[ CAS No. 53123-88-9 ] {[proInfo.proName]}

Name: 53123-88-9|(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone|98%
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Quality Control of [ 53123-88-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 53123-88-9 ]

Product Details of [ 53123-88-9 ]

CAS No. :	53123-88-9	MDL No. :	MFCD00867594
Formula :	C₅₁H₇₉NO₁₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QFJCIRLUMZQUOT-HPLJOQBZSA-N
M.W :	914.17	Pubchem ID :	5284616
Synonyms :	Sirolimus;AY-22989;D00753;C07909;SILA 9268A;SLM;RPM;RAP;RAPA;Wy 090217;NSC 226080;NSC-2260804;Rapamune	Chemical Name :	(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone

Safety of [ 53123-88-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 53123-88-9 ]

* 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.

Upstream synthesis route of [ 53123-88-9 ]
Downstream synthetic route of [ 53123-88-9 ]

[ 53123-88-9 ] Synthesis Path-Upstream 1~6

1
[ 75-21-8 ]
[ 53123-88-9 ]
[ 159351-69-6 ]

Yield	Reaction Conditions	Operation in experiment
6.9 g	With trifluorormethanesulfonic acid In toluene at 70℃; for 8 h; Autoclave	9.14 g rapamycin (0.01mol), 11g ethylene oxide (0.25 mol), 0.1 g trifluoromethanesulfonic acid, 30mL toluene was added to the autoclave after mixing, Warmed to 70 ° C, Maintaining 1.0 MPa pressure, the reaction was stopped after 8 hours, cooled to room temperature,The solvent was recovered under reduced pressure and the residue was purified by silica gel column chromatography (200-300 mesh silica gel,Eluent: ethyl acetate: petroleum ether = 20: 1),7.7 g 97.95percent of everolimus was obtained, which was purified by HP-20 resin column chromatography (eluent: acetonitrile: water = 65:35) 6.9 g of everolimus was obtained as a white solid, HPLC purity:99.6percent, Isomer content:0.12percent. Molar yield:72.0percent

Reference： [1] Patent: CN104876944, 2017, B, . Location in patent: Paragraph 0035-0050

2
[ 107-21-1 ]
[ 53123-88-9 ]
[ 159351-69-6 ]

Yield	Reaction Conditions	Operation in experiment
5.7 kg	Stage #1: With trifluoroacetic anhydride In tetrahydrofuran at 10℃; for 1.5 h; Inert atmosphere; Large scale Stage #2: With boron trifluoride diethyl etherate In tetrahydrofuran at 10℃; for 2 h; Large scale	620g of ethylene glycol and 6L of tetrahydrofuran were added to the reaction flask,Mix well to mix.The reaction temperature was controlled at 10 .Under nitrogen protection,1.41L trifluoroacetic anhydride was slowly added dropwise,Dropping is completed,Reaction for 1.5 hours,The reaction solution.9.14 kg of rapamycin was dissolved in 54 L of tetrahydrofuran,Added to the reaction solution,The reaction temperature was controlled at 10 .Slowly add 13ml boron trifluoride diethyl ether solution. Bi completed,The reaction was stirred for 2 hours. After the reaction is completed,60L saturated aqueous sodium bicarbonate solution was added,Stir wellThen suction filtered,To the filtrate was added 30 L of ethyl acetate,Liquid separation,The organic phase is washed with pure water until nearly neutral.The organic phase was dried over 500 g of anhydrous sodium sulfate for 2 hours, filtered,Concentrated under reduced pressure to a solventless outflow,A thick liquid. Column chromatography,The eluent is petroleum ether:Ethyl acetate = 1: 6. The collected effluent was concentrated under reduced pressure to give 6.3 kg of yellow foamy solid,Yield 66percent.A mixture of 26.8 L of methanol and ethyl acetate (v / v = 1/3) was added to the above yellow foamy solid,Stirring to dissolve,The temperature was controlled at 25 for 30 minutes,13.4 L cyclohexane was added dropwise,Bi completed,The temperature was controlled at 12 for 2 hours,Cool the feed liquid to about 0 slowly stirring 3h,Suction filtration,Drying at room temperature under vacuum gave 5.7 kg of a white solid,HPLC and mass spectrometry determined that the white solid was everolimus,Purity 98.1percent.

Reference： [1] Patent: CN106146535, 2016, A, . Location in patent: Paragraph 0037; 0038; 0039; 0040; 0041; 0042; 0043-0056

3
[ 53123-88-9 ]
[ 159351-69-6 ]

Reference： [1] Patent: WO2014/203185, 2014, A1,
[2] Patent: WO2016/20664, 2016, A1,
[3] Patent: CN105254646, 2016, A,
[4] Patent: CN105254646, 2016, A,
[5] Patent: CN105254646, 2016, A,
[6] Patent: CN105254646, 2016, A,
[7] Patent: WO2016/207205, 2016, A1,
[8] Patent: CN106146536, 2016, A,

4
[ 53123-88-9 ]
[ 1111-92-8 ]
[ 572924-54-0 ]

Reference： [1] Patent: US2004/73024, 2004, A1, . Location in patent: Page 38
[2] Patent: US2004/73024, 2004, A1, . Location in patent: Page 39

5
[ 331810-10-7 ]
[ 1111-92-8 ]
[ 572924-54-0 ]
[ 53123-88-9 ]

Yield	Reaction Conditions	Operation in experiment
81.03 %Chromat.	Stage #1: With 3,5-Lutidine In dichloromethane at 0 - 5℃; for 1.08333 h; Inert atmosphere Stage #2: at 0 - 5℃; for 1 h; Inert atmosphere	To a flask containing 31-trimethylsilylether Rapamycin (V-a) (300 mg, 0.304 mmole) was added dichloromethane (2 mL) under a stream of N_2(g). The resulting solution was stirred until 31-trimethylsilylether Rapamycin (V-a) was completely dissolved and cooled to 0-5° C. Next, a mixture of 3,5-lutidine (72 mg, 0.67 mmole) and dichloromethane (1 mL) was added therein dropwise over a period of more than 5 min. Then, a mixture of dimethylphosphinic chloride (DMP-Cl) (144 mg, 1.22 mmole) and dichloromethane (1 mL) was added therein dropwise over a period of more than 5 min. The resulting solution was kept at 0-5° C. for 1 hr, and monitored with HPLC. To the resulting solution was added ethyl acetate (40 mL) dropwise, followed by ethyl acetate until the final volume thereof was 300 mL. The resulting solution was successively washed with a NaHCO₃saturated solution (100 mL), an iced HCl solution (0.5 N. 100 mL), a NaHCO₃saturated solution (100 mL) and a NaCl saturated solution (100 mL), then the organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product of 42-(dimethylphosphinate) Rapamycin (Ridaforolimus) (I) (314 mg). The HPLC analysis data indicated that the crude product contained 81.03percent (area percent) of 42-(dimethylphosphinate) Rapamycin (Ridaforolimus) (I), 5.14percent of Rapamycin (II), 0.54percent of 31,42-bis(dimethyl phosphinate) Rapamycin (III), and 2.5percent of 42-(dimethylphosphinate)-31-trimethylsilylether Rapamycin (VI-a).

Reference： [1] Patent: US2014/58081, 2014, A1, . Location in patent: Paragraph 0047

6
[ 53123-88-9 ]
[ 572924-54-0 ]

Reference： [1] Patent: US2014/58081, 2014, A1,

[ 53123-88-9 ] Synthesis Path-Downstream 1~79

1
[ 80522-42-5 ]
[ 53123-88-9 ]
[ 151122-98-4 ]

Reference： [1]Journal of the American Chemical Society,1997,vol. 119,p. 962 - 973
[2]Tetrahedron Letters,1992,vol. 33,p. 7469 - 7472

2
[ 151122-98-4 ]
[ 53123-88-9 ]

Reference： [1]Journal of the American Chemical Society,1993,vol. 115,p. 9345 - 9346

3
[ 994-30-9 ]
[ 53123-88-9 ]
[ 155435-45-3 ]

Yield	Reaction Conditions	Operation in experiment
		A. Synthesis of <strong>[53123-88-9]Rapamycin</strong> 31-O-triethylsilyl ether [Compound 4d, RSi(CH2CH3)3]In a reaction flask, rapamycin (5.0 g, 5.5 mmol) and dichloromethane (75 ml) are added, with nitrogen fed therein, and the temperature of the reaction mixture is reduced to 05 C., then added with imidazole (1.5 g, 22.0 mmol), under agitation until completely miscible. Chlorotriethylsilane (3.1 g, 20.2 mmol) is dropwise added therein. After dropwise addition, the reaction mixture is agitated at 05 C. for 30 minutes.It undergoes the reaction at room temperature for 1.5 hours. Then, it is filtered and added with ethyl acetate (160 ml), and further washed with water (81 ml×3) and brine (33 ml). After drying and concentrating, a yellow oily product of rapamycin 31,42-bis-triethylsilyl ether (14) is obtained. Acetone (60 ml) is added and the temperature is reduced to 05 C. Aqueous solution of sulfuric acid (0.15N, 15 ml) is added dropwise and the reaction is conducted for one hour. Ethyl acetate (80 ml) is added, and then it is subsequently washed with brine (60 ml×2), saturated sodium bicarbonate solution (40 ml), pure water (60 ml×2) and brine (60 ml). After drying and concentrating, a yellow oily product (8.1 g) is obtained.
	With 1H-imidazole; In dichloromethane; at 0 - 5℃; for 3h;	[0043] To a flask containing <strong>[53123-88-9]Rapamycin</strong> (II) (10.0 g, 10.94 mmole) was added dichloromethane (60 mL) The resulting solution was cooled to 0-5 C, and then imidazole (3.0 g, 44.07 mmole) was added therein. After the resulting solution was stirred to dissolve the added imidazole completely, triethyl chlorosilane (6.1 g, 40.47 mmole) was added therein dropwise. Then, the resulting solution was stirred at 0-5 C for 3 h, followed by filtration at room temperature. The filter cake was washed with ethyl acetate (200 mL), and then to the filtrate was added ethyl acetate (200 mL). After the filtrate was successively washed with water (2x1 00mL) and a NaCl saturated solution (100 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated to obtain yellow oil 31,42-bis(triethylsilylether) <strong>[53123-88-9]Rapamycin</strong> (IV-b). To 31,42- bis(triethyl-silylether) Rapamyein (IV-b) was added tetrahydrofuran (32 mL). The resulting solution was cooled to 0-5 C., and then a mixture of acetic acid (98 mL) and water (52 mL) was added therein. The reaction solution was stirred at a temperature below 5 C for 2.5 h, followed by adding ethyl acetate (300 mL). Then, a NaHCO3 saturated solution was added into the reaction solution dropwise ate a temperature below 10 C. until the pH thereof was 7.0-7.5. After the organic layer and the aqueous layer were separated, the organic layer was collected, and the aqueous layer was extracted with ethyl acetate (300 mL). The overall organic layer was successively washed with water (2x150 mL) and a NaCl saturated solution (100 mL), dried over anhydrous sodium sulfate and concentrated to obtain a yellow oil crude produet of 31-triethylsilylether <strong>[53123-88-9]Rapamycin</strong> (V-b) (17.1 g). The crude product was purifed by cbromatography (eluted with ethyl aeetate:hexane 2:1) to provide a white solid of 31-triethylsilylether <strong>[53123-88-9]Rapamycin</strong> (V-b) (10.44 g). The yield thereof was 93%.
	With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice;	<strong>[53123-88-9]Rapamycin</strong> (5.00 g), triethylamine (2.77 g) and 4-dimethylaminopyridine (20 mg) were dissolved in dichloromethane (100 mL), and triethylchlorosilane (4.12) was added dropwise under ice-cooling. g), after the addition is completed, the ice water bath is cooled and reacted for 1 smallAt the same time, the temperature was gradually raised to room temperature, and the reaction was continued overnight, and TLC showed that the starting material disappeared completely. The reaction solution was filtered, and the filtrate was washed successively with 0.5M diluted hydrochloric acid, sat.

With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice;

<strong>[53123-88-9]Rapamycin</strong> (5.00 g, purity 98.4%),Triethylamine (2.77 g) and 4-dimethylaminopyridine (20 mg) were dissolved in dichloromethane (100 mL).After cooling in an ice water bath, triethylchlorosilane (4.12 g) was added dropwise, and after the addition was completed,The reaction was carried out under ice cooling for 1 hour, gradually warmed to room temperature, and allowed to react overnight.TLC showed that the starting material completely disappeared. The reaction solution is filtered,The filtrate was diluted with 0.5 M hydrochloric acid, saturated sodium bicarbonate,The saturated sodium chloride was washed sequentially, and the organic phase was concentrated under reduced pressure.The resulting residue was dissolved in acetone (100 ml).Add 0.25 M dilute sulfuric acid (15 mL) under ice-cooling, and stir at 0-10 C overnight.TLC showed that the original small polar product completely disappeared.The main product polarity is between rapamycin and it. Stop the reaction, separate the reaction solution,The organic phase was washed with saturated sodium hydrogen carbonate and brine and dried over anhydrous sodium sulfate.Concentration under reduced pressure gave 28-O-TES rapamycin (intermediate B-2, 6.01 g).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 459 - 462
[2]Journal of Organic Chemistry,1998,vol. 63,p. 10069 - 10073
[3]Patent: US2010/249415,2010,A1 .Location in patent: Page/Page column 13
[4]Patent: US2014/58081,2014,A1 .Location in patent: Paragraph 0043
[5]Patent: CN109776570,2019,A .Location in patent: Paragraph 0073; 0074; 0075; 0076; 0077; 0078
[6]Patent: CN109776569,2019,A .Location in patent: Paragraph 0072-0078

4
[ 108-30-5 ]
[ 53123-88-9 ]
[ 155589-16-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	Novozyme SP435; In toluene; at 45℃; for 40h;Product distribution / selectivity;	Example 1;: Synthesis of rapamycin 42-hemisuccinate; The lipase-catalyzed acylation is readily carried out by mixing rapamycin and succinic anhydride in a solvent with a lipase. Method 1: A mixture of rapamycin (2.0 g, 2.2 mmol), succinic anhydride (1.0 g, 10 mmol) and NOVOZYM SP435 (4.5 g) in toluene (20 mL) was stirred at 45C under N2 atmosphere for 40 hours (40 h). The enzyme was filtered off and washed with toluene, the combined organic solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2-MeOH (12:1) to furnish the title compound as a white solid (2.02 g, 91% yield).
86%	Novozyme SP435; In toluene; acetonitrile; at 45℃; for 144h;Product distribution / selectivity;	Method 2:; A mixture of rapamycin (91.4 mg, 0.1 mmol), succinic anhydride (120 mg, 1.2 mmol) and NOVOZYM SP435 (400 mg) in toluene-CH3CN (3 mL, 5:1 v/v) was stirred at 45C under N2 atmosphere for 144 h. The enzyme was filtered off and washed with toluene and the combined organic solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2-MeOH (12:1) to furnish the title compound as a white solid (87 mg), while rapamycin (10 mg) was recovered. The yield of 42-hemisuccinate is 96% based on the recovered rapamycin (86% based on the starting amount of rapamycin). MS: 1013 (M-)

Reference： [1]Organic Letters,2005,vol. 7,p. 3945 - 3948
[2]Patent: WO2005/105812,2005,A1 .Location in patent: Page/Page column 16
[3]Patent: WO2005/105812,2005,A1 .Location in patent: Page/Page column 16-17
[4]Chemical Biology and Drug Design,2016,vol. 88,p. 230 - 240
[5]Angewandte Chemie - International Edition,2019,vol. 58,p. 2433 - 2436
Angew. Chem.,2019,vol. 131,p. 2455 - 2458,4

5
[ 18523-48-3 ]
[ 53123-88-9 ]
[ 851077-42-4 ]

Yield	Reaction Conditions	Operation in experiment
57%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;	10202] Azidoacetic acid (compound 18) (253 mg, 2.5 mmoE) and rapamycin (2.28 g, 2.5 mmoE) were added to the reaction bottle, and dichloromethane was used to dissolve them, and the system was cooled in ice bath. 4-dimethylami- nopyridine (DMAP, 611 mg, 5 mmoE) and N,N-dicyclohexylcarbodiimide (DCC, 1.03 g, 5 mmoE) were added to the reaction bottle, and then, the system was stirred continuously at room temperature overnight. Afier the reaction solution was concentrated, the residues were purified by column chromatography to produce 1.42 g azidoacetic acid rapamycin ester (compound 19) at a yield of 57%, MS m/z: 1020 [M+Na].

