Name: Hygric acid | N-Methyl-L-proline
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SKU: A2668059
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Synonyms: N-Methyl-L-proline

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Quality Control of Hygric acid Purity: 99% SDS Specification

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Product Details of Hygric acid

CAS No. :	475-11-6
Formula :	C₆H₁₁NO₂
M.W :	129.16
SMILES Code :	O=C([C@H]1N(C)CCC1)O
Synonyms :	N-Methyl-L-proline
MDL No. :	MFCD00011565

Safety of Hygric acid

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Application In Synthesis of Hygric acid

* 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 [ 475-11-6 ]

[ 475-11-6 ] Synthesis Path-Downstream 1~54

1
[ 50-00-0 ]
[ 7776-34-3 ]
[ 475-11-6 ]

References: [1]Croatica Chemica Acta,1959,vol. 31,p. 157.

2
[ 50-00-0 ]
[ 147-85-3 ]
[ 475-11-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With palladium 10% on activated carbon; hydrogen; In methanol; water;	General procedure: L-Proline(2.0 g, 17.4 mmol) was dissolved in methanol (20 mL) and40 % aqueous formaldehyde (1.4 mL, 19.1 mmol) wasadded to this solution. Next, 10 % Pd/C catalyst (500 mg)was added to the reaction mixture and the resulting slurrywas stirred in hydrogen overnight. The slurry was then filtered through a Celite pad to remove the catalyst. Thepad was washed with methanol and the combined filtrateswere concentrated under reduced pressure. The residue wasdissolved in ethanol/benzene (1:1, 100 mL) and concentratedsecond time to provide a solid that was re-crystallizedin methanol/diethyl ether. In this way Nmethylproline7a was isolated as fine needles (2.1 g, 92 %yield); mp 109-111C; 1H NMR (D2O, 300 MHz):delta = 3.95-3.90 (1H, m, CH2 (CH2)2CHNCH3), 3.24-3.15(2H, m, CH2 (CH2)2CHNCH3), 2.97 (3H, s, CH2 (CH2)2CHNCH3), 2.22-2.01 (4H, m, CH2 (CH2)2CHNCH3); ESI-MS (m/z):130.2 [M + H] +(100).
89%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 24h;	L-proline (4.0 g, 34.8 mmol)Soluble in methanol (40mL),40% aqueous formaldehyde solution (2.8 mL, 38.2 mmol) was added in orderAnd 10% Pd on carbon (1g), addition, hydrogenation,Reaction at room temperature for 24 hours,After the reaction is complete, filterThe mother liquor was concentrated and dried to give 4g of a white solid with a yield of 89%.That is, N-methyl-L-proline (compound b).
88%	With sodium dihydrogenphosphate; zinc; In water; at 30℃; for 48h;	The vigorously stirred suspension of zinc dust(6.50 g; 100 mmol), L-proline (5.57 g; 50 mmol) and NaH2PO4 (11.90 g; 100 mmol) in water (22 mL) was treated with 35% aq. formaldehyde (2.10 mL).Stirring was continued for 48 h at 30C. The suspension was discarded, the filtrate was neutralized with2 M aq. ammonia to pH 8, concentrated under vacuum,the solid residue was dissolved in small amount of water and lyophilized. Dry residue was extracted with hot mixture of benzene-ethanol (1 : 1, v/v).Collected extracts were evaporated to dryness and then recrystallized from the mixture methanol/ether affording L-N-methylproline (1) (5.68 g; yield 88%)as white crystals m.p. 115-120C, lit. (12) m.p.115-116C.

References: [1]Journal of Organic Chemistry,2003,vol. 68,p. 2652 - 2667.
[2]Green Chemistry,2016,vol. 18,p. 4374 - 4392.
[3]European Journal of Organic Chemistry,2005,p. 934 - 938.
[4]Tetrahedron Letters,2007,vol. 48,p. 7680 - 7682.
[5]Medicinal Chemistry Research,2016,vol. 25,p. 1148 - 1162.
[6]Journal of the American Chemical Society,2012,vol. 134,p. 2823 - 2834.
[7]Patent: CN107963987,2018,A .Location in patent: Paragraph 0046-0048.
[8]Acta poloniae pharmaceutica,2014,vol. 71,p. 994 - 1003.
[9]Synthesis,2011,p. 490 - 496.
[10]Journal of Organic Chemistry,2013,vol. 78,p. 3592 - 3615.
[11]Archiv der Pharmazie,1976,vol. 309,p. 380,382.
[12]Journal of Biological Chemistry,1953,vol. 202,p. 193,194.
[13]Angewandte Chemie,1995,vol. 107,p. 1095 - 1098.
[14]Analytical Chemistry,2007,vol. 79,p. 8631 - 8638.
[15]European Journal of Organic Chemistry,2009,p. 3790 - 3794.
[16]Advanced synthesis and catalysis,2020.

