 (ddd, 1H), 7.51 (dd, 1H), 7.85 (s, 1H), 8.36 (s, 1H), 9.53 (s, 1H) ; Mass Spectrum: 503.5, 505.5.
58%	With cesium fluoride; In N,N-dimethyl acetamide; at 85℃; for 12h;	Reference Example 3; 6-[(1-tert-Butoxycarbonyl) piperidin-4-yl] oxy}-4-(3-chloro-2-fluoroanilino)-7- methoxyquinazoline; 4- (3-Chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (Reference Example 2,1870 mg, 5.85 mmol) was dissolved in DMA (50 ml). tert-Butyl (4- methanesulfonyloxy) piperidine-l-carboxylate (prepared as in Chemical & Pharmaceutical Bulletin 2001,49 (7), 822-829; 490 mg, 1.76 mmol) and cesium fluoride (890 mg, 5.85 mmol) were added, and the mixture was heated to 85C with stirring. At intervals of 2 hours, 4 hours and 6 hours, tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate and cesium fluoride were added in the above quantities to the reaction mixture. Heating was continued at 85C for a further 6 hours after the final addition. The solvent was evaporated, and the residue was partitioned between DCM (150 ml) and H20 (150 ml). The aqueous layer was extracted with DCM (4x 100 ml), and the extractions combined with the DCM layer. The combined DCM fractions were dried over MgS04 and evaporated. The residue was purified by chromatography, eluting with 0 to 2.5% (7: 1 MeOH/concentrated aqueous NH40H) in DCM. The appropriate fractions were combined and evaporated, giving the product as a light brown foam (2.40 g, 58%, allowing for 2.3 equivalents of residual DMA) ; 1H NMR : 1.40 (s, 9H), 1.60-1. 65 (m, 2H), 1.95-2. 00 (m, 2H), 3.20-3. 25 (m, 2H), 3.65-3. 70 (m, 2H), 3.92 (s, 3H), 4. 68 (m, 1H), 7.21 (s, 1H), 7.27 (dd, 1H), 7.47 (ddd, 1H), 7.51 (dd, 1H), 7.85 (s, 1H), 8.36 (s, 1H), 9.53 (s, 1H) ; Mass Spectrum : 503.5, 505.5

References: [1]Patent: WO2005/12290,2005,A1 .Location in patent: Page/Page column 41.
[2]Patent: US2009/286982,2009,A1 .Location in patent: Page/Page column 15.
[3]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4455 - 4459.
[4]Patent: WO2005/28470,2005,A1 .Location in patent: Page/Page column 54-55.
[5]Patent: WO2005/28469,2005,A1 .Location in patent: Page/Page column 59.
[6]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 162.
[7]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 742 - 746.
[8]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4908 - 4912.

11
[ 612501-80-1 ]
[ 612501-52-7 ]