Reference： [1]Patent: US2015/359900,2015,A1 .Location in patent: Paragraph 0200; 0202
[2]Journal of the American Chemical Society,2005,vol. 127,p. 4715 - 4721

6
[ 76823-03-5 ]
[ 53123-88-9 ]
C₄₀-(5-carboxyfluorescein)-rapamycin [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2005,vol. 127,p. 4715 - 4721

7
[ 53123-88-9 ]
17,18-29,30-bis-epoxide macrocyclic lactone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With sodium hydroxide; dihydrogen peroxide; In methanol; at 20℃; for 24h;	[0175] Add 0.8mL 5% NaOH-MeOH and 2ml 30%H2O2 to a solution of 1 gram <strong>[53123-88-9]Rapamycin</strong> in 40 ml methanol. The reaction mixture was stirred at room temperature for 24 hours. IfTLC indicated some rapamycin was still unreacted, additional mixture of 0.8mL 5% NaOH-MeOH and 2ml 30%H2O2 was added to the reaction solution. Stirring continued at room temperature until TLC indicated the reaction has completed. The solution was extracted with dichloromethane and brine 3 times. The organic layers were combined and washed with brine and water, dried over anhydrous MgSO4, filtered MgSO4 and the solution was evaporated to leave a raw product. This raw product was further purified using TLC plate and giving 0.4Og (40% yields) light yellow powder. 1H NMR (CDCl3) (-4:1 mixture of conformers, only signals of major conformer listed) Major changes compared with rapamycin delta (ppm) 1.75(s, IH), 1.98(s, IH), 6.71(ddd, 5H, Jl=IOHz, J2=8Hz, J3=2.8Hz). 13C DEPT 135 NMR (CDCl 3) (-4:1 mixture of conformers, only signals of major conformer listed) delta (ppm) 152, 140, 133, 128, 127, 126, 84, 83, 76, 74, 67, 59, 56, 44, 43, 41, 40, 36, 35, 34, 33, 31 , 29, 28, 22, 21, 20, 17, 16, 15, 13. Mass Spectra m/z=962 with <strong>[53123-88-9]Rapamycin</strong> m/z=930.
40%	With dihydrogen peroxide; sodium hydroxide; In methanol; water; at 20℃;	Add 0.8mL 5% NaOH-MeOH and 2ml 30%H2O2 to a solution of 1 gram <strong>[53123-88-9]Rapamycin</strong> in 40 ml methanol. The reaction mixture was stirred at room temperature for 24 hours. IfTLC indicated some rapamycin was still unreacted, additional mixture of 0.8mL 5% NaOH-MeOH and 2ml 30%H2O2 was added to the reaction solution. Stirring continued at room temperature until TLC indicated the reaction has completed. The solution was extracted with dichloromethane and brine 3 times. The organic layers were combined and washed with brine and water, dried over anhydrous MgSO4, filtered MgSO4 and the solution was evaporated to leave a raw product. This raw product was further purified using TLC plate and giving 0.4Og (40% yields) light yellow powder. 1H NMR (CDCl3) (-4:1 mixture of conformers, only signals of major conformer listed) Major changes compared with rapamycin delta (ppm) 1.75(s, 1H), 1.98(s, 1H), 6.71 (ddd, 5H, Jl=IoHz, J2=8Hz, J3=2.8Hz). 13C DEPT 135 NMR (CDCh) (~4:1 mixture of conformers, only signals of major conformer listed) delta (ppm) 152, 140, 133, 128, 127, 126, 84, 83, 76, 74, 67, 59, 56, 44, 43, 41 , 40, 36, 35, 34, 33, 31, 29, 28, 22, 21, 20, 17, 16, 15, 13. Mass Spectra m/z=962 with <strong>[53123-88-9]Rapamycin</strong> m/z=930.

Reference： [1]Patent: WO2008/33956,2008,A2 .Location in patent: Page/Page column 41
[2]Patent: WO2009/114010,2009,A1 .Location in patent: Page/Page column 61

8
[ 18292-38-1 ]
[ 53123-88-9 ]
C₃-methallyl-rapamycin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With boron trifluoride diethyl etherate; In dichloromethane; at -40℃; for 2h;	The synthetic procedure we currently use is a modified version of the procedure described in Liberles et al., July 1997, Proc. Natl. Acad. Sci. USA 94:7825-7830 for the preparation of C7 rapalogs. (Note that C7 and C3 as referred to herein refer to the ring positions C16 and C20, respectively, in the nomenclature of Liberles et al). Twenty two mgs of rapamycin are placed in a 3 ml flame-dried Wheaton vial equipped with a stir bar. The rapamycin is dissolved in 200 μl of methylene chloride and cooled to -40 degrees. Lower temperatures have been found to not work as efficiently. 50 μl of methallyl (or allyl) trimethyl silane (12 equiv.) is added, followed by 40 μl of neat BF3 etherate (13 equivalents). After 2 hours the reaction is over, as determined by TLC, and is quenched by addition of saturated NaHCO3. The reaction mixture is then washed with brine and dried with sodium sulfate. (The aqueous washes can be back-extracted with methylene chloride and combined with the reaction mixture.) The samples are filtered with a 0.45 micron Nylon filter and the solvent is evaporated under vacuum.The crude product is dissolved in 100 μl of chloroform for injection on the JAI recycling HPLC described below. Three predominant peaks are obtained that can be separated with baseline resolution after approximately 15-20 cycles. (Under certain reaction conditions, a fourth peak appears which elutes before the other three.) Of the three predominant peaks, the first is C7-S methallyl rapamycin, as determined by 1H-NMR. The middle peak is the compound of interest, C3-methallyl rapamycin, and the fourth peak is composed of side products resulting from oversilylation of rapamycin. Following this procedure, we obtained 4.2 mgs of pure C3-methallyl rapamycin. Since unmodified rapamycin coincidentally comigrates precisely with C3-methallyl rapamycin, and cannot be removed efficiently with the JAI, it is critical that rapamycin be completely consumed during the reaction. Overaddition products are far more easily removed than the unreacted starting material.The JAI-purified methallyl rapamycin can be verified by UV, NMR, and mass spectroscopy and biological activity. The presence of contaminants, such as rapamycin, can be easily determined by UV, as described below.This same procedure has been used to synthesize C3 allyl-rapamycin, and should be easily extended to synthesize a variety of other C3 derivatives.Analytical ConsiderationsOne particularly convenient diagnostic is UV spectroscopy. Consistent with disappearance of the triene, the UV spectra of the C3 compounds have a maximum absorbance at lambda 238 rather than 274-282, typically seen for the C7 (R) or (S) compounds. Since the C3 compounds have baseline absorbance in the region where rapamycin absorbs best, UV analysis is a good indicator of sample purity and the presence of any toxic contaminants.The loss of the triene in C3-methallyl rapamycin is also reflected in the 1H NMR. A 1H-NMR of methallyl rapamycin, taken in CDCL3, reveals a diagnostic peak from C5 at 6.0 ppm. The remainder of the olefinic protons all lie upfield between 5 and 5.6 ppm.Chromatographic Recovery of the C3 RapalogsAn instrument made by the Japan Analytical Industry Co., LTD. (JAI) efficiently purifies the C3 rapalogs. The instrument we used was a “LC-908 Recycling Preparative HPLC” and the column we used was “JAIGEL GS-310” with dimensions of “20×500 mm”.

Reference： [1]Patent: US6984635,2006,B1 .Location in patent: Page/Page column 62-63

9
[ 38222-83-2 ]
[ 53123-88-9 ]
[ 1111-92-8 ]
[ 3283-12-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In dichloromethane; ethyl acetate;	Dimethyl-phosphinic acid C-43 rapamycin ester To a cooled (0° C.) solution of rapamycin (0.1 g, 0.109 mmol) in 1.8 mL of dichloromethane was added 0.168 g (0.82 mmol) of 2,6-di-t-butyl-4-methyl pyridine, under a stream of N2, followed immediately by a solution of dimethylphosphinic chloride (0.062 g, 0.547 mmol) in 0.2 mL of dichloromethane. The slightly yellow reaction solution was stirred at 0° C., under an atmosphere of N2, for 3.5 h (reaction monitored by TLC). The cold (0° C.) reaction solution was diluted with ~20 mL EtOAc then transferred to a separatory funnel containing EtOAc (150 mL) and saturated NaHCO3 (100 mL). Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1100 mL), saturated NaHCO3(1100 mL), and brine (1*100 mL), then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 1:10:3:3 MeOH/DCM/EtOAc/hexane) to provide 0.092 g of a white solid: 1H NMR (300 MHz, CDCl3) d 4.18 (m, 1H), 4.10 (m, 1H), 3.05 (m, 1H), 1.5 (m, 6H); 31P NMR (121 MHz, CDCl3) d 53.6; 1013 m/z (M+Na).
	With sodium hydrogencarbonate; In dichloromethane; ethyl acetate;	Dimethyl-phosphinic acid C-43 rapamycin ester To a cooled (0° C.) solution of rapamycin (0.1 g, 0.109 mmol) in 1.8 mL of dichloromethane was added 0.168 g (0.82 mmol) of 2,6-di-t-butyl-4-methyl pyridine, under a stream of N2, followed immediately by a solution of dimethylphosphinic chloride (0.062 g, 0.547 mmol) in 0.2 mL of dichloromethane. The slightly yellow reaction solution was stirred at 0° C., under an atmosphere of N2, for 3.5 h (reaction monitored by TLC). The cold (0° C.) reaction solution was diluted with ~20 mL EtOAc then transferred to a separatory funnel containing EtOAc (150 mL) and saturated NaHCO3 (100 mL). Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1100 mL), saturated NaHCO3(1100 mL), and brine (1*100 mL), then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 1:10:3:3 MeOH/DCM/EtOAc/hexane) to provide 0.092 g of a white solid: 1H NMR (300 MHz, CDCl3) d 4.18 (m, 1H), 4.10 (m, 1H), 3.05 (m, 1H), 1.51 (m, 6H); 31P NMR (121 MHz, CDCl3) d 53.6; 1013 m/z (M+Na).
	With sodium hydrogencarbonate; In dichloromethane; ethyl acetate;	EXAMPLE 2Dimethyl-Phosphinic Acid C-43 Rapamycin EsterTo a cooled (0° C.) solution of rapamycin (0.1 g, 0.109 mmol) in 1.8 mL of dichloromethane was added 0.168 g (0.82 mmol) of 2,6-di-t-butyl-4-methyl pyridine, under a stream of N2, followed immediately by a solution of dimethylphosphinic chloride (0.062 g, 0.547 mmol) in 0.2 mL of dichloromethane.The slightly yellow reaction solution was stirred at 0° C., under an atmosphere of N2, for 3.5 h (reaction monitored by TLC).The cold (0° C.) reaction solution was diluted with ~20 mL EtOAc then transferred to a reparatory funnel containing EtOAc (150 mL) and saturated NaHCO3 (100 mL).Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1100 mL), saturated NaHCO3(1100 mL), and brine (1*100 mL), then dried over MgSO4 and concentrated.The crude product was purified by silica gel flash chromatography (eluted with 1:10:3:3 MeOH/DCM/EtOAc/hexane) to provide 0.092 g of a white solid: 1H NMR (300 MHz, CDCl3) delta4.18 (m, 1H), 4.10 (m, 1H), 3.05 (m, 1H), 1.51 (m, 6H); 31P NMR (121 MHz, CDCl3) delta 53.6; 1013 m/z (M+Na).

Reference： [1]Patent: US2003/220297,2003,A1
[2]Patent: US2005/32825,2005,A1
[3]Patent: US2012/289481,2012,A1

10
[ 110-89-4 ]
rapamycin 42-ester [ No CAS ]
[ 117322-30-2 ]
[ 53123-88-9 ]

Yield	Reaction Conditions	Operation in experiment
0.36 g (0.35 mmole, 44%)	In methanol; acetonitrile;	EXAMPLE 10 Rapamycin 42-ester with 1-aminocyclopentane carboxylic acid To a chilled (ice bath) solution of rapamycin 42-ester with 1-(9H-fluoren-9-ylmethoxycarbonylamino)-cyclopentane carboxylic acid (0.991 g, 0.794 mmol) in acetonitrile (4.5 mL) was added 0.47 mL (4.76 mmol) of piperidine in 2 mL of acetonitrile via an additional funnel. The reaction mixture was stirred at 0-5 C. for about two hours (a white precipitate formed after an hour). The reaction mixture was then filtered and concentrated (without heating) and applied to a flash column with a gradient of 1-1.5% methanol/chloroform to yield 0.36 g (0.35 mmole, 44%) of the title compound. Negative FAB-MS [M-H]- am/z 1024.