3
[ 475-11-6 ]
[ 74-88-4 ]
[ 471-87-4 ]

References: [1]Helvetica Chimica Acta,1925,vol. 8,p. 366.

4
[ 124-38-9 ]
[ 265660-44-4 ]
[ 475-11-6 ]
[ 475-11-6 ]

References: [1]Journal of the American Chemical Society,1993,vol. 115,p. 7515 - 7516.

5
[ 475-11-6 ]
[ 34381-71-0 ]

References: [1]Journal of Organic Chemistry,1983,vol. 48,p. 2195 - 2202.

6
[ 67-56-1 ]
[ 475-11-6 ]
[ 27957-91-1 ]

References: [1]Angewandte Chemie,1995,vol. 107,p. 1095 - 1098.

9
(-)-N-methyl-nicotone [ No CAS ]
[ 475-11-6 ]

References: [1]Helvetica Chimica Acta,1925,vol. 8,p. 366.

10
[ 104097-12-3 ]
[ 7664-93-9 ]
chromium trioxide [ No CAS ]
[ 475-11-6 ]

References: [1]Helvetica Chimica Acta,1925,vol. 8,p. 366.

11
[ 50-00-0 ]
L-proline-hydrochloride [ No CAS ]
[ 475-11-6 ]

References: [1]Croatica Chemica Acta,1959,vol. 31,p. 157.
[2]Journal of Biological Chemistry,1953,vol. 202,p. 193,194.

12
[ 475-11-6 ]
[ 487027-09-8 ]
[ 487027-10-1 ]

References: [1]Tetrahedron Asymmetry,2002,vol. 13,p. 2261 - 2266.

13
[ 475-11-6 ]
[ 487027-15-6 ]
[ 487027-16-7 ]

References: [1]Tetrahedron Asymmetry,2002,vol. 13,p. 2261 - 2266.

14
[ 3886-69-9 ]
[ 475-11-6 ]
1-Methyl-pyrrolidine-2-carboxylic acid ((R)-1-phenyl-ethyl)-amide [ No CAS ]

References: [1]Organic Letters,2005,vol. 7,p. 3151 - 3154.

15
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride [ No CAS ]
[ 475-11-6 ]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{1-[(2S)-1-methylpyrrolidin-2-ylcarbonyl]piperidin-3-yloxy}quinazoline [ No CAS ]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{1-[(2S)-1-methylpyrrolidin-2-ylcarbonyl]piperidin-3-yloxy}quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2.5h;	Example 61; 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[(2S)-1-methylpyrrolidin-2- ylcarbonyl] piperidin-3-yloxy} quinazoline; HATU (0.26g) was added to a solution of 4- (3-Chloro-2-fluoroanilino)-7-methoxy-6- (piperidin-3-yloxy) quinazoline dihydrochloride (250mg; prepared as described in Example 45), diisopropylethylamine (2101) and <strong>[475-11-6]N-methyl-L-proline</strong> (0.120g) in DMF (7. 5ml) and the mixture was stirred at room temperature for 2.5 hours. The DMF was removed under reduced pressure and the residue dissolved in methylene chloride (50ml) and washed with sodium bicarbonate (50ml) then water (50ml). Purification by flash column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4). The fractions containing the expected product were evaporated to give a foam. This foam was dissolved in methylene chloride (5ml) and crystallised by the addition of isohexane (50ml) to give the title product as a mixture of two diastereoisomers (0. 130g). 1H NMR Spectrum: (DMSO d6) 1.43-1. 62 (m, 2H), 1.66-1. 95 (m, 4H), 1.96-2. 18 (m, 4H), 2.20-2. 29 (m, 2H), 2.67-2. 80 (m, 1H), 2.96 (m, 1H), 3.03-3. 20 (m, 1H), 3.51-3. 80 (m, 2H), 3.80-4. 05 (m, 4H), 4.51-4. 68 (m, 1H), 7. 22-7. 31 (m, 2H), 7.47-7. 59 (m, 2H), 7.89 (m, 1H), 8. 39 (s, 1H), 9.55 (m, 1H) ; Mass Spectrum : (M+H)+ 514.