Yield	Reaction Conditions	Operation in experiment
77%	With ammonia; In methanol; water; at 50℃; for 2h;	6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXYQUINAZOLINE hydrochloride (8.72 g, 21.9 mmol) was dissolved in methanol (200 ml). Concentrated aqueous ammonia (15 ML) was added, and the solution heated to 50C with stirring for 2 hours, causing precipitation of a cream coloured solid. The solid was collected by filtration, washed with diethyl ether (3x 200 ml), and dried III VACUO at 60C over diphosphorous pentoxide, giving 4- (3-CHLORO-2-FLUOROANILINO)-6-HYDROXY-7-METHOXYQUINAZOLINE as an off white solid (5.40 g, 77%) ; 1H NMR : 3.95 (s, 3H), 7.19 (s, 1H), 7.23 (dd, 1H), 7.42 (dd, 1H), 7.50 (dd, 1H), 7.64 (s, 1H), 8. 32 (s, 1H), 9.43 (s, 1H), 9.67 (br. s, 1H); Mass Spectrum : 320.4, 322.4.
77%	With methanol; ammonia; water; at 50℃; for 2h;Product distribution / selectivity;	Reference Example 1; 6-Acetoxy-4- (3-chloro-2-fluoroanilino)-7-methoxyquinazoline hydrochloride; 6-Acetoxy-4-chloro-7-methoxyquinazoline (prepared as described in Example 25-5 of in WO01/66099, 6.00 g, 23.8 mmol) and 3-chloro-2-fluoroaniline (3.46 g, 23.8 mmol) were suspended in iso-propanol (200 ml). The mixture was heated to 80C under reflux for 3 hours. The solvent was evaporated; the residue was crystallised from acetonitrile, giving the product hydrochloride as a pale pink crystalline solid (8.16 g, 92%) ; 1H NMR : 2.37 (s, 3H), 4.00 (s, 3H), 7.34 (ddd, 1H), 7.48 (s, 1H), 7.52 (ddd, 1H), 7.61 (ddd, 1H), 8.62 (s, 1H), 8.86 (s, 1H) ; Mass Spectrum: 362.4, 364.4.
75.7%		Step 1: Preparation OF4- (3-CHLORO-2-FLUOROANILINO)-6-HVDROXV-7-METHOXYQUINAZOLINE; 6-Acetoxy-7-methoxy-4 (1H)-quinazolinone (150 g; prepared as described in W096/15118, Example 39 thereof), N, N-diisopropylethylamine (123 ml) and toluene (1275 ml) were stirred at 70C, under nitrogen. Phosphorus oxychloride (150 ml) was added over 15 minutes to the slurry at 70C. The mixture was held at 70C for 2 hours to complete the chlorination. A dark brown solution formed after 30 minutes following addition of the phosphorus oxychloride. Toluene (680 ml) was added to the reaction mixture, followed by addition of 3-chloro-2-fluoroaniline (78 ml) over 10 minutes at 70C. On completion of the addition, a solid precipitated resulting in a beige slurry. The slurry was held at 70C for 1 hour and then cooled to ambient temperature. The reaction mixture was filtered and washed with toluene (2 x 300 ml), aqueous IMS (2 x 450 ml and IMS (2 x 450 ML). The solid was left to pull dry on the filter overnight to give 6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7- methoxyquinazoline. HCl salt; NMR Spectrum: (DMSO d6) 2.39 (s, 3H); 4.02 (s, 3H); 7.36 (t, 1H) ; 7.58 (s, 1H); 7.64 (t, 1H) ; 8.79 (s, 1H) 8.91 (s, 1H); 11.93 (bs 1H); Mass Spectrum : M+H 362. 6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXYQUINAZOLINE. HCL salt (about 253 g), methanol (1900 ml) and water (632.5 ml) were stirred at ambient temperature. Sodium hydroxide solution (47% w/w; 108 ml) was added dropwise and the reaction mixture heated to 60C to form a dark solution. The solution was held at 60C for 1 hour and then screened to a clean vessel. The mixture was cooled to ambient temperature before acetic acid (72. 8 ml) was charged. The precipitated solid was filtered, washed with 50% aqueous methanol (500 ml) and methanol (500 ml), and then dried in a vacuum oven at 45C to give 4- (3-CHLORO-2- fluoroanilino) -6-hydroxy-7-methoxyquinazoline; (204.8 g; 75.7% yield); Melting point 265- 268C ; NMR Spectrum : (DMSO d6) 4.01 (s, 3H); 7.24 (s, 2H); 7.32 (t, 1H); 7.51-7. 56 (m, 2H); 7.78 (s, 1H); 8.58 (s, 1H); Mass Spectrum: (M+H) + 320.

76.2 g

With methanol; potassium carbonate; at 20℃; for 8h;

The hydrochloride salt of intermediate A (90 g, 0.226 mol) was dissolved in methanol (1 L), potassium carbonate (69 g, 0.5 mol) was added, and the reaction was stirred at room temperature for 8 hours.After the reaction was completed, the reaction liquid was filtered, and the solid was washed with a small amount of methanol.The filtrate was concentrated under reduced pressure, and the solid was added to water (60 mL), slurried at 70 C for 1 hour, cooled and filtered, washed with a small amount of methanol, and dried under vacuum at 50 C to obtain intermediate C (76.2 g, 94%).

References: [1]Patent: WO2005/26156,2005,A1 .Location in patent: Page/Page column 92.
[2]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 161.
[3]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 742 - 746.
[4]Patent: WO2005/12290,2005,A1 .Location in patent: Page/Page column 40.
[5]Patent: CN110903283,2020,A .Location in patent: Paragraph 0092-0095.

12
[ 740081-22-5 ]
[ 612501-52-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With ammonia methyl alcohol; In methanol; at 20℃; for 2h;	Taking compound 3 (200 mg) dissolved in methanol (2 ml) in, adding methanol and ammonia solution (7 N, 1 ml), then stirred at room temperature 2 hours; the reaction the fluid turns on lathe job to the compound 1 (white powder, 176 mg, quant.).
83%	With ammonia; N,N-diethylaniline; In methanol; at 20℃; for 18h;	To a stirred solution of compound 6 (2.30 g, 5.79 mmol) in MeOH (50 mL) was added concentrated ammonia (4.0 mL). The reaction mixture was stirred at rt for 18 h. The resultant precipitate was filtered, and washed with MeOH to afford 7 (1.54 g, 83%) as a pale yellow solid, mp 280-282 C. 1H NMR (DMSO-d6): d 9.75 (s, 1H), 9.48 (s, 1H), 8.35 (s, 1H), 7.66 (s, 1H), 7.52 (t, J = 6.5 Hz, 1H), 7.45 (t,J = 7.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.21 (s, 1H), 3.98 (s, 3H).
81%	With ammonia; In methanol; for 2h;Sealed tube; Inert atmosphere; Heating;	To JGK018 (550 mg, 1.520 mmol) was dropwise added ammonia solution (8.0 mL, 7 N in methanol). After being heated at 50 C (bath temperature) in sealed tube with stirring for 2 h, the reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting white solid were washed successively with Et20 (2 x 50 mL) and collected to give 13 (394 mg, 81%); The resulting spectroscopic data was matched with that of Zhang, X. et al. Med. Chem. 2015, 58, 8200-8215.