Reference： [1]Patent: US5385910,1995,A

11
C₅₇H₉₅NO₁₃Si₂ [ No CAS ]
[ 331810-13-0 ]
[ 53123-88-9 ]

Yield	Reaction Conditions	Operation in experiment
87.6%		A solution of crude rapamycin (20.0 g, 19.5 mmol, yellow index=24.23, purity=89% and B:C isomeric ratio=11:1) in 300 ml ethyl acetate was cooled to 0-5 C. Imidazole (6.0 g, 88.1 mmol) was added and the mixture stirred to form a solution. To this cold solution was added dropwise 8.73 g (80.4 mmol) of chlorotrimethylsilane over 30 min and stirred for a further 30 min at 0-5 C. to complete the formation of rapamycin 31,42-bis-O-trimethylsilyl ether. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to a dark foam, which was stirred with 400 ml of heptane at room temperature for 20-30 minutes. The mixture was filtered to separate the insoluble material. The filtrate was stirred with 3.0 g of Darco KB charcoal at room temperature for 20-30 minutes then filtered and the filtrate was further washed with water (160 ml), saturated sodium bicarbonate solution (80 ml) then with water (2×80 ml) to pH 6-7. The light yellow organic layer was concentrated under reduced pressure at 25-30 C. to obtain 24.0 g of product as a pale yellow foam. The foam (24.0 g) was dissolved in 100 ml of acetone, stirred and cooled to 0-5 C. To this cold solution was added, dropwise, 20 ml of 0.5 N sulfuric acid over 10 minutes. The mixture was stirred at 0-5 C. until reaction completion. A solution of sodium bicarbonate (1.68 g/20 ml water) was added over 2-5 minutes. The pot temperature was allowed to rise to 10-15 C. Acetic acid (2 ml) was added and the mixture stirred for 15-20 minutes. To the reaction mixture was added, portionwise, 50 ml of sodium acetate buffer solution (pH 5-5.5) over 10 minutes and the mixture stirred at ambient temperature for 60 hours. The reaction mixture was filtered and washed with acetone-water (1:1; v/v) mixture (2×60 ml). The product was dried in vacuum oven at 35-40 C. to constant weight to obtain 15.58 g of product as a white solid. The proton NMR of the product was identical with an authentic sample. The recovery yield was 87.6%, the purity of the product was 98.7%, the B:C isomeric ratio was 35:1, and the yellow index was 0.73.

Reference： [1]Patent: US2006/199954,2006,A1 .Location in patent: Page/Page column 4-5

12
[ 5309-70-6 ]
[ 53123-88-9 ]
sirolimus 42-bromoacetyl monoester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	Novozym 435TM lipase; In tert-butyl methyl ether; at 40℃; for 8h;Molecular sieve;	A. Preparation of <strong>[53123-88-9]Rapamycin</strong> 42-bromoacetate (VII) A mixture of rapamycin (914 mg, 1 mmol), vinyl bromoacetate (660 mg, 4 mmol), 5 A molecular sieves (100 mg) and Novozym 435 lipase (1.0 g) in anhydrous t-butyl methyl ether (TBME) (8 mL) was heated under N2 at 40 C. for 8 hours. The enzyme was removed by filtration and washed with TBME. The mixture was concentrated and precipitated into hexane. The rapamycin 42-bromoacetate (VII) was collected by filtration and dried in vacuo. Yield: 1.01 g (98%). MS (ESI) m/e 1035 (M-)

Reference： [1]Patent: US2007/212371,2007,A1 .Location in patent: Page/Page column 14-15

13
[ 53123-88-9 ]
[ 5736-06-1 ]
rapamycin 42-ester with 2,2-dimethyl[1,3]dioxalane-4-carboxylic acid [ No CAS ]
rapamycin 31,42-dester with 2,2-dimethyl[1,3]dioxalane-4-carboxylic acid [ No CAS ]

Reference： [1]Patent: EP1266899,2002,A2 .Location in patent: Example 5,6

14
[ 15022-08-9 ]
[ 53123-88-9 ]
[ 154492-14-5 ]

Yield	Reaction Conditions	Operation in experiment
73%	With novozyme 435; In tert-butyl methyl ether; at 60℃; for 18h;Inert atmosphere; Molecular sieve;	Example 10 42-O-(Allyloxycarbonyl)rapamycin A mixture of rapamycin (0.03 g, 0.0328 mmol), diallyl carbonate (0.028 g, 0.197 mmol), Novozyme 435 (0.045 g) and molecular sieves (5 A) in anhydrous tert-butyl methyl ether (TBME) (0.5 mL) was stirred at 60 C. under an N2 atmosphere for 18 hours. The enzyme was filtered off, washed with TBME and the combined organic solvent concentrated under N2. The residue was purified by column chromatography (hexane/acetone, 2.5:1) to furnish the title compound as a white solid (73%, 0.024 g). Rf=0.58 (THF/heptane, 1:1). 1H NMR (400 MHz/CDCl3); 4.50-4.57 (m, 1H), 4.63 (d, 2H), 5.27 (dd, 2H), 5.91-5.98 (m, 1H). 13C NMR (100 MHz/CDCl3); 68.3, 80.3, 118.8, 131.7, 154.6. MS (ESI-TOF) m/z 1020.5 [M+Na]+.

Reference： [1]Patent: US2009/253733,2009,A1 .Location in patent: Page/Page column 13-14

15
[ 7570-02-7 ]
[ 53123-88-9 ]
[ 1188536-56-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	With novozyme 435; In tert-butyl methyl ether; toluene; at 60℃; for 18h;Inert atmosphere;	Example 9; 42-O-(Vinyloxycarbonyl)rapamycin; A mixture of mercury(II) oxide yellow (162 g, 750 mmol), mercury(II) acetate (6 g, 25 mmol), ethanol (90 mL) and H2O (30 mL) was placed in a 500 mL three-necked flask equipped with a magnetic stirrer, thermometer, reflux condenser and addition funnel. The mixture was stirred at room temperature for 30 minutes until homogeneous. Ethyl vinyl ether (118.8 g, 1650 mmol) was added to the reaction mixture over a period of 30 minutes, during which time the temperature rose to 55 C. The reaction mixture was filtered whilst hot then allowed to crystallise for 3 hours at 4 C. The crystals were washed with ethanol and dried under vacuum for 24 hours. Mercuric diacetaldehyde was isolated as a white solid (55%, 118.8 g). 1H NMR (250 MHz/CDCl3); 2.32 (d, 6H, 2×CH3, J=5.0 Hz), 9.33 (q, 2H, 2×CH, J=2.5 Hz). 13C NMR (60 MHz/CDCl3); 51.1 (2×CH3), 199.4 (2×CO). A mixture of mercuric diacetaldehyde (110 g, 381.02 mmol) in anhydrous THF (40 mL) was placed in a 250 mL three-necked flask equipped with a magnetic stirrer, thermometer, reflux condenser fitted with a CaCl2 guard tube and an addition funnel. The mixture was stirred and cooled to 0 C. in an ice bath. Phosgene (14 g, 140 mmol) in anhydrous toluene (20%) was added gradually over a period of 20 minutes. The temperature was maintained at 0 C. for 1 hour with good stirring and then allowed to warm to room temperature for a further 1 hour. After this time the temperature was slowly raised to 60 C. and maintained for 1 hour. The product, divinyl carbonate, was obtained as a solution in toluene by distillation at atmospheric pressure. 1H NMR (250 MHz/CDCl3); 4.95 (dd, 2H, 2×CHCH trans, J=6.0, 2.0 Hz), 5.35 (dd, 2H, 2×CHCH cis, J=14.0, 2.0 Hz), 7.50 (dd, 2H, 2×CHCH2, J=14.0, 6.0 Hz). 13C NMR (60 MHz/CDCl3); 98.5 (CHCH2), 99.2 (CHCH2), 143.1 (2×CHCH2), 151.1 (CO). A mixture of rapamycin (0.03 g, 0.0328 mmol), divinyl carbonate (0.022 g, 0.197 mmol) and Novozyme 435 (0.045 g) in anhydrous tert-butyl methyl ether (TBME) (0.5 mL) and anhydrous toluene (0.13 mL) was stirred at 60 C. under an N2 atmosphere for 18 hours. The enzyme was filtered off, washed with TBME and the combined organic solvent concentrated under N2. The residue was purified by column chromatography (hexane/acetone, 3:1) to furnish the title compound as a white solid (88%, 0.0283 g). Rf=0.62 (THF/heptane, 1:1). 1H NMR (400 MHz/CDCl3); 4.54-4.58 (m, 1H), 4.58 (dd, 1H), 4.92 (dd, 1H), 7.11 (dd, 1H). 13C NMR (100 MHz/CDCl3); 80.9, 97.8, 142.9, 152.6. MS (ESI-TOF) m/z 1006.6 [M+Na]+.

Reference： [1]Patent: US2009/253733,2009,A1 .Location in patent: Page/Page column 13

16
[ 53123-88-9 ]
[ 105-58-8 ]
[ 154492-10-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	With novozyme 435; In tert-butyl methyl ether; at 60℃; for 18h;Inert atmosphere; Molecular sieve;	Example 8 42-O-(Ethoxycarbonyl)rapamycin A mixture of rapamycin (0.06 g, 0.0656 mmol), diethyl carbonate (0.047 g, 0.0394 mmol), Novozyme 435 (0.09 g) and molecular sieves (5 A) in anhydrous tert-butyl methyl ether (TBME) (1.0 mL) was stirred at 60 C. under an N2 atmosphere for 18 hours. The enzyme was filtered off, washed with TBME and the combined organic solvent concentrated under N2. The residue was purified by column chromatography (hexane/acetone, 3:1) to furnish the title compound as a white solid (79%, 0.0509 g). Rf=0.56 (THF/heptane, 1:1). 1H NMR (400 MHz/CDCl3); 1.31 (t, 3H), 4.22 (q, 2H), 4.48-4.55 (m, 1H). 13C NMR (100 MHz/CDCl3); 14.2, 65.8, 80.0, 154.8. MS (ESI-TOF) m/z 1008.6 [M+Na]+.

Reference： [1]Patent: US2009/253733,2009,A1 .Location in patent: Page/Page column 12-13

17
[ 1188536-57-3 ]
[ 53123-88-9 ]
[ 1188536-52-8 ]

Yield	Reaction Conditions	Operation in experiment
78%	With novozyme 435; In tert-butyl methyl ether; at 60℃; for 18h;Inert atmosphere;	Example 2; 42-O-(cis-Octadec-9'-enyloxycarbonyl)rapamycin; Vinyl chloroformate (0.29 mL, 3.13 mmol) was slowly added to a solution of oleyl alcohol (0.50 mL, 1.58 mmol) in anhydrous pyridine (5 mL, 62 mmol) at 0 C. under an atmosphere of N2 over a period of 30 minutes. The reaction mixture was stirred for a further 1 hour at 0 C. then allowed to warm to room temperature over a period of 1 hour. The temperature was then raised to 50 C. and stirring was continued for a further 1 hour. The reaction was quenched with 15% HCl (35 mL) and the aqueous layer extracted with CH2Cl2 (3×35 mL). The combined organic layers were washed with H2O (2×50 mL) and dried (MgSO4). The solvent was removed in vacuo and the compound purified by column chromatography (hexane/ether, 5:1) to afford cis-octadec-9-enyl vinyl carbonate as a colourless liquid (95%, 0.50 g). Rf=0.82 (hexane/ether, 3:1). 1H NMR (250 MHz/CDCl3); 0.88 (t, 3H, CH3CH2CH2, J=6.5 Hz), 1.27 (brs, 16H, CH3CH2CH2CH2CH2CH2CH2CH2CH2CHCH2CH2CH2CH2CH2CH2CH2CH2O), 1.30 (brs, 6H, CH2CH2CH2CH2CH2CH2CH2CHCHCH2CH2CH2CH2CH2CH2CH2CH2O), 1.69 (p, 2H, CH2CH2O(CO)OCHCH2, J=7.0 Hz), 1.97-2.05 (m, 4H, CH2CHCHCH2), 4.19 (t, 2H, CH2O(CO)OCHCH2, J=6.5 Hz), 4.57 (dd, 1H, CH2O(CO)OCHCH trans, J=6.0, 2.0 Hz), 4.91 (dd, 1H, CH2O(CO)OCHCH cis, J=14.0, 2.0 Hz), 5.28-5.41 (m, 2H, CH2CHCHCH2), 7.09 (dd, 1H, CH2O(CO)OCHCH2, J=14.0, 6.0 Hz). 13C NMR (60 MHz/CDCl3); 14.5 (CH3), 23.1 (CH2CH3), 26.0 ((CO)OCH2CH2CH2), 27.6 (CH2CHCHCH2), 27.6 (CH2CHCHCH2), 28.9 ((CO)OCH2CH2), 29.6 ((CO)OCH2CH2CH2CH2), 29.7 (CH2CH2CH2CH3), 29.8 (CH2CH2CH2CH2CH3), 29.8 ((CO)OCH2CH2CH2CH2CH2), 29.9 ((CO)OCH2CH2CH2CH2CH2CH2), 29.9 (CH2CH2CH2CH2CH2CH3), 30.1 ((CO)OCH2CH2CH2CH2CH2CH2CH2), 30.2 (CH2CH2CH2CH2CH2CH2CH3). 32.2 (CH2CH2CH3), 69.2 (CH2CHO(CO)OCH2), 98.0 (CH2CHO), 130.2 (CH2CHCHCH2), 130.4 (CH2CHCHCH2), 143.0 (CH2CHO), 153.2 (CO). HRMS m/z (CI, NH3) found 339.2902 [M+H]+, requires C21H39O3 339.2899. A mixture of rapamycin (0.03 g, 0.0328 mmol), cis-octadec-9-enyl vinyl carbonate (0.067 g, 0.20 mmol) and Novozyme 435 (0.03 g) in anhydrous tert-butyl methyl ether (TBME) (0.5 mL) was stirred at 60 C. under an N2 atmosphere for 18 hours. The enzyme was filtered off, washed with TBME and the combined organic solvent concentrated under N2. The residue was purified by column chromatography (hexane/acetone, 4:1) to furnish the title compound as a white solid (78%, 0.031 g). Rf=0.71 (THF/heptane, 1:1). 1H NMR (400 MHz/CDCl3); 0.88 (t, 3H), 1.26-1.50 (m, 22H), 1.69-1.87 (m, 2H), 1.94-2.03 (m, 4H), 4.13 (t, 2H), 4.49-4.55 (m, 1H), 5.33-5.36 (m, 2H). 13C NMR (100 MHz/CDCl3); 14.1, 22.7, 23.9, 28.6, 28.6, 29.1, 29.2, 29.3, 29.4, 29.4, 29.5, 29.5, 29.8, 31.2, 31.9, 68.1, 80.0, 129.8, 130.0, 155.0. MS (ESI-TOF) m/z 1230.8 [M+Na]+.