References: [1]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 154-155.

16
(2S,4R)-N-{1-[4-(3-amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide [ No CAS ]
[ 475-11-6 ]
(2S,4R)-1-Methyl-pyrrolidine-2-carboxylic acid [3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; 1,2-dichloro-ethane; In dichloromethane;	(2S,4R)-1-Methyl-pyrrolidine-2-carboxylic acid [3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-amide (H-59) (2S,4R)-N-{1-[4-(3-Amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide (100 mg, 0.204 mmol) was dissolved in methylene chloride (2 mL) and pyridine (2 mL). N-methyl proline (33 mg, 0.255 mmol) and EDC (63 mg, 0.255 mmol) were added and the reaction was stirred for 1 hour. The mixture was partitioned between methylene chloride and water; the methylene chloride layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate) to afford the product. 1H-NMR (CDCl3) delta: 1.1 (s, 3H), 1.2 (m, 1H), 1.8 (m, 2H), 2.0 (m, 2H), 2.0 (s, 3H), 2.2 (m, 2H), 2.3 (m, 1H), 2.4 (s, 3H), 2.6 (m, 1H), 3.2 (m, 2H), 3.4 (q, 2H), 4.0 (t, 2H), 4.1 (m, 1H), 4.8 (m 1H), 5.6 (bs, 1H), 6.5 (d, 1H), 6.6 (d, 2H), 6.9 (t, 1H), 7.2 (m, 6H), 7.4 (d, 2H). MS m/z: 603 (M+1).

References: [1]Patent: US2005/256158,2005,A1 .

17
[ 1001017-53-3 ]
[ 475-11-6 ]
[2S]-(4-[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl]-(1-methyl-pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With HATU; In dichloromethane; at 20℃; for 168h;	Example 25; <n="54"/>(4-{ [ [3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yI)-propyl] [2S] -(1-methyl- pyrroIidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester; The product of example 1, step (ix) (0.43 g), l-methyl-pyrrolidine-2-carboxylic acid (0.13g) and HATU (0.37g) were stirred in DCM (5ml) at rt for 7 days. The reaction mixture was purified by SCX and RPHPLC, to give the title compound. Yield 24mg. 1H NMR delta (DMSO- d6) 9.92 (IH, d), 9.61 (IH, s), 7.30 - 7.03 (5H, m), 6.44 (2H, s), 4.67 - 4.56 (2H, m), 4.54 - 4.42 (2H, m), 4.15 - 4.05 (4H, m), 3.69 - 3.58 (4H, m), 2.84 - 2.73 (4H, m), 2.05 (3H, s), 2.10 - 1.97 (2H, m), 1.97 - 1.84 (2H, m), 1.86 - 1.73 (2H, m), 1.66 - 1.53 (2H, m), 1.37 - 1.24 (2H, m), 0.96 - 0.83 (3H, m). MS: APCI (+ve): 554 (M+ 1).

References: [1]Patent: WO2008/4948,2008,A1 .Location in patent: Page/Page column 52-53.

18
[ 71989-31-6 ]
[ 71989-14-5 ]
[ 76-05-1 ]
[ 475-11-6 ]
Me-Pro-Pro-Asp-NH₂ trifluoroacetic acid salt [ No CAS ]

References: [1]Tetrahedron,2007,vol. 63,p. 8420 - 8424.

19
[ 67605-64-5 ]
[ 475-11-6 ]
N-[5-(4-aminophenyl)-10,15,20-triphenylporphyrinyl]-L-prolin(N-methyl)amide [ No CAS ]

References: [1]Journal of the American Chemical Society,2007,vol. 129,p. 6688 - 6689.

20
[ 124-22-1 ]
[ 475-11-6 ]
(2S)-N-dodecyl-1-methylpyrrolidine-2-carboxamide [ No CAS ]

References: [1]Tetrahedron Asymmetry,2007,vol. 18,p. 1868 - 1876.