77%	With ammonia; In methanol; water; at 50℃; for 2h;	6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXYQUINAZOLINE HYDROCHLORIDE FROM step 1 (8.72 g, 21.9 mmol) was dissolved in methanol (200 ml). Concentrated aqueous ammonia (15 ml) was added, and the solution heated to 50C with stirring for 2 hours, causing precipitation of a cream coloured solid. The solid was collected by filtration, washed with diethyl ether (3x 200 ml), and dried in vacuo at 60C over diphosphorous pentoxide, giving the product as an off white solid (5.40 g, 77%); H NMR : 3.95 (s, 3H), 7.19 (s, 1H), 7.23 (dd, 1H), 7.42 (dd, 1H), 7.50 (dd, 1H), 7.64 (s, 1H), 8.32 (s, 1H), 9.43 (s, 1H), 9.67 (br. s, 1H) ; Mass Spectrum: 320.4, 322.4.
77%	With ammonia; In water; at 50℃; for 2h;	6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXYQUINAZOLINE hydrochloride from step 1 (8.72 g, 21.9 mmol) was dissolved in methanol (200 ml). Concentrated aqueous ammonia (15 ml) was added, and the solution heated to 50C with stirring for 2 hours, causing precipitation of a cream coloured solid. The solid was collected by filtration, washed with diethyl ether (3x 200 ml), and dried in vacuo at 60C over diphosphorous pentoxide, giving the product as an off white solid (5.40 g, 77%). 1H NMR : 3.95 (s, 3H), 7.19 (s, 1H), 7.23 (dd, 1H), 7.42 (dd, 1H), 7.50 (dd, 1H), 7.64 (s, 1H), 8.32 (s, 1H), 9.43 (s, 1H), 9.67 (br. s, 1H); Mass Spectrum : 320.4, 322.4.
	With methanol; potassium carbonate; at 20℃;	Intermediate 74-[(3-Chloro- -fluorophenyl)aminol-7-methoxyquinazolin-6-olTo a solution of Intermediate 6 (181 g, 0.396 mol) in MeOH (2 L) was added potassium carbonate (138 g, 1 mol) and the reaction mixture was stirred at RT overnight. The reaction mixture was filtered and the solid washed with MeOH. The filtrate was concentrated in vacuo to afford Intermediate 7 (280 g, 60% purity, contained potassium carbonate). 1H NMR (DMSO-d6400MHz): delta 8.01 (s, 1H), 7.61-7.58 (m, 1H), 7.27-7.24 (m, 1H), 7.17-7.13 (m, 1H), 6.95 (s, 1H), 6.83 (s, 1H), 3.79 (s, 3H).
	With potassium carbonate; In methanol; at 20℃;	To a solution of Intermediate 6 (181 g, 0.396 mol) in MeOH (2 L) was added potassium carbonate (138 g, 1 mol) and the reaction mixture was stirred at RT overnight. The reaction mixture was filtered and the solid washed with MeOH. The filtrate was concentrated in vacuo to afford Intermediate 7 (280 g, 60% purity, contained potassium carbonate). 1H NMR (DMSO-d6 400 MHz): delta 8.01 (s, 1H), 7.61-7.58 (m, 1H), 7.27-7.24 (m, 1H), 7.17-7.13 (m, 1H), 6.95 (s, 1H), 6.83 (s, 1H), 3.79 (s, 3H).
30 g	With methanol; ammonium hydroxide; at 20 - 30℃; for 6h;	35g of compound 4,100g ammonia water,70g of methanol was added to the reaction flask,At a reaction temperature of 20-30 C,Stir for 6h,After TLC detection reaction is complete, suction filtration, and then dried at 40 ~ 50 C, to obtain 30g of compound 5;

References: [1]Patent: CN108329276,2018,A .Location in patent: Paragraph 0075; 0076.
[2]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4455 - 4459.
[3]Patent: WO2019/67543,2019,A1 .Location in patent: Page/Page column 82; 95.
[4]Patent: WO2005/28469,2005,A1 .Location in patent: Page/Page column 59.
[5]Patent: WO2005/28470,2005,A1 .Location in patent: Page/Page column 54.
[6]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4908 - 4912.
[7]Patent: WO2014/135876,2014,A1 .Location in patent: Page/Page column 38.
[8]Patent: US2014/255428,2014,A1 .Location in patent: Paragraph 0224-0225.
[9]Patent: CN109438423,2019,A .Location in patent: Paragraph 0034; 0038; 0044; 0050; 0063.