Reference： [1]Patent: US2009/253733,2009,A1 .Location in patent: Page/Page column 9

18
[ 75-77-4 ]
[ 53123-88-9 ]
[ 331810-10-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With 1H-imidazole; In ethyl acetate; at 0 - 5℃; for 2h;	Respectively rapamycin (5.5mmol, 5.0g) and imidazole (1.5g) was added to ethyl acetate (80mL), cooled to 0-5 C after the addition was complete, Was added dropwise trimethylsilyl chloride (40mmol, 4.3g), incubated for 2 hours. When the silicon ether to form a double protection products, dilute sulfuric acid was added to the reaction mixture was poured (15mL, 1N H 2 SO 4), and stirring was continued for about 16h the reaction, after the completion of the reaction, the reaction liquid were washed with saturated sodium bicarbonate, saturated brine, the organic layer was Dried over anhydrous sodium sulfate, and evaporated to dryness to give a white foamy solid 5.1g, yield: 95%
91%	With 1H-imidazole; In ethyl acetate; at 0 - 5℃; for 0.5h;	The reaction flask was sequentially added with ethyl acetate (1.7 L) and rapamycin.(140g, compound 1),Stir and dissolve. Add imidazole (47g), cool down to 0 ~ 5 C,TMS-Cl (66.5g) was added dropwise, and the reaction was controlled at 0 to 5 C for 0.5 h.The TLC monitors until the reaction of the starting material is completed. Adjust the dilute sulfuric acid to pH=1,Continue to react for 2.5 h, adjust to pH=7 with imidazole, and wash with saline.Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate.Concentrate by silica gel column chromatography(Mobile phase conditions: ethyl acetate / n-hexane gradient elution)Purified white compound 2(Yield: 91%).
81%		Example 1 : 42-0-[MorphoIinosulfonylcarbamyl]-rapamycinStep-1: 31-O-TMS-rapamycinTo an ice-cooled solution of rapamycin (5.5 g, 6 mmol) and imidazole (3.2 g, 48 mmol) in ethyl acetate (30 mL) was added chlorotrimethylsilane (5.2 g, 48 mmol) dropwise by syringe. The reaction mixture was stirred at room temperature for 30 minutes. Upon completion of the reaction, sulfuric acid (0.5 N, 24 mL) was added dropwise. The reaction mixture was stirred at O0C for 1.5 h, diluted with brine, and extracted with ethyl acetate (3 x 30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography eluted with ethyl acetate-petroleum ether (1 :1) to obtain 31 -O-TMS- rapamycin (4.8 g, 81%).

47%	With 1H-imidazole; In ethyl acetate; at 0 - 5℃; for 2h;	rapamycin (11mmol, 10.0g) and imidazole (3.0g) was added to ethyl acetate (160mL) solution, after the addition was complete and cooled to 0-5 deg.] C, was added dropwise trimethylsilyl chloride (mmol, 8.6 g), incubated for 2 hours.When the silicon ether to form a double protection products, dilute sulfuric acid was added to the reaction mixture was poured (25mL, 1NH2SO4), Stirring was continued for about 16h the reaction, after the completion of the reaction, the reaction liquid were washed with saturated sodium bicarbonate, saturated brine, the organic layer was dried over anhydrous sodium sulfate, and evaporated to dryness to give 10.2 g of white foamy solid, yield 47%.
	With 1H-imidazole; In dichloromethane; for 6h;	Preparation Example 2; Preparation of Compound Y31; 400 mg (0.44 mmol) of rapamycin and 449 mg (6.6 mmol) of imidazole were dissolved in 20 ml of double-distilled CH2Cl2, and 0.22 ml (1.76 mmol) of trimethyl chlorosilane was added dropwise therein. Then, the reaction was traced by TLC, and stirred for about 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography eluting with petroleum ether/acetone (volume ratio, 4:1) to give the rapamycin-31-OTMS (total weight: 277 mg).573 mg of the compound 31 (4.34 mmol) and 453 mg (1.53 mmol) of triphosgene were added into a 50 ml round bottomed flask, and 30 ml of double-distilled CH2Cl2 was added therein under a nitrogen atmosphere, followed by dropwise addition of 377 mul (4.67 mmol) of dry pyridine under ice-water bath. After the dripping, the mixture was warmed up to room temperature naturally and the reaction continued for 2 hours. After that, 277 mg (0.28 mmol) of rapamycin-31-OTMS was added therein. The reaction was completed 4 hours later, as monitored by TLC. The reaction mixture was neutralized to be weak acidic by adding 1N HCl, extracted by dichloromethane. The dichloromethane extract was washed by water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by column chromatography eluting with petroleum ether/acetone (volume ratio, 4:1) to give a compound Y44 (total weight: 240 mg).240 mg of the compound Y44 was dissolved in 4 ml of THF, and at a temperature of 0-5 C., 1.7 ml of 2NH2SO4 was added dropwise therein. The reaction was traced by TLC until the reaction was completed, and then the reaction mixture was neutralized to be weak basic by adding 5% NaHCO3. The mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed by saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with petroleum ether/acetone (volume ratio, 1.5:1) to give a compound Y31 (total weight, 120 mg).
	With 1H-imidazole; In dichloromethane; for 6h;	400mg (0.44mmol) of rapamycin and 449mg (6.6mmol) of imidazole were dissolved in 20ml of double-distilled CH2Cl2, and 0.22ml (1.76mmol) of trimethyl chlorosilane was added dropwise therein. Then, the reaction was traced by TLC, and stirred for about 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography eluting with petroleum ether/acetone (volume ratio, 4:1) to give the rapamycin-31-OTMS (total weight: 277mg).

Reference： [1]Patent: CN104341434,2016,B .Location in patent: Paragraph 0210-0212
[2]Patent: CN109206441,2019,A .Location in patent: Paragraph 0066; 0067; 0068
[3]Patent: WO2009/131631,2009,A1 .Location in patent: Page/Page column 31
[4]Patent: CN104530081,2016,B .Location in patent: Paragraph 0109-0111
[5]Journal of Medicinal Chemistry,2010,vol. 53,p. 452 - 459
[6]Patent: US2011/166172,2011,A1 .Location in patent: Page/Page column 11-12
[7]Patent: EP2351757,2011,A1 .Location in patent: Page/Page column 13-14

19
[ 1192722-09-0 ]
[ 53123-88-9 ]
[ 1192722-11-4 ]

Yield	Reaction Conditions	Operation in experiment
45%	With 2,6-dimethylpyridine; In toluene; at 0 - 20℃; for 2.5h;Inert atmosphere;	Step-3: 42-O-r2,2,2-Trifluoro-l-(4-(2-hvdroxyethvnpiperidin-l-vnethyll rapamycin (M)To a solution of rapamycin (500 mg, 0.55 mmol) and 2,6-lutidine (250 mg, 2.5 mmol) in toluene (5 mL) at room temperature under nitrogen was added 2-(l-(2,2,2-trifluoroacetyl)piperidin-4-yl)ethyl trifluoromethanesulfonate (0.78 g, 2.2 mmol). The reaction mixture was stirred at room temperature for 30 min, O0C for 2 h, then concentrated. The crude product was purified by silica gel chromatography eluted with hexane-ethyl acetate (1 :1 to 1 :2) to give the title compound as a light yellow solid (350 mg, 45%). m/z (relative intensity, %): 1119 [M-I] +', 1143 [M+Na]+

Reference： [1]Patent: WO2009/131631,2009,A1 .Location in patent: Page/Page column 40

20
[ 106114-40-3 ]
[ 53123-88-9 ]
[ 1192722-13-6 ]

Yield	Reaction Conditions	Operation in experiment
58%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; at 60℃; for 1.5h;	Example 10Step-1: 42-O-[3-Iodopropyll-rapamvcin CN)To a solution of rapamycin (0.5 g, 0.55 mmol) in dichloromethane (2 mL) was added Hunig's base (N,N-diisopropylethylamine, 4.93 mL, 28.4 mmol) and 3-iodopropyltrifluoromethanesulfonate (1.35 g, 4.36 mmol) sequentially. The reaction mixture was heated to 600C, stirred for 1.5 h, and diluted with ethyl acetate (50 mL). The organic layer was washed with 1 N aqueous HCl (50 mL), water (50 mL), and brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography eluted with ethyl acetate-hexane (2:3) to afford the intermediate N (0.34 g, 58%).

Reference： [1]Patent: WO2009/131631,2009,A1 .Location in patent: Page/Page column 41

21
[ 53123-88-9 ]
α-methyl-6-nitropiperonylol succinimidyl carbonate [ No CAS ]
[ 1261297-65-7 ]

Yield	Reaction Conditions	Operation in experiment
36%	dmap; In dichloromethane; at 20℃; for 24h;Inert atmosphere;	Under argon, rapamycin (Rap) 1 (20.0 mg, 0.0219 mmol) was dissolved in dry DCM (0.6 ml). DMAP (5.4 mg, 0.0438 mmol) and NPOC-NHS 2 (39.0 mg, 0.109 mmol) were added. The reaction mixture was stirred at rt for 24 h, the volatiles were evaporated, and the product was purified by column chromatography on Si02 (eluted with DCM/ethyl acetate 10: 1 , 5 : 1 , 2: 1 , 1 :1), delivering 9.1 mg (36% yield) of NPOC-Rap 3 as a light yellow solid. NMR (400 MHz, CDC13) delta 7.48 (s, 1H), 7.05 (s, 1H), 6.44-6.03 (m, 7H), 5.94-5.83 (m, 1H), 5.60-5.47 (m, 1H), 5.43 (m, 1H), 5.38-5.31 (m, 1H), 5.20-5.08 (m, 1H), 4.50-4.38 (m, 1H), 4.14-4.09 (m, 2H), 3.98-3.73 (m, 2H), 3.67-3.55 (m, 2H), 3.35-3.31 (m, 7H), 3.13-3.03 (m, 5H), 2.87-2.50 (m, 3H), 2.40-2.11 (m, 2H), 2.03-1.52 (m, 15H), 1.47-1.32 (m, 6H), 1.24-0.86 (m, 24H); MS calcd for [M + Na]+ C6iHg6N2NaOi9 1 173.5723, found 1 173.7

Reference： [1]Journal of the American Chemical Society,2011,vol. 133,p. 420 - 423
[2]Patent: WO2012/24558,2012,A2 .Location in patent: Page/Page column 35

22
[ 1296664-71-5 ]
[ 53123-88-9 ]
[ 1296664-70-4 ]

Yield	Reaction Conditions	Operation in experiment
100%		Example-15: Preparation of rapamycin 42-ester with 5-methyl-2, 2-diphenyl-l,3- dioxane-5-carboxylic acid. Formula- (Hd3)In a flask, (116mg) Benzoic 5-methyl-2,2-diphenyl-l,3-dioxane-5-carboxylic anhydride was dissolved into 3.5 ml toluene. The reaction mass was cooled at 0-10 C and subsequently (35mg) N, N-dimethyl amino pyridine (DMAP) was added and stirred for 5 min. Then a solution of (66mg) rapamycin in 4 ml toluene was added and further stirred for 7 hrs at 25-30 C. After completion of the reaction toluene and water were added, layer was separated. The toluene layer was washed with NaHCC>3 solution and water. Dry it by adding sodium sulfate and concentrate it on rotavapour to obtain yellow colored oily compound.Weight: 145 mg (Quantitative)ESI MS =1194.9 [M]+(+ve mode)

Reference： [1]Patent: WO2011/51960,2011,A2 .Location in patent: Page/Page column 28

23
[ 1315553-35-5 ]
[ 53123-88-9 ]
[ 1316755-19-7 ]

Yield	Reaction Conditions	Operation in experiment
47.8%	dmap; In dichloromethane; at 0 - 5℃; for 18.25h;	Example-6Preparation of Tem<strong>[53123-88-9]sirolimus</strong> Acetal; <strong>[53123-88-9]Rapamycin</strong> (1.0 g) and anhydride (5.3 g) obtained in Example-5 were added to CH2Cl2 (10 ml) at 20-25 C. The mixture was then cooled to 0-5 C. and a solution of DMAP (1.5 g) in CH2Cl2 (5 ml) was added in 15 minutes. The reaction mixture was stirred at 0-5 C. for 18 hours. The reaction mixture was washed with DM water (10 ml). The organic layer was washed with 0.5N H2SO4 (15 ml), 5% aqueous NaHCO3 (20 ml) and DM water (10 ml). The organic layer was concentrated to dryness and the residue was purified by flash chromatography on silica gel using acetone-dichloromethane (2:23) as eluent to obtain title compound (0.6 g, 47.8%).13C NMR (100 MHz, CDCl3) delta 17.74 & 19.20 (CH3), 41.99 & 42.40 (C), 57.53 & 57.88 (OCH3), 101.66 &101.77 (CH), 113.51 & 113.68 (ArCH), 127.39 &127.60 (ArCH), 173.56 & 177.47 (CO; ester)IR (KBr, cm-1) 1725M/z (ES+) 1166 [M+NH4]30 M/z (ES-) 1147 [M-H]-

Reference： [1]Patent: US2011/184167,2011,A1 .Location in patent: Page/Page column 11-12