21
[ 7311-30-0 ]
[ 475-11-6 ]
(2S)-N-dodecyl-N,1-dimethylpyrrolidine-2-carboxamide [ No CAS ]

References: [1]Tetrahedron Asymmetry,2007,vol. 18,p. 1868 - 1876.

22
[ 475-11-6 ]
N-[5-(4-aminophenyl)-10,15,20-triphenylporphyrinyl]-L-(N,N-dimethyl)prolinium amide iodide [ No CAS ]

References: [1]Journal of the American Chemical Society,2007,vol. 129,p. 6688 - 6689.

23
[ 475-11-6 ]
(1S,2S)-(1-oxido)-(1-methyl)-(N-(R)-1-phenylethyl)-2-pyrrolidinecarboxamide [ No CAS ]

References: [1]Organic Letters,2005,vol. 7,p. 3151 - 3154.

24
C₆H₉NO₂ [ No CAS ]
[ 475-11-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogen;palladium 10% on activated carbon; In methanol; water;	L-Proline (86) (2.0 g, 17.4 mmol) was dissolved in methanol (20 ml) and to this solution was added 40% aqueous formaldehyde solution (1.4 ml, 19.1 mmol). This was followed by the addition of 10% palladium-on-charcoal catalyst (500 mg) and the resulting slurry was stirred in a hydrogen atmosphere overnight. The slurry was then filtered through a Celite pad to remove the catalyst. The pad was washed with methanol and the combined filtrates were concentrated under reduced pressure. The residue was taken up in ethanol-benzene (1: 1, [100ML)] and concentrated a second time to provide a solid, which was recrystallised from methanol-diethyl ether. In this way N-methyl proline (87) was isolated as fine needles (2.2 g, 98%). Mp 142- 145 C [[?]23D -78.0 ] (c 2.0, MeOH). 1H NMR (300 MHz, D2O) 3.71-3. 65 and 3.55-3. 51 (2m, [1H),] 3.00-2. 91 (m, [1H),] 2.74 (s, 3H), 2. [34-2. 28] (m, [1H),] 1. [99-1. 78] (m, [3H). 13C] NMR [(75] MHz, [CDC13)] [5] 173.06, 70.18, 55.83, 40.26, 28.34, 22.37. IR (KBr disk) v 3000-2800 (CH, saturated), 2675 and 2605 (ammonium ion), 1669 [(CO2H),] 1612 [(C02-),] 1468, [1401,,] 1354, 1327,1234, 1183,1112, 1056,1025, 808,775 [CM~1.] HRMS calcd for [C6H1LNO2] (M+) 129.0790 found 129.0784.

References: [1]Patent: WO2004/7427,2004,A1 .Location in patent: Page 79-80.

25
[ 187345-38-6 ]
[ 475-11-6 ]
C₂₃H₄₁N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20 - 25℃;	[0356] To a solution of <strong>[475-11-6]N-methyl-L-proline</strong> monohydrate (0.26 g, 1.79 mmol) and benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (1.4 g, 2.69 mmol) in anhydrous dichloromethane (3.0 ml) at 25 C. is added diisopropylethylamine (0.63 ml, 3.62 mmol) under an inert atmosphere. To this solution is added a solution of ethyl (2E,4S)-2,5-dimethyl-4-[methyl(3-methyl-L-valyl)amino]hex-2-enoate (0.39 g, 1.27 mmol, WO 99/32509) in anhydrous dichloromethane (2.0 ml). The resulting reaction mixture is stirred at room temperature overnight. The reaction mixture is evaporated in vacuo. The residue (300 mg, 0.78 mmol) is dissolved in methanol (6.85 ml), water (1.8 ml) and tetrahydrofuran (3.25 ml). To this reaction mixture is added aqueous lithium hydroxide solution (3.54 ml, 3.54 mol) The resulting mixture is stirred at room temperature overnight. The reaction mixture is diluted with dichloromethane/water. The organic layer is washed with citric acid, brine, dried over sodium sulfate and filtered. The solvent is removed in vacuo, and the residue is chromatographed by HPLC (0.01% trifluoroacetic acid in water/acetonitrile) to give the product as a yellow oil, 0.08 g (28% yield). MS: m/z 396.28 (M+1)

References: [1]Patent: US2005/37977,2005,A1 .Location in patent: Page 39.