13
[ 612501-52-7 ]
[ 358-23-6 ]
[ 848488-66-4 ]

Yield	Reaction Conditions	Operation in experiment
79%	With pyridine; In dichloromethane; at 0 - 20℃; for 18h;	The 4- [ (3-chloro-2-fluorophenyl) amino] -7-methoxyquinazoline-6-carbaldehyde starting material was prepared as follows: A suspension of 4- [ (3-chloro-2-fluorophenyl) amino] -6-hydroxy-7- methoxyquinazoline (800 mg, prepared as described in Reference Example 2 of W003/82831 in methylene chloride (150 ml) was cooled to 0C and pyridine (1.5 ml) added. Triflic anhydride (507 u, l) was then added dropwise and the resulting solution left to stir to room temperature. After 18 hours the reaction mixture was washed with water and brine, dried over MgS04, filtered and evaporated under reduced pressure. The residues were then triturated with methylene chloride to give 4- [ (3-chloro-2-fluorophenyl) amino] -7- methoxyquinazolin-6-yl trifluoromethanesulfonate as a white solid which was collected by filtration and dried (880 mg, 79%) ; 1H NMR Spectrum : (DMSO d6) 4.13 (s, 3H), 7.37 (m, 1H), 7.56 (m, 1H), 7.64 (m, 1H), 7.66 (s, 1H), 8. 86 (s, 1H), 9.06 (s, 1H), 11.7 (bs, 1H); Mass Spectrum: (M+H) + 452.
79%	With pyridine; In dichloromethane; at 0 - 20℃; for 18h;	A suspension of 4- (3-CHLORO-2-FLUOROANILINO)-6-HYDROXY-7-METHOXYQUINAZOLINE (800 mg) in methylene chloride (150 ml) was cooled to 0C and to it added pyridine (1.5 ml). Triflic anhydride (507 NUL) was then added dropwise and the resulting solution left to stir to ambient temperature. After 18 hours the reaction mixture was washed with water and brine, dried over MGS04, filtered and evaporated under reduced pressure. The residues were then triturated with methylene chloride to give 4- (3-CHLORO-2- fluoroanilino) -6-trifluoromethanesulfonyloxy-7-methoxyquinazoline as a white solid which was collected by filtration and dried (880 mg, 79%) ; 1H NMR Spectrum: (DMSO D6) 4.13 (s, 3H), 7.37 (m, 1H), 7.56 (m, 1H), 7.64 (m, 1H), 7.66 (s, 1H), 8.86 (s, 1H), 9.06 (s, 1H), 11.7 (bs, lH). Mass Spectrum: (M+H) + 452.

References: [1]Patent: WO2005/75439,2005,A1 .Location in patent: Page/Page column 121.
[2]Patent: WO2005/26156,2005,A1 .Location in patent: Page/Page column 90.