24
[ 69739-34-0 ]
[ 53123-88-9 ]
[ 1334337-70-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane; at 20℃; for 1h;	To a solution of rapamycin (999 mg, 1.09 mmol) and anhydrous Et3N (0.6 mL, 4.45 mmol) in anhydrous CH2Cl2 (3 mL) was added TBSOTf (0.85 mL, 3.79 mmol). The solution was stirred for 1 h at rt, and then quenched with H2O. The resulting mixture was diluted with EtOAc (120 mL), washed with saturated NaHCO3 and brine, dried and concentrated in vacuo. The crude residue was subjected to silica gel column chromatography (hexane-EtOAc, 8:1) to afford 2 (1.37 g, 100%) as a yellow solid: 1H NMR (400 MHz, CDCl3): delta 6.39-5.82 (m, 4 H), 5.52-4.91 (m, 4 H), 4.45-3.98 (m, 2 H), 3.83 (d, J = 4.0 Hz, 1 H), 3.40 (s, 3 H), 3.27 (s, 3 H), 3.10 (s, 3 H), 2.89-2.83 (m, 1 H), 2.66-2.40 (m, 3 H), 2.23-2.19 (m, 3 H), 1.70 (s, 3 H), 0.17-0 (m, 18 H); 13C NMR (100 MHz, CDCl3): delta 210.3, 206.6, 197.9, 169.5, 167.0, 139.3, 139.0, 136.6, 132.0, 130.8, 127.4, 126.7, 126.4, 101.7, 86.6, 84.3, 83.2, 78.0, 75.7, 74.3, 67.7, 58.1, 57.8, 56.1, 51.4, 45.8, 44.1, 41.4, 40.8, 40.6, 40.2, 38.2, 36.8, 35.7, 34.0, 33.9, 33.0, 32.0, 30.1, 27.1, 26.6, 26.3, 26.0, 25.9, 25.8, 25.7, 24.9, 22.0, 21.0, 19.3, 18.2, 18.1, 15.7, 15.5, 14.0, 13.9, 11.0, -2.5, -3.2, -4.5, -4.6, -4.7, -4.9; HR-ESIMS calcd for C69H121O13NSi3Na [M + Na]+ 1278.8043, found 1278.8049.
100%	With triethylamine; In dichloromethane; at 20℃; for 1h;	To a solution of rapamycin (999 mg, 1.09 mmol) and anhydrous triemylarnine (Et3N) (0.6 mL, 4.45 mmol) in anhydrous dichloromethane (CH2C12) (3 mL) is added tert- butyldimethylsilyl triflate (TBSOTf) (0.85 mL, 3.79 mmol). The solution is stirred for 1 hour at room temperature and quenched with water. The resulting mixture is diluted with ethyl acetate (EtOAc) (120mL), washed with saturated sodium bicarbonate (NaHC03) and brine, and dried and concentrated in vacuo. The crude residue is subjected to silica gel column chromatography (Hexanes/EtOAc, 8:1) to afford 2 (1.37 g, 100) as a yellow solid: 1H NMR (400 MHz, CDC13): delta 6.39-5.82 (m, 4 H), 5.52-4.91 (m, 4 H), 4.45-3.98 (m, 2 H), 3.83 (d, 7- 4.0Hz, 1 H), 3.40 (s, 3 H), 3.27 (s, 3 H). 3.10 (s. 3 H), 2.89-2.83 (m, 1 H), 2.66-2.40 (m, 3 H), 2.23-2,19 (m, 3 H), 1.70 (s, 3 H), 0.17-0 (m, 18 H); 13C NMR (100 MHz, CDC13): delta 210.3, 206.6, 197.9, 169.5, 167.0, 139.3, 139.0, 136.6, 132.0, 130.8, 127.4, 126.7, 126.4, 101.7, 86.6, 84.3, 83.2, 78.0, 75.7, 74.3, 67.7, 58.1, 57.8. 56.1, 51.4. 45.8, 44.1. 41.4, 40.8, 40.6, 40.2, 38.2, 36.8, 35.7, 34.0. 33,9, 33.0, 32.0, 30.1, 27.1, 26.6, 26.3, 26.0, 25.9, 25.8, 25.7, 24.9, 22.0, 21.0, 19.3, 18.2,18.1,15.7,15.5,14.0,13.9,11.0, -2.5, -3.2, -4.5, -4.6, -4.7, -4.9; HR-ES1MS calcd for C69H121013NSi3Na [M+Na] 1278.8043, found 1278.8049.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 5070 - 5072
[2]Patent: WO2012/75048,2012,A2 .Location in patent: Page/Page column 68

25
[ 1255792-06-3 ]
[ 53123-88-9 ]
[ 1360453-31-1 ]

Yield	Reaction Conditions	Operation in experiment
41%	dmap; In dichloromethane; at 20℃; for 24h;	PEGylated, caged rapamycin 12 was synthesized by linking rapamycin 1 to a photocleavable PEG group of 500 and 5,000 Da, The carbonate caging group 9 was selectively reacted with the C-40 hydroxy group of rapamycin 1 in the presence of DMAP as a catalyst, providing the caged rapamycin 10 in 41% yield. The alkyne moiety in 10 was then reacted with the 5000 Da PEG azide reagent 11 (or a corresponding 500 Da PEG azide reagent) in a [3+2] cycloaddition reaction, providing the PEGylated, caged rapamycin 12. The PEGylated (500 Da) rapamycin analog was characterized by NMR and MS.

Reference： [1]Chemical Communications,2015,vol. 51,p. 5702 - 5705
[2]Patent: WO2012/24558,2012,A2 .Location in patent: Page/Page column 37

26
[ 4136-95-2 ]
C₇H₁₃BO₄ [ No CAS ]
[ 53123-88-9 ]
C₅₈H₉₀BNO₁₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74.8%		2) Add 0.24 g (1.42 mmol) of the intermediate II-1, 20 mL of dichloromethane, 0.28 g (2.18 mmol) of N,N-diisopropylethylamine, and 0.32 g (1.31 mmol) of 2,4,6-trichlorobenzoyl chloride to a 100 mL four-mouth bottle to yield a reaction solution. Stir the solution in the presence of nitrogen gas at the temperature of 14C for 4 h. Cool the reaction solution to the temperature of -10C, add 1.00 g (1.09 mmol) of rapamycin and 0.27 g (2.18 mmol) of DMAP to the reaction solution, and heat the reaction solution to the temperature of 14C for reaction. After the reaction lasts for 14 h, add 30 mL of water to the reaction solution while stirring to form a mixture. Thereafter, transfer the mixture to a separating funnel for separating an organic phase from a water phase. Wash the organic phase by using a 2N sulfuric solution (10 mL×2), water (10 mL), a 5% sodium bicarbonate aqueous solution (10 mL), and saturated brine (10 mL), respectively, and dry the organic phase by using anhydrous magnesium sulfate. Filter, precipitate, and separate a resulting product by using silica gel column chromatography. 0.31 g of a white solid intermediate III-1 is obtained, and the yield thereof is 74.8% (according to the amount of rapamycin participating in the reaction).

Reference： [1]Patent: EP2662377,2013,A1 .Location in patent: Paragraph 0023

27
[ 4136-95-2 ]
C₅₈H₉₀BNO₁₆ [ No CAS ]
[ 53123-88-9 ]
C₆₂H₉₆BNO₁₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65.6%		2) Add 0.32 g (1.42 mmol) of the intermediate II-2, 20 mL of dichloromethane, 0.28 g (2.18 mmol) of N,N-diisopropylethylamine, and 0.32 g (1.31 mmol) of 2,4,6-trichlorobenzoyl chloride to a 100 mL four-mouth bottle to yield a reaction solution. Stir the solution in the presence of nitrogen gas at the temperature of 14C for 4 h. Cool the reaction solution to the temperature of -10C, add 1.00 g (1.09 mmol) of rapamycin and 0.27 g (2.18 mmol) of DMAP to the reaction solution, and heat the reaction solution to the temperature of 14C for reaction. After the reaction lasts for 14 h, add 30 mL of water to the reaction solution while stirring to form a mixture. Thereafter, transfer the mixture to a separating funnel for separating an organic phase from a water phase. Wash the organic phase by using a 2N sulfuric solution (10 mL×2), water (10 mL), a 5% sodium bicarbonate aqueous solution (10 mL), and saturated brine (10 mL), respectively, and dry the organic phase by using anhydrous magnesium sulfate. Filter, precipitate, and separate a resulting product by using silica gel column chromatography. 0.40 g of a white solid intermediate III-2 is obtained, and the yield thereof is 65.6% (according to the amount of rapamycin participating in the reaction).

Reference： [1]Patent: EP2662377,2013,A1 .Location in patent: Paragraph 0026

28
C₇H₁₃BO₄ [ No CAS ]
[ 53123-88-9 ]
C₅₈H₉₀BNO₁₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74.8%		2) Add 0.24 g (1.42 mmol) of the intermediate II-1, 20 mL of dichloromethane, 0.28 g (2.18 mmol) of N,N-diisopropylethylamine, and 0.32 g (1.31 mmol) of 2,4,6-trichlorobenzoyl chloride to a 100 mL four-mouth bottle to yield a reaction solution. Stir the solution in the presence of nitrogen gas at the temperature of 14 C. for 4 h. Cool the reaction solution to the temperature of -10 C., add 1.00 g (1.09 mmol) of rapamycin and 0.27 g (2.18 mmol) of DMAP to the reaction solution, and heat the reaction solution to the temperature of 14 C. for reaction. After the reaction lasts for 14 h, add 30 mL of water to the reaction solution while stirring to form a mixture. Thereafter, transfer the mixture to a separating funnel for separating an organic phase from a water phase. Wash the organic phase by using a 2N sulfuric solution (10 mL×2), water (10 mL), a 5% sodium bicarbonate aqueous solution (10 mL), and saturated brine (10 mL), respectively, and dry the organic phase by using anhydrous magnesium sulfate. Filter, precipitate, and separate a resulting product by using silica gel column chromatography. 0.31 g of a white solid intermediate III-1 is obtained, and the yield thereof is 74.8% (according to the amount of rapamycin participating in the reaction).

Reference： [1]Patent: US2013/296550,2013,A1 .Location in patent: Paragraph 0030

29
C₁₁H₁₉BO₄ [ No CAS ]
[ 53123-88-9 ]
C₆₂H₉₆BNO₁₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65.6%		2) Add 0.32 g (1.42 mmol) of the intermediate II-2, 20 mL of dichloromethane, 0.28 g (2.18 mmol) of N,N-diisopropylethylamine, and 0.32 g (1.31 mmol) of 2,4,6-trichlorobenzoyl chloride to a 100 mL four-mouth bottle to yield a reaction solution. Stir the solution in the presence of nitrogen gas at the temperature of 14 C. for 4 h. Cool the reaction solution to the temperature of -10 C., add 1.00 g (1.09 mmol) of rapamycin and 0.27 g (2.18 mmol) of DMAP to the reaction solution, and heat the reaction solution to the temperature of 14 C. for reaction. After the reaction lasts for 14 h, add 30 mL of water to the reaction solution while stirring to form a mixture. Thereafter, transfer the mixture to a separating funnel for separating an organic phase from a water phase. Wash the organic phase by using a 2N sulfuric solution (10 mL×2), water (10 mL), a 5% sodium bicarbonate aqueous solution (10 mL), and saturated brine (10 mL), respectively, and dry the organic phase by using anhydrous magnesium sulfate. Filter, precipitate, and separate a resulting product by using silica gel column chromatography. 0.40 g of a white solid intermediate III-2 is obtained, and the yield thereof is 65.6% (according to the amount of rapamycin participating in the reaction).

Reference： [1]Patent: US2013/296550,2013,A1 .Location in patent: Paragraph 0033

30
[ 53123-88-9 ]
[ 169119-33-9 ]

Yield	Reaction Conditions	Operation in experiment
45%		To a mixture solution of rapamycin (2.6 g, 2.8 mmol) and2,6-lutidine (1.2 g, 11.3 mmol) in dichloromethane (DCM)(30.0 mL) was added trifluoromethanesulfonic anhydride(2.4 g, 8.5 mmol) dropwise at 0C. The mixture was stirredat 0C for 2 h. Water was added to quench the reaction. Thesolution was extracted with dichloromethane; the organic layerwas washed with saturated NaHCO3 aqueous solution andbrine, dried over Na2SO4, filtered, and evaporated. Sodiumazide (0.18 g, 8.5 mmol) was added gradually to the solution ofresidue in acetone (60 mL). The reaction mixture was stirredvigorously at 25C for 6 h. The reaction mixture was dilutedwith EtOAc and washed thoroughly with brine, dried overNa2SO4, filtered, and concentrated. Silica gel chromatography(PE/EtOAc=3 : 1) of the crude mixture afforded 2 (1.2 g,45%).
	With sodium azide; 2,6-di-tert-butyl-4-methylpyridine; trifluoromethylsulfonic anhydride; In dichloromethane;	[00512] Reference for the synthesis of the known monomer: Wang, B.; Zhao, J.Z. 2014; <strong>[53123-88-9]Rapamycin</strong> analogs and methods for making same. WO2014082286. Hangzhou Zylox Pharma Co., Ltd, which is incorporated by reference in its entirety.

Reference： [1]Chemical and Pharmaceutical Bulletin,2016,vol. 64,p. 346 - 355
[2]Tetrahedron Letters,2013,vol. 54,p. 6999 - 7003
[3]Patent: WO2014/82286,2014,A1
[4]Patent: US2015/51242,2015,A1
[5]Patent: WO2018/204416,2018,A1 .Location in patent: Paragraph 00512

31
[ 3685-22-1 ]
[ 53123-88-9 ]
[ 1508263-14-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 2h;	Compound 5 was prepared by dissolving 94 mg rapamycin in 2.5 mL methylene chloride in a 7.5-mL borosilicate glass vial with a stir bar and capped. The solution was stirred at ambient temperature for two minutes, then 78.0 mg 4-N,N-dimethylaminopyridine was added and allowed to dissolve. 118 mg racemic 4-hydroxycylohexane carboxyl acid and 204 mg N,N-dicyclohexylcarbodiimide were added in the reaction mixture. The reaction continued stirring at ambient temperature for 2 hours. Synthesis of product was verified by taking 2 muEpsilon of the reaction mixture and diluting in 0.5 mL acetonitrile and analyzed by High Resolution LCMS.

Reference： [1]Patent: WO2013/182503,2013,A1 .Location in patent: Page/Page column 10; 11

32
[ 138-59-0 ]
[ 53123-88-9 ]
[ 1504576-28-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide at 20℃; for 19h;	IIF Rapamycin 40-O-Cyclic Hydrocarbon Ester with Shikimic Acid (Compound 6) Compound 6 was prepared by dissolving 14.0 mg rapamycin in 100 methylene chloride contained in a 1.5-mL HPLC glass vial with stirring bar and capped. The solution was stirred at ambient temperature for two minutes, then 1.0 mg 4-N,N-dimethylaminopyridine was added. In a second 1.5-mL HPLC glass vial, 2.0 mg shikimic acid and 100 dimethylformamide were combined and mixed. Using a syringe, the shikimic acid/dimethylformamide solution mixture was added dropwise into the rapamycin solution. 3.0 mg N,N-dicyclohexylcarbodiimide was added and the reaction was continued with stirring for 19 hours at ambient temperature. Synthesis of product was verified by taking 2 of the reaction mixture and diluting in 0.5 mL acetonitrile and analyzed by High Resolution LCMS.