26
[ 345582-96-9 ]
[ 125700-67-6 ]
[ 475-11-6 ]
[ 345583-03-1 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	EXAMPLE 125 (2S)-N-{3-Chloro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}-1-methylpyrrolidine-2-carboxamide A mixture of the product from example 120 step (ii) (0.1 g), <strong>[475-11-6]N-methyl-L-proline</strong> (0.044 g), N,N-diisopropylethylamine (0.17 ml), 1-hydroxybenzotriazole (0.043 g), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.103 g) in N,N-dimethylformamide (3 ml) were stirred at room temperature overnight then partitioned between ethyl acetate and water. The organic layer was washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluding with 4% methanol/dichloromethane. Yield 0.038 g. MS: APCI(+ve) 469(M+1) 1H NMR: delta(DMSO-d6) 9.73(1H, s), 7.88(1H, d), 7.59(1H, dd), 7.38(1H, t), 7.30(2H, d), 7.14-7.10(2H, m), 5.15(2H, s), 4.04-3.98(1H, m), 3.30(2H, d), 3.12-3.08(1H, m), 2.90-2.67(5H, m), 2.35-2.29(1H, m), 2.33(3H, s), 2.18-2.09(1H, m) 1.87(2H, br d), 1.82-1.75(3H, m)

References: [1]Patent: US2003/40513,2003,A1 .

27
[ 23602-98-4 ]
[ 475-11-6 ]
[ 190660-12-9 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 257 Preparation of 1-N-(N-(N-methyl prolyl)-leucinyl)-amino-3-N-(2-dibenzofuran-sulfonyl)-amino-propan-2-one Following the procedure of Example 250(a)-(c), except substituting "N-methyl proline" for "4-pyridyl acetic acid" and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) M+H+ =543.

References: [1]Patent: US5998470,1999,A .

Yield	Reaction Conditions	Operation in experiment
37%; 95%		EXAMPLE 1 Benzeneacetamide. 3,4-dichloro-N-methyl-N-1-(1-methyl-2-pyrrolidinyl) -1-phenylmethyl]-hydrochloride STR4 N-methyl-L-proline was prepared following a procedure given in Helv. Chim. Acta 1967, 50, 8, p. 2527. Collected 7.1 g white crystals (95% yield). 2-benzoyl-N-methylpyrrolidine was also prepared according to a method given in Helv. Chim. Acta 1967, 50, 8, p. 2527. Collected 5.5 g (37% yield) yellow crystals after recrystallization from hexane.

29
[ 147-85-3 ]
[ 475-11-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	With formaldehyd;palladium-carbon; In methanol;	3a. N-Methyl (L)-proline To 175 mL of methanol containing (L)-proline (33 g, 286.7 mmol) and 37 wt % of aqueous formaldehyde (24 mL) was added 10% Pd/C (1.65 g), and the reaction mixture was hydrogenated at 4 Arm of H2. After the reaction was complete, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was triturated with ether and dried under high vacuum. The crude product was obtained as a white powder (33.44 g, 90%). MS (DCl/NH3) m/e 130 (M+H)+, 147 (M+NH4)+; 1 H-NMR (D2 O) d 1.94-2.23 (m, 4 H); 2.45-2.57 (m, 1H); 2.94 (s, 3 H); 3.16 (m, 1 H); 3.74 (m, 1 H); 3.90 (dd, 1 H).
90%	With formaldehyd;palladium-carbon; In methanol;	3a. N-Methyl (L)-proline To 175 mL of methanol containing (L)-proline (33 g, 286.7 mmol) and 37 wt % of aqueous formaldehyde (24 mL) was added 10% Pd/C (1.65 g), and the reaction mixture was hydrogenated at 4 Atm of H2. After the reaction was complete, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was triturated with ether and dried under high vacuum. The crude product was obtained as a white powder (33.44 g, 90%). MS (DCl/NH3) m/e 130 (M+H)+, 147 (M+NH4)+; 1 H-NMR (D2 O) d 1.94-2.23 (m, 4 H); 2.45-2.57 (m, 1 H); 2.94 (s, 3 H); 3.16 (m, 1 H); 3.74 (m, 1 H); 3.90 (dd, 1 H).
90%	With formaldehyd;palladium-carbon; In methanol;	3 a. N-Methyl (L)-proline To 175 mL of methanol containing (L)-proline (33 g, 286.7 mmol) and 37 wt % of aqueous formaldehyde (24 mL) was added 10% Pd/C (1.65 g), and the reaction mixture was hydrogenated at 4 Atm of H2. After the reaction was complete, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was triturated with ether and dried under high vacuum. The crude product was obtained as a white powder (33.44 g, 90%). MS (DCl/NH3) m/e 130 (M+H)+, 147 (M+NH4)+; 1H-NMR (D2 O) d 1.94-2.23 (m, 4H); 2.45-2.57 (m, 1H); 2.94 (s, 3 H); 3.16 (m, 1 H); 3.74 (m, 1 H); 3.90 (dd, 1 H).