14
[ 612501-52-7 ]
[ 254882-06-9 ]
[ 908294-09-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; at -15 - 20℃; for 2h;Cooling with acetone-dry ice;	Example 1; (2S,4S)-4-({4-[(3-cIiloro-2-fluorophenyl)amiiio]-7-methoxyquinazolin-6-yl}oxy)-l- methylpiperidine-2-carboxamide; The title compound was prepared as shown in scheme A:Scheme AMolecular sieves (5 g) followed by aqueous formaldehyde (10 ml) were added to a stirred solution of (25',45)-4-({4-[(3-cMoro-2-fluoiOphenyl)arnino]-7-methoxyquinazolin-6- yl}oxy)rhoiperidine-2-carboxamide (5) (3.1 g, 6.97 ??nol) in DCM-AcOH (100:10 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (2.93 g, 13.9 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (100 ml) and the reaction was carefully neutralised with saturated aqueous NaHCOs(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam The residue was purified by flash chromatography (silica gel, DCM-NH3ZMeOH 2%) to give the title product as a white solid (1.8 g, 56%): 1H NMR Spectrum: (DMSO d6) 1.86-1.91 (m, 3H), 2.07-2.09 (m, IH), 2.20 (s, 3H), 2.47-2.49 (m, IH), 2.71-2.81 (m, 2H), 3.96 (s, 3H), 4.82 (m, IH), 7.02 (s, IH), 7.23 (s, IH), 7.26-7.29 (m, 2H), 7.47-7.53 (m, 2H), 7.82 (s, IH), 8.37 (s, IH), 9.60 (s, IH); Mass Spectrum: (M+H)+ 460.1. The starting material (25,45)-4-({4-[(3-croro-2-fluorophenyl)amiiiotao]-7- methoxyquinazolin-6-yl}oxy)pirhoeridine-2-carboxamide (5) was prepared as follows:DTAD (13.3 g, 57.9 mmol) dissolved in 50 ml of DCM was added over a period of 10 minutes to a stirred suspension of 4-[(3-cMoro-2-fluororhohenyl)arnino]-7-methoxyquinazolin- 6-ol (1) (4.94 g, 15.5 mmol, prepared as described in WO 03/082831, Reference Example 2 therein), triphenylphosphine (18.3 g, 69.5 mmol) and (2S,4R)-N~(te/t-butoxycarbonyi)-4- hydroxypiperidine-2-carboxyric acid methyl ester (ex ACROS, 6 g, 23.2 mmol) in DCM (150 ml) at -150C (acetone/ice). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours, concentrated to approximately 50 ml and purified directly by flash chromatography (silica gel, eluting with a gradient from 100% DCM to DCM/EtOAc (80/20) to DCM/EtOAc (50/50) to give 1-tert-butyl 2-methyl (2S,4S)-4-({4-[(3-chloro-2- fluoiOphenyl)amino]-7-methoxyquinazohn-6-yl}oxy)piperidine-l,2-dicarboxylate (2) (6 g, 69%) as a white foam; 1H NMR Spectrum: (DMSO (J6) 1.47-1.53 (m, HH), 1.86-1.91 (m, IH), 2.25-2.36 (m, IH), 2.95-3.13 (m, IH), 3.70 (s, 3H), 3.95 (s, 3H), 3.98-4.04 (m, IH), 4.45 (m, IH), 4.86-4.94 (m, IH), 7.31 (t, IH), 7.51-7.64 (m, 3H), 7.80 (s, IH), 8.39 (s, IH), 9.54 (s, IH): Mass Spectrum: (M+H)÷ 561.1. A stirred solution of 1-f°rr-butyl 2-methyl (25,45)-4-( { 4-[(3-chloro-2- fluorophenyl)amino]-7-methoxyquinazohn-6-yl}oxy)pirhoeridine-l,2-dicarboxylate (2) (6 g, 10.7 mmol) in THF (30 ml) and water (30 ml) was prepared at room temperature then cooled to 00C and solid LiOH-H2O (0.54 g, 12.9 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, acidified with acetic acid and extracted with DCM. The resulting residue was evaporated to dryness, azeotroped with toluene (3 x 50 ml) and dried to a constant weight to give (21Sr,4S)-l-(te7t-butoxycarbonyl)-4-({4-[(3-chloiO-2- fluorophenyl)amino]-7-methoxyquinazoun-6-yl}oxy)piperidine-2-carboxylic acid (3) (5.27 g, 90%), which was used without further purification; Mass Spectrum: (M+H)+ 547.1. A stirred solution of (25',45)-l-(fert-butoxycarbonyl)-4-({4-[(3-chloro-2- fluororhohenyl)amino]-7-methoxyquinazoUn-6-yl}oxy)rhoirhoeridine-2-cai-boxylic acid (3) (5 g, 9.16 mmol) in THF (50 ml) was cooled to -15C (acetone/ice). NMM (1.5 ml, 13.7 mmol) was added to the solution followed by IBCF (1.54 ml, 11.9 mmol). The reaction mixture was held at -150C (the formation of the mixed anhydride was monitored by TLC (THF)). After 5-10 minutes, the reaction mixture was treated with concentrated aqueous ammonia (3 ml) at -150C and allowed to warm to room temperature. The reaction mixture was diluted with DCM (250 ml), washed with water (2 x 20 ml) and concentrated to give tert-butyl (25',45)-2- (aminocarbonyl)-4-({4-[(3-cMoro-2-fluorophenyl)amino]-7-methoxyquinazorin-6- yl}oxy)piperidine-l-carboxylate (4) (5 g, 100%) as a pale yellow foam which was used without further purification; Mass Spectrum: (M+H)+ 546.1.TFA (15 ml) was added over a period of 5 minutes to a stirred solution of tert-butyl (25,45)-2-(arninocarbonyl)-4-({4-[(3-cMoro-2-fluorophenyl)amino]-7-methoxyquialphaazorJn-6- yl}oxy)piperidine-l-carboxylate (4) (5 g, 9.16 mmol) in DCM (15 ml) at 00C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour after which time, the reaction was complete. The reaction mixture was concentrated to dryness, azeotroped twice with toluene and the residue was purified by flash chromatography (silica gel, DCM- NH3ZMeOH 5%) to give (2^4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7- memoxyquinazolin-6-yl}oxy)piperidin...

References: [1]Patent: WO2006/90163,2006,A1 .Location in patent: Page/Page column 67-69.