Reference： [1]Current Patent Assignee: BIOTRONIK SE & Co. KG - WO2013/182503, 2013, A1 Location in patent: Page/Page column 11

33
[ 75-77-4 ]
[ 53123-88-9 ]
[ 331810-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-imidazole; In ethyl acetate; at 0 - 5℃; for 1.5h;	To a flask containing <strong>[53123-88-9]Rapamycin</strong> (II) (2.5 g, 2.73 mmole) was added ethyl acetate (75 mL). The resulting solution was cooled to 0-5 C., and then imidazole (0.75 g, 10.93 mmole) was added therein. After the resulting solution was stirred to dissolve the added imidazole completely, trimethyl chlorosilane (1.1 g, 10.11 mmole) was added therein dropwise. Then, the resulting solution was stirred at 0-5 C. for 1.5 h, and the reaction was monitored by TLC (ethyl acetate:hexane=1:5). When there was no starting material observed, 0.5N of a sulfuric acid solution (5 mL) was added dropwise into the resulting solution, and the resulting solution was stirred at 0-5 C. for 2 hr and monitored by TLC (ethyl acetate:hexane=1:5). After ethyl acetate (200 mL) was added into the resulting solution, the organic layer was successively washed with a NaCl saturated solution (100 mL), a NaHCO3 saturated solution (100 mL), water?100 mL) and a NaCl saturated solution (100 mL), dried over anhydrous sodium sulfate and concentrated to obtain a crude product of 31-trimethylsilylether <strong>[53123-88-9]Rapamycin</strong> (V-a) (2.758 g). The HPLC analysis data indicated that the crude product contained 94.5% (area %) of 31-trimethylsilylether <strong>[53123-88-9]Rapamycin</strong> (V-a) and 5.5% of <strong>[53123-88-9]Rapamycin</strong> (II).
	With 1H-imidazole; In ethyl acetate; at 0℃; for 0.5h;	General procedure: Rapa (5 g, 5.5 mmol) and imidazole (3.74 g, 55 mmol) were dissolved in ethyl acetate (50 mL) and the solution was stirred at 0 C, then a solution of trimethylchlorosilane (2.98 g, 27.5 mmol) in ethyl acetate (5 mL) was added into the reaction solution within 30 min. After the Rapa was transformed into Rapa-31,42-bis-OTMS, dilute sulfuric acid solution (0.5 mol/L, 10 mL) was slowly added dropwise to the reaction mixture within 3 h. The organic layer was washed three times with water. The organic layer was concentrated and dried over MgSO4. The residue was purified by chromatography on silica gel (EA/PE v/v = 1:5) to obtain Rapa-31-OTMS (4.7 g, 4.8 mmol, yield 88%).
	With 1H-imidazole; In ethyl acetate; at 0 - 5℃; for 0.5h;	A 2g (2.19mmol) was dissolved in 25ml dry rapamycin in ethyl acetate, cooled to 0-5 .Imidazole was charged to the reaction mixture 1.50g (22mmol), 30min was slowly added dropwise 1.2g (11mmol) 5ml ethyl acetate solution of trimethylsilyl chloride, to complete conversion to the intermediate 2.3h the reaction mixture was slowly added dropwise within 0.5 mol / H2SO4 solution 10ml L, the intermediate 2 to be completely transformed by column chromatography extraction to give 1.3g white foam product intermediate 3.

		9 g of rapamune, 4.5 g of 2,6-dimethylpyridine, 100 ml of tetrahydrofuran was added to a 250 ml three-necked flask, the ice salt was cooled in a water bath, stirred and dissolved. After 5 hours, 7 ml of (CH3)3SiCl was added dropwise, and the reaction was carried out for 3 hours. After TLC, the reaction was carried out without rapamune spots. The double protection reaction was completed and 5 ml of HCl was added dropwise. After 5 hours of reaction, TLC detection, unparalleled protection of rapamune spots, the hydrolysis reaction is completed. The reaction solution was extracted with 200 ml of ethyl acetate, and the ethyl acetate layer was washed with 50 ml of water and 50 ml of NaHCO3 saturated solution, washed with 50 ml of brine. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried over anhydrous Na2SO4. Ethyl acetate was distilled off under reduced pressure to give a single protection of 9.6 g.
	With 1H-imidazole; In ethyl acetate; at 0 - 10℃;Inert atmosphere;	Under N2 protection, 91.4g rapamycin,1200 ml of ethyl acetate and 20.4 g of imidazole were added to a 2 L glass reaction flask.Stir and cool down to about 0 C;32.6 g of trimethylchlorosilane was added dropwise at a temperature of 0 to 10 C.Continue the insulation reaction,TLC was used to detect the progress of the reaction until the rapamycin reaction was complete;Control the temperature 0 ~ 10 C, slowly add 1N hydrochloric acid 110mL, after the completion of the addition;TLC detects the progress of the reaction until the rapamycin double protection reaction is complete.Add 540ml of pure water and dispense.The aqueous layer was extracted twice with ethyl acetate 300 ml/time;Combine the organic layers with 540 ml of saturated aqueous NaHCO3,Wash with 540 ml of saturated saline solution,Drying over anhydrous sodium sulfate for 4 hours; filtering; evaporating ethyl acetate under reduced pressure;A milky white blister solid, 31-hydroxy protected rapamycin;The yield was 92.9%.
	With 1H-imidazole; In ethyl acetate; for 0.5h;Cooling with ice;	<strong>[53123-88-9]Rapamycin</strong> (5.00 g) and imidazole (1.86 g) were dissolved in ethyl acetate (100 mL), and trimethylchlorosilane (2.97 g) was added dropwise with cooling in an ice water bath. After the addition was completed, cooling in an ice water bath was continued. The reaction was stirred for 30 minutes and TLC showed the material disappeared completely.
	With 1H-imidazole; In ethyl acetate; for 0.5h;Cooling with ice;	<strong>[53123-88-9]Rapamycin</strong> (5.00 g, purity 98.4%),Imidazole (1.86 g) was dissolved in ethyl acetate (100 mL).Trimethylchlorosilane (2.97 g) was added dropwise while cooling in an ice water bath.After the completion of the dropwise addition, the reaction was stirred for 30 minutes while cooling in an ice water bath.TLC showed that the starting material completely disappeared.The ice water bath was cooled and added with 0.5 M hydrochloric acid (8 mL).The reaction was stirred and TLC showed that the original small polar product completely disappeared.The main product polarity is between rapamycin and it. Stop the reaction, separate the reaction solution,The organic phase was washed successively with saturated sodium bicarbonate and brine.Dry over anhydrous sodium sulfate and concentrate under reduced pressure.28-O-TMS rapamycin (Intermediate B-1, 5.89 g) was obtained as a white solid.

Reference： [1]Patent: US2014/58081,2014,A1 .Location in patent: Paragraph 0044
[2]Pharmaceutical Research,2014,vol. 31,p. 706 - 719
[3]Molecules,2014,vol. 19,p. 7770 - 7784
[4]Archiv der Pharmazie,2016,vol. 349,p. 428 - 441
[5]Patent: CN105461738,2016,A .Location in patent: Paragraph 0093; 0094
[6]Patent: CN106146536,2016,A .Location in patent: Paragraph 0016; 0028; 0029
[7]Archiv der Pharmazie,2018,vol. 351
[8]Patent: CN108948046,2018,A .Location in patent: Paragraph 0019; 0036; 0037; 0039; 0040; 0042; 0043; 0046
[9]Patent: CN109776570,2019,A .Location in patent: Paragraph 0062; 0063; 0064; 0065
[10]Patent: CN109776569,2019,A .Location in patent: Paragraph 0059-0064

34
[ 53123-88-9 ]
[ 106-96-7 ]
[ 1612887-84-9 ]

Yield	Reaction Conditions	Operation in experiment
68%	With caesium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 30h;	To a stirred solution of <strong>[53123-88-9]Rapamycin</strong> (3 g. 3.2 mmol) and Cs2CO3 (3.2 g. 9.6 mmol) indried DMF (90 mL) was added Nal (1.5 g. 9.6mmol) and 3-bromoprop-1-yne (1.2 g. 9.6 mmol).The reaction mixture was stirred at rt for 30 hours. Upon the completion of reaction. 300 mL water was added in and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed by brine (300 mL) and dried over anhydrous Na2SO4. After concentration the residue was purified with silica gel chromatography (50% to 1 00% of ethyl acetate in petroleum ether as eluent) to give the compound A1 (2.1 g. 68%) as a light green oil.
68%	With caesium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 30h;	To a stirred solution of <strong>[53123-88-9]Rapamycin</strong> (3 g, 3.2 mmol) and Cs2CO3 (3.2 g, 9.6 mmol) in dried PMF (90 mL) was added Nal (1.5 g, 9.6 mmol) and 3-bromoprop-1-yne (1.2 g, 9.6 mmol). The reaction mixture was stirred at rt for 30 hours. Upon the completion of reaction, 300 mL water was added in and extracted with ethyl acetate (200 mL×3). The combined organic layer was washed by brine (300 mL) and dried over anhydrous Na2SO4. After concentration, the residue was purified with silica gel chromatography (50% to 100% of ethyl acetate in petroleum ether as eluent) to give the compound A1 (2.1 g, 68%) as a light green oil. LCM (m/z) ES-950 (M-1)-.

Reference： [1]Patent: WO2014/82286,2014,A1 .Location in patent: Paragraph 29
[2]Patent: US2015/51242,2015,A1 .Location in patent: Paragraph 0058

35
[ 53123-88-9 ]
2-[tert-butyl(diphenyl)silyl]oxy}ethyl trifluoromethansulphonate [ No CAS ]
[ 1314705-20-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydrogencarbonate; methylamine; In dichloromethane; at 20℃;	In a 100 ml single-necked flask,4.50 g of rapamycin and 9.50 g of 2- (t-butyldiphenylsilyl) oxyethyl trifluoromethanesulfonate, respectively,Then add 150ml of dichloromethane, stirred at room temperature, the solution was milky white suspension.Then add methylamine, sodium bicarbonate, stirred at room temperature, the reaction 4 to 5 hours.Concentrate under reduced pressure to give a white foamy solid,Washed with a small amount of petroleum ether, suction filtration, vacuum drying,This gave 4.89 g of the compound of formula (I-a) as a white solid intermediate in 81% yield.
53%	With N-ethyl-N,N-diisopropylamine; In toluene; at 20 - 80℃; for 2h;	To a solution of <strong>[53123-88-9]Rapamycin</strong> (400 mg. 0.43 mmol) and DIPEA (278 mg. 2.15 mmol) in toluene (30 ml) was added intermediate 16 (0.93 g, 2.15 mmol) at rt and stirred at 80 deg for 2 hours. Then 50 mL water was added and extracted with EtOAc (30 mL x 3). The combined organic layer was washed by 0.5 N HCI saturated NaHC03 and brine, dried over anhydrous Na2SO4. After concentration the residue was purified with silica gel chromatography (25% to 40% of EtOAc in petroleum ether as eluent) to give intermediate 17 (280 mg. 53%) give as a white solid.
53%	With N-ethyl-N,N-diisopropylamine; In toluene; at 80℃; for 2h;	To a solution of <strong>[53123-88-9]Rapamycin</strong> (400 mg, 0.43 mmol) and DIPEA (278 mg, 2.15 mmol) in toluene (30 mL) was added intermediate 16 (0.93 g, 2.15 mmol) at rt and stirred at 80 deg for 2 hours. Then, 50 mL water was added and extracted with EtOAc (30 mL×3). The combined organic layer was washed by 0.5 N HCL, saturated NaHCO3 and brine, dried over anhydrous Na2SO4. After concentration, the residue was purified with silica gel chromatography (25% to 40% of EtOAc in petroleum ether as eluent) to give intermediate 17 (280 mg, 53%) give as a white solid. LCMS (m/z) ES- 1194 (M-1)-.

50%	With 2,6-dimethylpyridine; In toluene; at 60 - 70℃; for 6h;	In a single-necked flask of 100ml,Add 5.00g of <strong>[53123-88-9]Rapamycin</strong> and 14.18g of 2-(tert-butyl diphenyl di) oxygen ethyl trifluoromethanesulfonate, and then add 40ml toluene solvent, room temperature stirring, the solution is ivory suspension. Then add the lambda3.53g of 2,6-two methyl pyridine, temperature stirring, control of temperatures between 60c-70c, reaction 6 hours. After cold to room temperature, the reaction solution showed a yellowish suspended solution. The filter removes the solid residue in the reaction solution, and the toluene solution is clarified by light yellow. Wet sample column chromatography, divided into three gradient elution: first with N-hexane as a elution agent, until the elution agent TLC has no toluene absorption point, the volumetric weight ratio of n-hexane and raw material rapamycin used in this gradient is 100250ml/g, and then the mixture of N-hexane and Ethyl acetate (volume ratio controlled within 4:12:1 range) For the elution, TLC is only included in the elution solution of 1 of the tacrolimus intermediates, the intermediate component, the elution to the no TLC elution does not contain according to the Division 1, enters the next gradient; the volume-weight ratio of the mixture of the elution agent used in this gradient is 250550ml/g with that of the raw material rapamycin; Finally, the mixture of ethyl acetate and N-hexane (volume ratio controlled within the 1:110:1 range) C2 (50100l/kg rapamycin) was used as a elution agent to recover the raw material components of rapamycin, a TLC-containing elution solution was collected, and the elution to TLC Elution was not stopped and the removal of mitomycinThe volume-weight ratio of the detergent C2 with the raw material rapamycin was 50100ml/g in this gradient, and the specific elution conditions were shown in table 1. The intermediate component is condensed by decompression and condenses into foam-like white solid 2.51 g (yield: 50), Purity:%,esi-msm/z (%): 1218.67 (100%) [M+na+]+. A white solid-like rapamycin 0.80g (recovery: 16%)
	With (1-ethylpropyl)diisopropylamine; In toluene; at 40℃; for 22.5h;	To a solution of 2-((tert-butyldiphenylsilyl)oxy)ethanol (13.1 g, 43.8 mmol) in toluene (51 g) was added N,N-Diisopropylpentan-3-amine (8.7 g, 50.3 mmol) The clear solution was then cooled to 0C and trifluoromethanesulfonic acid anhydride (12.3 g, 43.8 mmol) was added dropwise such that the temperature was maintained between (-2C - 2C). Following the addition a further portion of toluene (5 g) was used for washing. After 1 .5 h N,N-Diisopropylpentan-3-amine (8.7 g, 50.3 mmol) was added followed by toluene (3 g) and <strong>[53123-88-9]Rapamycin</strong> (10.0 g, 10.9 mmol ) washing with toluene (18 g). The reaction was then heated to 40C and allowed to stir at this temperature for 22.5 h at which point less than 5 Area% <strong>[53123-88-9]Rapamycin</strong> was remaining according to HPLC analysis. The reaction was cooled to ambient temperature and pyridine (1 .0 mL) was then added to quench the reaction which was stirred for a further 30 mins. The reaction was filtered and diluted with isopropyl acetate. The organic solution was washed with 1 M citric acid solution, 10% sodium bicarbonate solution followed by water, dried (MgS04) and concentrated in vacuo. To the crude residue (35.6 g) was added THF (240 mL) and this solution was then added dropwise at 0 C to a HF*pyridine solution (1 :1 , 38.1 g). The reaction was heated to 45 C for 3.5 h then allowed to cool to ambient temperature and diluted with isopropylacetate (300 g). The reaction was then added slowly to an 8% aqueous solution of sodium bicarbonate and further washed with isopropylacetate (250 g). The organic phase was then separated and washed with saturated aqueous sodium chloride solution, dried (MgS04) and concentrated in vacuo. The residue was diluted with isopropylacetate, BHT (0.2% m/m) was added, and the yield of everolimus determined by HPLC analysis against an external standard (6.81 g, 65%).