References: [1]Patent: US5424444,1995,A .
[2]Patent: US5508418,1996,A .
[3]Patent: US5516912,1996,A .

30
[ 475-11-6 ]
[ 933-94-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	With sulfuryl dichloride; trimethyl orthoformate; In methanol; ethyl acetate;	10a N-Methyl-proline Methyl Ester A 2-L three neck round-bottom flask equipped with an overhead stirrer, internal temperature monitor, and addition funnel was charged with N-methyl proline (155.3 g, 1.20 mole) and methanol (800 mL). The vessel was chilled to 0 C. and sulfuryl chloride (110 mL, 1.33 mole) was added dropwise via the addition funnel at a rate such that the internal temperature remained ?+15 C. The cold bath was replaced with a heating mantle and trimethyl orthoformate (150 mL, 1.37 mole) was added quickly over 5 min. The reaction was heated to gentle reflux for 5 hours, then cooled to room temperature. The bulk of the solvent was evaporated in vacuo. The remainder was basified with saturated Na2 CO3 solution (ca. 1 L, pH 9-10) and partitioned with ethyl acetate (1 L). The aqueous phase was extracted with ethyl acetate (4500 mL), and the combined organics were washed with brine (11 L) and then dried (Na2 SO 4). After filtration and solvent evaporation the residue was distilled at reduced pressure (13 mm Hg, bp 56 C.) to give 125.7 g (73% yield, ?99% ee).
73%	With sulfuryl dichloride; trimethyl orthoformate; In methanol; ethyl acetate;	10a N-Methyl-proline methyl ester A 2-L three neck round-bottom flask equipped with an overhead stirrer, internal temperature monitor, and addition funnel was charged with N-methyl proline (155.3 g, 1.20 mole) and methanol (800 mL). The vessel was chilled to 0 C. and sulfuryl chloride (110 mL, 1.33 mole) was added dropwise via the addition funnel at a rate such that the internal temperature remained ?+15 C. The cold bath was replaced with a heating mantle and trimethyl orthoformate (150 mL, 1.37 mole) was added quickly over 5 min. The reaction was heated to gentle reflux for 5 hours, then cooled to room temperature. The bulk of the solvent was evaporated in vacuo. The remainder was basified with saturated Na2 CO3 solution (ca. 1 L, pH 9-10) and partitioned with ethyl acetate (1 L). The aqueous phase was extracted with ethyl acetate (4500 mL), and the combined organics were washed with brine (11 L) and then dried (Na2 SO 4). After filtration and solvent evaporation the residue was distilled at reduced pressure (13 mm Hg, bp 56 C.) to give 125.7 g (73% yield, ?99% ee).

References: [1]Patent: US5424444,1995,A .
[2]Patent: US5516912,1996,A .

31
[ 475-11-6 ]
[ 27957-91-1 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In hydrogenchloride; methanol;	3b. N-Methyl (L)-Proline Methyl Ester To a solution of N-methyl (L)-proline, from step 3a, in methanol at 0 C. is added thionyl chloride (1.1 eq) dropwise, and the reaction mixture is slowly allowed to warm to room temperature. Upon completion of the reaction the solvent is removed in vacuo, and the crude product is dissolved in 10% aq. HCl and washed with ether. The aqueous layer is adjusted to pH--12 with K2 CO3 (solid) and extracted with CH2 Cl2. The combined CH2 Cl2 layers are dried (MgSO4) and concentrated to afford the crude product as a clear oil.
	With thionyl chloride; In hydrogenchloride; methanol;	3b. N-Methyl (L)-Proline Methyl Ester To a solution of N-methyl (L)-proline, from step 3a, in methanol at 0 C. is added thionyl chloride (1.1 eq) dropwise, and the reaction mixture is slowly allowed to warm to room temperature. Upon completion of the reaction the solvent is removed in vacuo, and the crude product is dissolved in 10% aq. HCl and washed with ether. The aqueous layer is adjusted to pH ~12 with K2 CO3 (solid) and extracted with CH2 Cl2. The combined CH2 Cl2 layers are dried (MgSO4) and concentrated to afford the crude product as a clear oil.