15
[ 612501-52-7 ]
[ 321744-26-7 ]
[ 908294-14-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; at -15 - 20℃; for 2h;Cooling with acetone-dry ice;Product distribution / selectivity;	Example 3; (2R,4J?)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-niethoxyqumazoin-6-yl}oxy)-iV,l- dimethylpiperidine-2-carboxamide; EPO <DP n="72"/>Molecular sieves (5 g) followed by aqueous formaldehyde (10 ml) were added to a stirred solution of (2jR,4i?)-4-({4-[(3-cMoro-2-fluorophenyl)amino]-7-metlioxyquiriazonn-6- yl}oxy)-N-methylpiperidine-2-carboxamide (3.6 g, 7.84 mmol) in DCM-AcOH (100: 10 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (3.31 g, 15.7 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (100 ml) and the reaction was carefully neutralised with saturated aqueous NaHCO3(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam. The residue was purified by flash chromatography (silica gel, DCM-NH3ZMeOH 2%) to give the title product as a white solid (1.8 g, 49 %): 1H NMR Spectrum: (DMSO d6) 1.85-1.96 (m, 3H), 2.07 (m, IH), 2.15 (s, 3H), 2.45-2.50 (m, IH), 2.59 (d, 3H), 2.71 (m, IH), 2.84 (m, IH), 3.96 (s, 3H), 4.81 (m, IH), 7.23 (s, IH), 7.28 (t, IH), 7 'Al '-7.53 (m, 2H), 7.81 (s, 2H), 8.37 (s, IH), 9.59 (s, IH); Mass Spectrum: (M+H)+474.1.The starting material (2i?,4i?)-4-({4-[(3-cUoro-2-fluorophenyl)amino]-7- methoxyquhiazorJn-6-yl}oxy)-N-methylpiperidine-2-carboxarnide was prepared as follows:DTAD (7.26 g, 31.5 mmol) dissolved in 50 ml of DCM was added over a period of 10 minutes to a stirred suspension of 4-[(3-cHoro-2-fluorophenyl)arnrrio]-7-methoxyqurnazonn- 6-ol (5.00 g, 15.7 mmol), triphenylphosphine (8.57 g, 62.6 mmol) and (2R,4S)-N-(tert- butoxycarbonyl)-4-hydroxypiperidine-2-carboxylic acid methyl ester (ex ACROS, 5.42 g, 20.9 mmol) in DCM (150 ml) at -15C (acetone/ice). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours, concentrated to approximately 50 ml and purified directly by flash chromatography (silica gel, eluting with a gradient from 100% DCM to DCM/EtOAc (80/20) to DCM/EtOAc (50/50) to give 1-te/t-butyl 2-methyl (2R,4R)-4-({4- [(3-chloro-2-fluorophenyl)aitauiino]-7-methoxyquinazonn-6-yl}oxy)piperidine-l,2- dicarboxylate (5.5 g, 81%) as a white foam; 1H NMR Spectrum: (DMSO d6) 1.47-1.53 (m, HH), 1.86-1.91 (m, IH), 2.25-2.36 (m, IH), 2.95-3.13 (m, IH), 3.70 (s, 3H), 3.95 (s, 3H), EPO <DP n="73"/>3.98-4.04 (m, IH), 4.45 (m, IH), 4.86-4.94 (m, IH), 7.31 (t, IH), 7.51-7.64 (m, 3H), 7.80 (s, IH), 8.39 (s, IH), 9.54 (s, IH); Mass Spectrum: (M+H)+ 561.1.A stirred solution of 1-te/t-butyl 2-methyl (22?,4i?)-4-({4-[(3-chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)pirhoeridine-l,2-dicarboxylate (6.5 g, 11.6 mmol) in THF (35 ml) and water (35 ml) was prepared at room temperature then cooled to O0C and solid LiORH2O (0.53 g, 12.7 mmol) was added. The reaction was allowed to stir at room temperature for 3 hours, acidified with acetic acid and extracted with DCM. The resulting residue was evaporated to dryness, azeotroped with toluene (3 x 50 ml) and dried to a constant weight to give (2i?,42?)-l-(t°t-butoxycarbonyl)-4-({4-[(3-chloro-2- fluorophenyl)ar?ino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylic acid (5.35 g, 84%), which was used without further purification; Mass Spectrum: (M+H)+ 547.1.A stirred solution of (2R,4i?)-l-(tert-butoxycarbonyl)-4-({4-[(3-chloro-2- fluorophenyl)amino]-7-methoxyquinazoMn-6-yl}oxy)piperidine-2-carboxylic acid (5.35 g, 9.80 mmol) in THF (50 ml) was cooled to -150C (acetone/ice). NMM (1.49 ml, 14.9 mmol) was added to the solution followed by IBCF (2.0 ml, 12.75 mmol). The reaction mixture was held at -150C (the formation of the mixed anhydride was monitored by TLC (THF)). After 5- 10 minutes, the reaction mixture was treated with a 2.0M solution of methylamine in THF (10 ml) at -15C and allowed to warm to room temperature. The reaction mixture was diluted with DCM (250 ml), washed with water (2 x 20 ml) and concentrated to give tert-batyl (22?,4i?)-4-({4-[(3-cMoiO-2-fluorophenyl)amino]-7-methoxyquinazoun-6-yl}oxy)-2-[(methylamino)carbonyl]piperidine-l-carboxylate (5.94g, 100%) as a pale yellow foam which was used without further purification; Mass Spectrum: (M+H)+ 560.1.TFA (25 ml) was added over a period of 5 minutes to a stirred solution of tert-butyl (2R,4i?)-4-({4-[(3-cMoro-2-fluorophenyl)amino]-7-methoxyquinazonn-6-yl}oxy)-2- [(methylamino)carbonyl]piperidine-l-carboxylate (5.94 g, 10.63 mmol) in DCM (25 ml) at O0C, was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour after which time, the reaction was complete. The reaction mixture was concentrated to dryness, azeotroped twice with toluene and the residue was purified by flash chromatography (silica gel, DCM-NH3MeOH 5%) to give (2i?,42?)-4-({4-[(3-chloro-2- fluorophenyl)a?iino]-7-methoxyquiazohn-6-yl}oxy)-N-methylrhoiperidine-2-carboxamide (3.6 g, 74%) as a white solid ; 1H NMR Spectr...