Reference： [1]Patent: CN104557975,2017,B .Location in patent: Paragraph 0033; 0034
[2]Patent: WO2014/82286,2014,A1 .Location in patent: Paragraph 49
[3]Patent: US2015/51242,2015,A1 .Location in patent: Paragraph 0085
[4]Patent: CN108047265,2018,A .Location in patent: Paragraph 0026; 0027; 0031; 0033; 0039; 0044
[5]Patent: WO2014/203185,2014,A1 .Location in patent: Page/Page column 22; 23; 24; 25; 26; 28; 29

36
[ 7200-25-1 ]
[ 53123-88-9 ]

Yield	Reaction Conditions	Operation in experiment
		Re-suspend sediment by shaking and 10 minute sonication. Lyophilize suspension to produce un-agglomerated Sirolimus/polyarginine powder solid lyophilisate 66 (Flexi-Dry MP) (step 58).

Reference： [1]Patent: US2014/371717,2014,A1 .Location in patent: Page/Page column

37
[ 53123-88-9 ]
[ 159351-69-6 ]

Reference： [1]Patent: WO2014/203185,2014,A1
[2]Patent: WO2016/20664,2016,A1
[3]Patent: CN105254646,2016,A
[4]Patent: CN105254646,2016,A
[5]Patent: CN105254646,2016,A
[6]Patent: CN105254646,2016,A
[7]Patent: WO2016/207205,2016,A1
[8]Patent: CN106146536,2016,A
[9]Patent: CN109776570,2019,A
[10]Patent: CN109776570,2019,A
[11]Patent: CN109776569,2019,A
[12]Patent: CN109776569,2019,A

38
2-(trityloxy)ethyltrifluoromethane sulfonate [ No CAS ]
[ 53123-88-9 ]
42-O-trityl-everolimus [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%		To a 500 ml volumetric flask under atmospheric conditions, 19.1 g of 2- (trityloxy) ethyl trifluoromethanesulfonate of Formula 5, 20 ml of methylene chloride,2,6-dimethylpyridine 4.68 ml was added, and the mixture was stirred at room temperature for 10 minutes.5.0 g of rapamycin of the formula (3) was added and reacted for 16 hours.Ethyl acetate (200 ml) was added to the reaction solution, After cooling to 5 C, the mixture was washed with 100 ml of 5% sodium hydrogencarbonate and 100 ml of 10% aqueous solution of copper sulfate, and then anhydrous magnesium sulfate was added thereto to remove moisture. This was filtered off under reduced pressure, washed with ethyl acetate, and concentrated under reduced pressure. The product was subjected to a Si60 chromatography column under a composition ratio of ethyl acetate / n-hexane (2/3 v / v) mobile phase to obtain 3.4 g (yield 52%) of an intermediate compound of formula (2).
6.85 g	With (1-ethylpropyl)diisopropylamine; In toluene; at 40℃; for 21h;	Step (a) To a solution of 2-(trityloxy)ethanol (10.7 g, 35.2 mmol) in toluene (42.8 g) was added N,N- Diisopropylpentan-3-amine (7.0 g, 40.4 mmol) The clear solution was then cooled to 0C and Trifluoromethanesulfonic acid anhydride (10.0 g, 35.2 mmol) was added dropwise such that the temperature was maintained between (-2C - 2C). After 2 h N,N-Diisopropylpentan-3-amine (7.0 g, 40.4 mmol) was added to the reaction mixture followed by toluene (14.4 g) and <strong>[53123-88-9]Rapamycin</strong> (8.24 g, 8.79 mmol ) washing with toluene (2.4 g). The reaction was then heated to 40 C and allowed to stir at this temperature for 21 h at which point less than 5 Area% <strong>[53123-88-9]Rapamycin</strong> was remaining according to HPLC analysis. The reaction was cooled to ambient temperature and pyridine (0.8 ml_) was then added to quench the reaction which was stirred for a further 30 mins. The reaction was diluted with isopropyl acetate. The organic solution was washed with 1 M citric acid solution, 10% sodium bicarbonate solution followed by water, dried (MgS04) and concentrated in vacuo. The reaction mixture was purified using flash column chromatography (ethyl acetate in heptanes) affording a yellow oil (6.85 g, 65% yield). Step (b) The trityl-protected everolimus derivative (5.0 g, 4.165 mmol) was then dissolved in hexafluoroisopropanol and heated to 58 C for 3.5 h. The reaction was then allowed to cool to ambient temperature and was diluted with ethyl acetate (50 ml_) and concentrated in vacuo. This dilution/concentration procedure was repeated once more and then the crude product was filtered over silica gel (25 g) eluting with heptane/ethyl acetate. Recrystallization from heptanes/ethyl acetate afforded the desired product as white crystals (1 .60 g, 40.1 %). HPLC analysis of the mother liquor against an external standard indicated that a further 12% yield Everolimus was contained therein.

Reference： [1]Patent: KR101529963,2015,B1 .Location in patent: Paragraph 0066-0067
[2]Patent: WO2014/203185,2014,A1 .Location in patent: Page/Page column 26; 27

39
[ 7423-55-4 ]
[ 53123-88-9 ]
42-(3-maleimidopropionyl)-sirolimus [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With dmap; diisopropyl-carbodiimide; In 1,2-dichloro-ethane; at 0 - 2℃; for 2.5h;	A 100 ml 3-neck flask was equipped with a magnetic stirring bar, a dropping funnel and an inside thermometer. The flask was loaded with 500 mg of sirolimus, 120 mg of 3-maleimidopropionic acid and 33 mg of DMAP. The substances were dissolved in 20 ml of dichloroethane and the mixture cooled to 0 C. 0.17 ml of diisopropylcarbodiimide (DIC) was diluted with 5 ml of DCE and then added to the reaction mixture under control of the temperature (0 C. to 2 C.). The reaction was followed by HPLC. After 2.5 h at 0 C., the reaction mixture was diluted with 100 ml of DCM and quenched with 100 ml of a 0.5% NaHCO3 solution. After the phases were separated, the organic phase was washed with 100 ml of 0.1 N HCl solution and 50 ml of brine. The organic phase was dried with sodium sulfate. The solvent was evaporated under reduced pressure and the crude product purified by column chromatography on silica (DCM:methanol//60:1) to give the title compound (220 mg, 206 mmol, 44%) as a colorless solid. (1203) TLC: (DCM:MeOH//10:1), Rf=0.55. (1204) MS (ESI): m/z=1087.53 [M+Na]+.

Reference： [1]Patent: US2015/297738,2015,A1 .Location in patent: Paragraph 1202-1204

40
[ 103935-47-3 ]
[ 53123-88-9 ]
43-O-(2-bromoethyl)oxyrapamycin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-ethyl-N,N-diisopropylamine; In toluene; at 25 - 60℃;	2-Bromoethyl trifluoromethanesulfonate (5.0 g, 19.5 mmol)was added to a solution of rapamycin (6.0 g, 6.6 mmol) andDIPEA (4.2 g, 32.8 mmol) in 100 mL of toluene at 25C. Themixture was stirred at 60C until the reaction completed.The reaction mixture was washed with a saturated NaHCO3solution, water and brine. The organic layer was dried andconcentrated. The residue was purified by flash column chromatography(silica gel, petrol/EA, 5 : 1) to afford the desiredcompound 6 (5.0 g, 75%) as yellow solids. mp:
53.9%	In toluene; at 70℃;	10 g (0.01 mol) of rapamycin (A-1) was poured into a 250 ml flask, the water was removed twice with DCM and then dissolved in 100 ml of toluene,Placed in 70 oil bath temperature 5min,Then 40 g of 1-bromoethyl trifluoromethanesulfonate was added to react,The TLC plate was traced and the reaction was terminated when the bisetherification by-product corresponded to the reactant amount.Extraction with EA, followed by 1 N HCl solution,Saturated sodium bicarbonate, washed with saturated sodium chloride,Drying over anhydrous sodium sulfate. Placed at -20 under the conditions of the preservation of the column.Silica gel column chromatography, wet column,Mobile phase: PE: EA = 3: 1, 1: 1.Toluene was first eluted from the column with petroleum ether and then passed through a column with PE: EA = 3: 1,Finally, 1: 1 through the column. Until the intermediate 2 outflow completely.Rotary evaporation,Finally, 6 g of 43-O- (2-bromoethyl) -oxorapamycin was obtained,Yield: 53.9%.
46.7%	With N-ethyl-N,N-diisopropylamine; In toluene; at 60℃; for 3h;	2-bromoethanesulfonate side chain (25 g, 98 mmol) was added to a 300 mL toluene solution of rapamycin (10 g, 10.9 mmol) and diisopropylethylamine (55 mmol) Add to completion, heating to 60 C reaction 3h. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with saturated hydrochloric acid, saturated sodium bicarbonate and brine, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give a pale yellow solid, which was finally separated by column chromatography to obtain 5.2 g White solid, yield: 46.7%

Reference： [1]Chemical and Pharmaceutical Bulletin,2016,vol. 64,p. 346 - 355
[2]Archiv der Pharmazie,2016,vol. 349,p. 428 - 441
[3]Patent: CN107501294,2017,A .Location in patent: Paragraph 0099; 0100; 0106; 0109; 0113; 0117; 0121; 0125
[4]Patent: CN104341434,2016,B .Location in patent: Paragraph 0151-0152

41
[ 103935-48-4 ]
[ 53123-88-9 ]
43-O-(3-bromopropyl)oxyrapamycin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.3%	With N-ethyl-N,N-diisopropylamine; In toluene; at 60℃; for 3h;	<strong>[53123-88-9]Rapamycin</strong> (8.0 g, 8.7 mmol) and diisopropylethylamine (5.6 g, 44 mmol) were added to a 50 mL toluene solution and a 3-bromopropyl sulfonate side chain (11.8 g, 28.5 mmol ), Plus completed, heated to 60 C reaction 3h. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with hydrochloric acid, saturated sodium bicarbonate and brine, and the organic layer was dried over anhydrous sodium sulfate and evaporated to give a pale yellow solid, which was separated by column chromatography to obtain 4.8 g of white Solid, yield: 53.3%

Reference： [1]Archiv der Pharmazie,2016,vol. 349,p. 428 - 441
[2]Patent: CN104341434,2016,B .Location in patent: Paragraph 0182-0183

42
2-(methoxymethoxy)ethyl trifluoromethanesulfonate [ No CAS ]
[ 53123-88-9 ]
42-O-[2-(methoxymethoxy)ethyl]rapamycin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine; In toluene; at 60℃; for 12h;	To a 100 mL three-necked flask, toluene (50 mL), rapamycin (2.00 g, 2.20 mmol), 2- (methoxymethoxy) ethyl trifluoromethanesulfonate (2.62 g , Heated to 60 C and stirred for 12 hours. Heating was stopped, 100 mL of ethyl acetate was added and the mixture was quenched with 30 mL of saturated ammonium chloride (20 mL, And the resulting crude product was subjected to column chromatography (petroleum ether: ethyl acetate (v / v) = 6: 1 to 0: 1), and the mixture was dried over anhydrous sodium sulfate, filtered and concentrated. Gradient elution) to give the intermediate: 42-O-[2-(methoxymethoxy)ethyl]rapamycin 1. 39 g, HPLC purity 95%, molar yield 63%.

Reference： [1]Patent: CN105254646,2016,A .Location in patent: Paragraph 0025-0027

43
[ 22809-37-6 ]
[ 53123-88-9 ]
C₅₇H₈₈BrNO₁₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With pyridine; In dichloromethane; at -5 - 25℃; for 2.16667h;Inert atmosphere;	To a solution of rapamycin (200 mg, 0.22 mmol) and pyridine (174 mg, 2.2 mmol) in dry DCM (4 mL) was added a solution of 6-bromohexanoyl chloride (85 mg, 0.4 mmol) in dry DCM (1 mL) at -5 C dropwise over a period of ~10 min under nitrogen. The reaction was stirred at RT for 2 hrs. TLC analysis indicated ~90% conversion of rapamycin. The reaction was quenched with water (3 mL). The reaction was combined with a previous batch (3125-029) for work-up. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3 mL × 3). The organic layers were combined and washed with water (3 mL × 2), 1N HCl (3 mL × 2) and water (3 mL). After drying over anhydrous Na2SO4, filtration and solvent removal, the crude mixture containing intermediate A (~ 300mg) was purified by silica gel column (eluent: hexane/ethyl acetate = 3/1~2/1) to produce intermediate A (170 mg) as white foam. The yield was 57%. LCMS (ESI+): m/z 1114 (M+Na). The analytical data is depicted in Figure 1 (mass spectrum of intermediate A), and Figure 2 (1H-NMR spectrum of intermediate A).

Reference： [1]Patent: WO2016/205334,2016,A1 .Location in patent: Page/Page column 52; 53

44
[ 75-21-8 ]
[ 92886-86-7 ]
[ 53123-88-9 ]
[ 1314705-20-8 ]

Yield	Reaction Conditions	Operation in experiment
71%Chromat.		Example 5: Synthesis of 40-O-[2-(f-butyldiphenylsilyl)oxy]ethyl-rapamycin A mixture of 7.9 ml of 1 M ethylene oxide solution in toluene and 1 .01 g of Lambda/,/nu-diisopropyl- ethylamine was added under stirring to 2.53 g of f-butyldiphenylsilyl trifluoromethane- sulfonate. The resulting mixture was stirred for further 1 hour at 40C. Then, 0.66 ml of 1 ,2- dimethoxyethane and 1.82 g of W,/v-diisopropylethylamine trifluoromethanesulfonate were added. The resulting mixture was stirred at 20C until complete dissolution, before 1 .0 g of rapamycin was added. The reaction mixture was purged with nitrogen for 10 min, heated to 48-50C and stirred at this temperature for 18 h. Subsequently, the reaction mixture was cooled to 20C, and 0.2 ml of pyridine and 16 ml of heptane were added. The resulting mixture was stirred for 10 minutes. The precipitate formed was obtained by filtration and washed with a mixture of 8.0 ml of toluene and 8.0 ml of heptane. Then, 1 ml of 0.2% solution of 2,6-di-f-butyl-4-methylphenol in heptane was added to the filtrate and the resulting crude 40-O-[2-(f-butyldiphenylsilyl)oxy]ethyl-rapamycin solution was subjected to the deprotection step. HPLC analysis of the obtained 40-O-[2-(f-butyldiphenylsilyl)oxy]ethyl- rapamycin solution showed an overall yield of 71 % (932 mg).

Reference： [1]Patent: WO2016/207205,2016,A1 .Location in patent: Page/Page column 14

45
[ 53123-88-9 ]
[ 657-24-9 ]
1-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl]-19-methoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0⁴,9]hexatriaconta-16,24,26,28-tetraen-30-yl]carbamimidamido-N,N-dimethylmethanimidamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.5%		To a solution of rapamycin in dry DCM (25 ml), /?-toluenesulfonic acid monohydrate was added at rt under an argon atmosphere. The solution was stirred for 10 min followed by the addition of metformin in one portion and stirred for 2h. The reaction mixture was quenched with sat. NaHCCb solution and extracted with EtOAc:water. The organic layer was additionally washed with brine and dried over MgS04, filtered and concentrated under reduced pressure. The mixture was purified by SFC to give 20mg (Yield: 5.5%). The compound was used as is.