References: [1]Patent: US5424444,1995,A .
[2]Patent: US5516912,1996,A .

32
[ 771-61-9 ]
[ 475-11-6 ]
C₁₂H₁₀F₅NO₂ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 1530 - 1533.

33
[ 911417-28-2 ]
[ 475-11-6 ]
[ 1024582-70-4 ]

Yield	Reaction Conditions	Operation in experiment
		A suspension of (S)-l-methylpyrrolidine-2-carboxylic acid monohydrate (14 mg, 0.11 mmol), PyBOP (57 mg, 0.11 mmol), DffiA (49 muL, 0.28 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-lH-indazole-l- carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2Cl2 and extracted with H2O (3x). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired oil product tert-butyl 5-(2-(3-((S)-l-methylpyrrolidine-2- carboxamido)phenyl)-quinazolin-4-ylamino)- 1 H-indazole- 1 -carboxylate.
		A suspension of (S)- l -methylpyrroliotadine-2-carboxylic acid monohydrate ( 14 mg. 0 1 1 mmol). PyBOP* (57 mg. 0.1 1 mmol). DIEA (49 muL. 0.28 mmol) in CH2Cl2 (0 5 ml_) was stirred at RT for 10- 15 minutes This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)- l H-indazole- l - carboxylate ( 100 mg, 0 22 mmol) and CH2CI2 ( 1 mL) The reaction mixture was stirred at RT for 1 5 h Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2CI2 and extracted with H2O (3x). Organic layer was dried under NajSCXj and concentrated /// vacuo to give the desired oil product tert-butyl 5-(2-(3-((S)- l-methylpyrrolidine-2- carboxamido)phenyl)-quinazolin-4-yIamino)-1H-indazole- l -carboxylate.
		[0203] A suspension of (S)-l-methylpyrrolidine-2-carboxylic acid monohydrate(14 mg, 0.11 mmol), PyBOP (57 mg, 0.11 mmol), DIEA (49 muh, 0.28 mmol) in CH2Cl2 (0.5 niL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)qumazolin-4-ylamino)-lH-indazole-l- carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2Cl2 and extracted with H2O (3x). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired oil product tert-butyl 5-(2-(3-((S)-l-methylpyrrolidine-2- carboxamido)phenyl)-quinazolin-4-ylamino)- 1 H-indazole- 1 -carboxylate.

References: [1]Patent: WO2008/54599,2008,A2 .Location in patent: Page/Page column 118.
[2]Patent: WO2010/104851,2010,A1 .Location in patent: Page/Page column 113; 1142.
[3]Patent: WO2006/105081,2006,A2 .Location in patent: Page/Page column 102.

34
C₃₄H₄₄N₄O₅S [ No CAS ]
[ 475-11-6 ]
C₄₀H₅₃N₅O₆S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2996 - 2999.

35
[ 475-11-6 ]
[ 147539-41-1 ]
tert-butyl 4-[methyl(1-methyl-L-prolyl)amino]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;	Reference Example 5 By allowing benzyl 4-(methylamino)piperidine-1-carboxylate to react with EDCI hydrochloride, HOBt and 1-methyl-L-proline, tert-butyl 4-[methyl(1-methyl-L-prolyl)amino]piperidine-1-carboxylate was obtained. Then, trifluoroacetic acid was added thereto to obtain N,1-dimethyl-N-piperidin-4-yl-L-prolinamide. ES: 226.

References: [1]Patent: EP2000469,2008,A2 .Location in patent: Page/Page column 14.

36
[ 913541-69-2 ]
[ 475-11-6 ]
[ 1013941-81-5 ]

References: [1]Organic and Biomolecular Chemistry,2008,vol. 6,p. 567 - 576.

37
[ 1105044-16-3 ]
[ 475-11-6 ]
[ 1105044-40-3 ]