References: [1]Patent: WO2006/90163,2006,A1 .Location in patent: Page/Page column 70-73; 73-75.

16
6-acetoxy-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline hydrochloride [ No CAS ]
[ 612501-52-7 ]

Yield	Reaction Conditions	Operation in experiment
98%		Step 2: 4-(3-Chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline6-Acetoxy-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline hydrochloride from step 1 (33.5 kg, 69.6 mol) was suspended in methanol (198 kg). To the stirred suspension at 25 C. was added water (86 kg) and sodium hydroxide (31.5 kg, 32%). The resulting solution was stirred at 60 C. for 4.5 hours and then cooled to 25 C. Acetic acid (approximately 16.0 kg) was added until a pH of 5.5-6.0 was achieved at which point the product precipitates from solution. After the addition of further methanol (5.5 kg) the suspension was stirred for 90 minutes. The product was filtered then washed with 25% aqueous methanol (39.0 kg MeOH+17.0 kg Water) and then methanol (55.5 kg). The crude solid was dried under vacuum at 40 C. The crude solid was slurried with water (145 kg) and stirred for 2 hours at 65 C. The slurry was cooled to 20 C. and filtered. The filter cake was washed with methanol (2×21.5 kg), then dried under vacuum at 40 C. to give a the title product as a light brown solid (21.85 kg, 98%); 1H NMR: 3.95 (s, 3H), 7.19 (s, 1H), 7.23 (dd, 1H), 7.42 (dd, 1H), 7.50 (dd, 1H), 7.64 (s, 1H), 8.32 (s, 1H), 9.43 (s, 1H), 9.67 (br.s, 1H); Mass Spectrum: 320.4, 322.4.

References: [1]Patent: US2009/286982,2009,A1 .Location in patent: Page/Page column 14.

17
[ 612501-52-7 ]
[ 141120-33-4 ]
[ 1046137-43-2 ]

Yield	Reaction Conditions	Operation in experiment
47%	With potassium carbonate; In N,N-dimethyl-formamide; at 50 - 80℃;	At 50 C. 12.5 g potassium carbonate and 16 g 8-methanesulphonyloxy-1,4-dioxa-spiro[4,5]decane (cf for example Journal of Medicinal Chemistry (1992), 35(12), 2243-7) are added to 18.1 g <strong>[612501-52-7]4-[(3-chloro-2-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline</strong> (cf for example Bioorganic & Medicinal Chemistry Letters (2006), 16(18), 4908-4912) in 125 ml dimethylformamide and the mixture is stirred for 18 hours at 80 C. Another 4.7 g potassium carbonate and 4.0 g of 8-methanesulphonyloxy-1,4-dioxa-spiro[4,5]decane are added and the mixture is stirred for another 7 hours at 80 C. The reaction mixture is cooled, diluted with water and ethyl acetate and the precipitate formed is suction filtered and dried.Yield: 12.2 g (47% of theory)Mass spectrum (ESI+): m/z=460, 462 [M+H]+
47%	With potassium carbonate; In N,N-dimethyl-formamide; at 50 - 80℃; for 25h;	12.5 g potassium carbonate and 16 g 8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan (cf. for example Journal of Medicinal Chemistry (1992), 35(12), 2243-7) in 125 ml dimethylformamide are added at 50 C. to 18.1 g <strong>[612501-52-7]4-[(3-chloro-2-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline</strong> (cf. for example Bioorganic & Medicinal Chemistry Letters (2006), 16(18), 4908-4912) and the mixture is stirred for 18 hours at 80 C. Another 4.7 g potassium carbonate and 4.0 g 8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan are added and the mixture is stirred for a further 7 hours at 80 C. The reaction mixture is cooled, diluted with water and ethyl acetate and the precipitate formed is suction filtered and dried. Yield: 12.2 g (47% of theory) Mass spectrum (ESI+): m/z=460, 462[M+H]+

References: [1]Patent: US2010/22505,2010,A1 .Location in patent: Page/Page column 10.
[2]Patent: US2012/115825,2012,A1 .Location in patent: Page/Page column 11.

18
[ 612501-52-7 ]
[ 1046452-47-4 ]
4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 125℃;	Prepared by reacting <strong>[612501-52-7]4-[(3-chloro-2-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline</strong> with (cis)-1-methanesulphonyloxy-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexane in N-methyl-2-pyrrolidinone at 125 C. in the presence of potassium carbonate.

References: [1]Patent: US2010/22505,2010,A1 .Location in patent: Page/Page column 23.

19
[ 612501-52-7 ]
[ 1178976-86-7 ]
[ 1178976-85-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In N,N-dimethyl-formamide; at 50 - 80℃;	Example III Methyl trans-1-tert.-butoxycarbonylamino-4-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-cyclohexanecarboxylate A mixture of 3.30 g 4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol in 23 ml N,N-dimethylformamide is heated to 50 C. Then 2.30 g potassium carbonate and 4.40 g methyl cis-1-tert.-butoxycarbonylamino-4-methanesulphonyloxy-cyclohexanecarboxylate are added. The reaction mixture is heated to 80 C. and stirred overnight at this temperature. Then a further 1.00 g methyl cis-1-tert.-butoxycarbonylamino-4-methanesulphonyloxy-cyclohexanecarboxylate and 0.90 g potassium carbonate are added. After another four hours at 80 C. the reaction mixture is cooled to ambient temperature, diluted with ethyl acetate and washed several times with water. The organic phase is washed with saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is purified by chromatography through a silica gel column with methylene chloride/methanol/conc. ammonia (98/2/0.1 to 8/2/0.1). Yield: 5.50 g (93% of theory) Mass spectrum (ESI+): m/z=575, 577 [M+H]+

References: [1]Patent: US2011/46148,2011,A1 .Location in patent: Page/Page column 11-12.

20
[ 612501-52-7 ]
[ 957035-42-6 ]
4-[(3-chloro-2-fluoro-phenyl)amino]-6-[cis-4-(amino)-cyclohexyl-oxy]-7-methoxy-quinazoline dihydrochloride [ No CAS ]

References: [1]Patent: US2011/136805,2011,A1 .

21
[ 612501-52-7 ]
[ 957035-42-6 ]
[ 1024014-97-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;	Example 3 4-[(3-chloro-2-fluoro-phenyl)amino]-6-[cis-4-(tert.-butoxycarbonyl-amino)-cyclohexyl-oxy]-7-methoxy-quinazoline Prepared by reacting 5 g of <strong>[612501-52-7]4-[(3-chloro-2-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline</strong> and 8.7 g of the compound of Example IV (16) in the presence of 4.3 g potassium carbonate in 40 ml N,N-dimethylformamide at 80 C. Mass spectrum (ESI+): m/z=517, 519 [M+H]+

References: [1]Patent: US2011/136805,2011,A1 .Location in patent: Page/Page column 33-34.

22
[ 612501-52-7 ]
(S)-tert-butoxycarbonylamino-(cis-4-methanesulfonyloxy-cyclohexyl)-acetic acid methyl ester [ No CAS ]
[ 1207988-39-3 ]

Yield	Reaction Conditions	Operation in experiment
32%	With potassium carbonate; In N,N-dimethyl-formamide; at 50 - 80℃;	Example IVmethyl cis/trans-(S)-tert.-butoxycarbonylamino-{4-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-cyclohexyl}-acetate 10.00 g 4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol in 70 ml N,N-dimethylformamide are heated to 50 C., combined with 7.00 g potassium carbonate as well as 14.00 g methyl cis/trans-(S)-tert.-butoxycarbonylamino-(4-methanesulphonyloxy-cyclohexyl)-acetate and heated to 80 C. The reaction mixture is stirred overnight at 80 C., then another 3.50 g methyl cis/trans-(S)-tert.-butoxycarbonylamino-(4-methanesulphonyloxy-cyclohexyl)-acetate and 2.60 g potassium carbonate are added.After a further four hours at 80 C. the reaction mixture is cooled and diluted with ethyl acetate and water. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried on magnesium sulphate and evaporated down. The crude product is purified by chromatography through a silica gel column with methylene chloride/methanol/conc. Ammonia (99/1/0.1 auf 8/2/0.1) as eluant.Yield: 5.90 g (32% of theory)Mass spectrum (ESI+): m/z=589, 591 [M+H]+

References: [1]Patent: US2011/190248,2011,A1 .Location in patent: Page/Page column 21.

23
[ 612501-52-7 ]
[ 1046137-42-1 ]

References: [1]Patent: US2012/115825,2012,A1 .

24
[ 612501-52-7 ]
4-[(3-chloro-2-fluoro-phenyl)amino]-6-(cis-4-hydroxy-cyclohexyloxy)-7-methoxy-quinazoline [ No CAS ]
4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(4-ethyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline [ No CAS ]

References: [1]Patent: US2012/115825,2012,A1 .

25
[ 230955-75-6 ]
[ 612501-52-7 ]

References: [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 742 - 746.
[2]Patent: WO2014/135876,2014,A1 .
[3]Patent: US2014/255428,2014,A1 .
[4]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4455 - 4459.
[5]Patent: CN109438423,2019,A .
[6]Patent: WO2019/67543,2019,A1 .
[7]Patent: CN110903283,2020,A .

26
[ 612501-52-7 ]
2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)acetamide [ No CAS ]

References: [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 742 - 746.
[2]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4455 - 4459.

27
[ 612501-52-7 ]
[ 1441145-46-5 ]