Reference： [1]Patent: WO2017/44720,2017,A1 .Location in patent: Paragraph 00174

46
[ 75-21-8 ]
[ 53123-88-9 ]
[ 159351-69-6 ]

Yield	Reaction Conditions	Operation in experiment
6.9 g	With trifluorormethanesulfonic acid; In toluene; at 70℃; under 7500.75 Torr; for 8h;Autoclave;	9.14 g rapamycin (0.01mol), 11g ethylene oxide (0.25 mol), 0.1 g trifluoromethanesulfonic acid, 30mL toluene was added to the autoclave after mixing, Warmed to 70 C, Maintaining 1.0 MPa pressure, the reaction was stopped after 8 hours, cooled to room temperature,The solvent was recovered under reduced pressure and the residue was purified by silica gel column chromatography (200-300 mesh silica gel,Eluent: ethyl acetate: petroleum ether = 20: 1),7.7 g 97.95% of everolimus was obtained, which was purified by HP-20 resin column chromatography (eluent: acetonitrile: water = 65:35) 6.9 g of everolimus was obtained as a white solid, HPLC purity:99.6%, Isomer content:0.12%. Molar yield:72.0%

Reference： [1]Patent: CN104876944,2017,B .Location in patent: Paragraph 0035-0050

47
[ 107-21-1 ]
[ 53123-88-9 ]
[ 159351-69-6 ]

Yield	Reaction Conditions	Operation in experiment
5.7 kg		620g of ethylene glycol and 6L of tetrahydrofuran were added to the reaction flask,Mix well to mix.The reaction temperature was controlled at 10 .Under nitrogen protection,1.41L trifluoroacetic anhydride was slowly added dropwise,Dropping is completed,Reaction for 1.5 hours,The reaction solution.9.14 kg of rapamycin was dissolved in 54 L of tetrahydrofuran,Added to the reaction solution,The reaction temperature was controlled at 10 .Slowly add 13ml boron trifluoride diethyl ether solution. Bi completed,The reaction was stirred for 2 hours. After the reaction is completed,60L saturated aqueous sodium bicarbonate solution was added,Stir wellThen suction filtered,To the filtrate was added 30 L of ethyl acetate,Liquid separation,The organic phase is washed with pure water until nearly neutral.The organic phase was dried over 500 g of anhydrous sodium sulfate for 2 hours, filtered,Concentrated under reduced pressure to a solventless outflow,A thick liquid. Column chromatography,The eluent is petroleum ether:Ethyl acetate = 1: 6. The collected effluent was concentrated under reduced pressure to give 6.3 kg of yellow foamy solid,Yield 66%.A mixture of 26.8 L of methanol and ethyl acetate (v / v = 1/3) was added to the above yellow foamy solid,Stirring to dissolve,The temperature was controlled at 25 for 30 minutes,13.4 L cyclohexane was added dropwise,Bi completed,The temperature was controlled at 12 for 2 hours,Cool the feed liquid to about 0 slowly stirring 3h,Suction filtration,Drying at room temperature under vacuum gave 5.7 kg of a white solid,HPLC and mass spectrometry determined that the white solid was everolimus,Purity 98.1%.

Reference： [1]Patent: CN106146535,2016,A .Location in patent: Paragraph 0037; 0038; 0039; 0040; 0041; 0042; 0043-0056

48
[ 53123-88-9 ]
[ 79-04-9 ]
43-O-(2-chloroacetyl)oxyrapamycin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.6%	With triethylamine; In dichloromethane; at 0℃;	5 g (55 mmol) of rapamycin, 2 times with DCM,Pour into a 250 ml round bottom flask and dissolve in 50 ml DCM.The temperature was lowered to 00C for 5 min, then 3.5 ml (33 mmol) of triethylamine was added, and finally 1.3 ml (16.5 mmol) of chloroacetyl chloride was added dropwise (the solution changed from pale yellow to red, and solid precipitated).The dropping time was 20 min, the 00C temperature was kept and the TLC plate was tracked. Extract with DCM, then use water in turn,1NH2SO4, saturated sodium hydrogencarbonate, and saturated sodium chloride were washed once, dried over anhydrous sodium sulfate, filtered, and then evaporated to give 6 g of crude product.The silica gel column was eluted with a gradient, and the mobile phase: PE: EA = 3: 1-1:1, and finally, 3 g of 43-O-(2-chloroacetyl)-oxyrapamycin was obtained in a yield of 55.6%.

Reference： [1]Patent: CN108148076,2018,A .Location in patent: Paragraph 0085; 0087; 0088

49
[ 823-78-9 ]
[ 53123-88-9 ]
40(R)-O-m-bromobenzylrapamycin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With silver(l) oxide; In n-heptane; dichloromethane; at 60℃;	[00415] To a dry reaction flask was added rapamycin (1.0 g, 1.09 mmol, 1.0 equiv) followed by heptanes (8.7 mL) and DCM (3.4 mL). 3-Bromobenzyl bromide (2.17 g, 8.72 mmol, 8.0 equiv) and silver(I) oxide (3.01 g, 13.0 mmol, 12.0 equiv) were added to the solution and the reaction flask was capped and heated at 60 C until full consumption of rapamycin, as determined by LCMS analysis. The reaction was then cooled to room temperature, diluted with EtOAc (15 mL), filtered through Celite, and concentrated under reduced pressure to provide a yellow solid. Purification by chromatography on silica gel (10?40% EtOAc/heptanes) afforded the product (Intermediate 1 ) as a white solid (788 mg, 67% yield). LCMS (ESI) m/z: [M + Na] calcd for 1104.50; found 1104.5.

Reference： [1]Patent: WO2018/204416,2018,A1 .Location in patent: Paragraph 00415

50
[ 21663-79-6 ]
[ 53123-88-9 ]
C₅₄H₈₂N₂O₁₃ [ No CAS ]
C₅₄H₈₂N₂O₁₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium acetate In methanol at 20℃; for 72h;	[00487] To a solution of rapamycin (200.0 mg, 0.219 mmol, 1 equiv) in MeOH (5.00 mL) was added sequentially sodium acetate (0.0718 g, 0.875 mmol) and 3-(aminooxy)prop-l-yne hydrochloride (0.0941 g, 0.875 mmol, 4.0 equiv) at room temperature. The reaction was stirred at room temperature for 72 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with 20 mL portions of H2O and brine. The solution was dried over Na2S04, filtered, and concentrated. The resulting residue was purified via combiflash chromatography (0→80% EtO Ac/hex) to yield the Z isomer followed by the E isomer, both as colorless oils. Both products were taken up separately in 95% aq MeCN and lyophilized to white powders. Z isomer: LCMS (ESI) m/z: [M + Na] calcd for 989.57; found 989.5. E isomer: LCMS (ESI) m/z [M + Na] calcd for found 989.5.

Reference： [1]Current Patent Assignee: REVOLUTION MEDICINES INC - WO2018/204416, 2018, A1 Location in patent: Paragraph 00487

51
[ 16754-39-5 ]
[ 53123-88-9 ]
C₅₄H₈₀N₂O₁₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid In dichloromethane at -40℃;	Monomer 39. [00488] The preparation of the monomer proceeds by reacting rapamycin with prop-2-yn- 1-yl carbamate in the presence of TFA.

Reference： [1]Current Patent Assignee: REVOLUTION MEDICINES INC - WO2018/204416, 2018, A1 Location in patent: Paragraph 00488

52
1,2-O-isopropylidene-D-malic acid [ No CAS ]
[ 53123-88-9 ]
40-(1,2-O-isopropylidene-D-malic acid-4-yl)rapamycin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With dmap; dicyclohexyl-carbodiimide; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; at -10℃; for 12h;Inert atmosphere;	Under the protection of nitrogen,Add 1828 mg (2 mmol) of rapamycin and 382 mg (2.2 mmol) of 1,2-O-isopropylidene-D-malic acid to a 50 mL eggplant bottle, add 25 mL of anhydrous dichloromethane, and cool to -10 C. 618 mg (3.0 mmol) of DCC (N,N-dicyclohexylcarbonic acid diimide) and 366 mg (3.0 mmol) of DMAP (4-dimethylaminopyridine) (esterification catalyst) were added, and kept at a low temperature of -10 C. After 12 hours, suction filtration, washing with water, brine, and brine 40-(1,2-D-isopropylidene-D-malic acid-4-yl)-rapamycin 1624 mg,Yield: 76%.

Reference： [1]Patent: CN108864148,2018,A .Location in patent: Paragraph 0039; 0044; 0045; 0051

53
C₃₀H₄₈O₁₇Si [ No CAS ]
[ 53123-88-9 ]
C₈₁H₁₂₅NO₂₉Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;Inert atmosphere;	1,3-dicyclohexylcarbodiimide (DCC) (100 mg, 0.49 mmol)and 4-dimethylaminopyridine (DMAP) (12 mg, 0.10 mmol)were added to dry CH2Cl2 (5 ml) containing RAP (298 mg,0.33 mmol) and TES-o(LA)8 (254 mg, 0.36 mmol). The reactionmixturewas stirred overnight at room temperature underargon and determined to be complete by TLC. The resultingmixture was concentrated under reduced pressure and theresidue was purified via a CombiFlash Rf 4x system usinggradient elution of hexane and ethyl acetate. The purifiedproduct was concentrated under reduced pressure to provideRAP-o(LA)8-TES (296 mg, Yield: 57%). 1H NMR of RAPo(LA)8-TES (500 MHz, CDCl3, major rotamer): delta 6.38 (dd,J = 10.5, 15.0 Hz, 1H), 6.30 (dd, J = 10.0, 15.0 Hz, 1H), 6.14(dd, J = 10.0, 15.0 Hz, 1H), 5.96 (d, J = 11.0 Hz, 1H), 5.54(dd, J = 9.0, 15.0 Hz, 1H), 5.41 (d, J=9.5 Hz, 1H), 5.28 (d,J = 6.0 Hz, 1H), 5.19-5.11 (m, 8H), 4.77 (s, 1H), 4.71 (ddd,J = 5.0, 9.5, 11.5 Hz, 1H), 4.40 (q, J=6.5 Hz, 1H), 4.17 (d,J = 6.0 Hz, 1H), 3.74 (d, J=6.0 Hz, 1H), 3.57 (d, J =14.0 Hz, 1H), 3.37 (s, 3H), 3.33 (s, 3H), 3.14 (s, 3H), 2.71(dd, J = 6.0, 17.0 Hz, 1H), 1.51 (d, J=7.0 Hz, 3H), 1.50 (d,J=7.0Hz, 3H), 1.09 (d, J = 6.5 Hz, 3H), 1..05 (d, J=6.5Hz,3H), 0.99-0.94 (m, 15H), 0.90 (d, J = 7.0 Hz, 3H), 0.63 (q,J = 8.0 Hz, 6H).

Reference： [1]Pharmaceutical Research,2019,vol. 36

54
[ 22979-35-7 ]
[ 91-56-5 ]
[ 53123-88-9 ]
C₆₈H₉₂N₂O₁₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%		Weigh rapamycin (0.05mmol), isatin 3a (0.10mmol) and rhodium octanoate dimer(0.0005mmo),They were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes, phenyldiazo 2a (0.10 mmol) was dissolved in dry dichloromethane (1.0 mL), and slowly added dropwise. In the reaction system (about 1 hour),Stirring was continued for half an hour, and the solvent was removed by rotary evaporation to obtain a crude product;Further, the rapamycin analogue I-a was isolated by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4) in a yield of 93%.

Reference： [1]Patent: CN109776571,2019,A .Location in patent: Paragraph 0022-0025

55
[ 443-69-6 ]
[ 22979-35-7 ]
[ 53123-88-9 ]
C₆₈H₉₁FN₂O₁₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		Weigh rapamycin (0.05mmol), isatin 3c (0.10mmol) and rhodium octanoate dimer(0.0005mmo),They were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes,Phenyldiazo 2a (0.10 mmol) was weighed and dissolved in dry dichloromethane (1.0 mL), and slowly added dropwise to the reaction system (about 1 hour), and stirring was continued for half an hour.The solvent was removed by rotary evaporation to give a crude product. The rapamycin analog I-f was obtained by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4).The yield was 76%.

Reference： [1]Patent: CN109776571,2019,A .Location in patent: Paragraph 0042-0045

56
[ 324-03-8 ]
[ 22979-35-7 ]
[ 53123-88-9 ]
C₆₈H₉₁FN₂O₁₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%		Weigh rapamycin (0.05mmol), isatin 3g (0.10mmol) and rhodium octanoate (0.0005mmo),They were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes,Phenyldiazo 2a (0.10 mmol) was weighed and dissolved in dry dichloromethane (1.0 mL), and slowly added dropwise to the reaction system (about 1 hour), and stirring was continued for half an hour.The solvent was removed by rotary evaporation to give a crude product. The rapamycin analog I-g was obtained by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4).The yield was 88%.

Reference： [1]Patent: CN109776571,2019,A .Location in patent: Paragraph 0046-0049

57
[ 6341-92-0 ]
[ 22979-35-7 ]
[ 53123-88-9 ]
C₆₈H₉₁ClN₂O₁₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		Weigh rapamycin (0.05mmol), isatin 3h (0.10mmol) and rhodium octanoate dimer(0.0005mmo),They were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes,Phenyldiazo 2a (0.10 mmol) was weighed and dissolved in dry dichloromethane (1.0 mL), and slowly added dropwise to the reaction system (about 1 hour), and stirring was continued for half an hour.The solvent was removed by rotary distillation to give a crude product. The rapamycin analog I-h was obtained by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4).The yield was 82%.

Reference： [1]Patent: CN109776571,2019,A .Location in patent: Paragraph 0050-0053

58
[ 317-20-4 ]
[ 22979-35-7 ]
[ 53123-88-9 ]
C₆₈H₉₁FN₂O₁₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		Weigh rapamycin (0.05mmol), isatin 3j (0.10mmol) and rhodium octanoate dimer(0.0005mmo),They were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes,Phenyldiazo 2a (0.10 mmol) was weighed and dissolved in dry dichloromethane (1.0 mL), and slowly added dropwise to the reaction system (about 1 hour), and stirring was continued for half an hour.The solvent was removed by rotary evaporation to give a crude product. The rapamycin analog I-j was obtained by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4).The yield was 85%.

Reference： [1]Patent: CN109776571,2019,A .Location in patent: Paragraph 0058-0061

59
[ 7477-63-6 ]
[ 22979-35-7 ]
[ 53123-88-9 ]
C₆₈H₉₁ClN₂O₁₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%		Weigh rapamycin (0.05mmol), isatin 3k (0.10mmol) and rhodium octanoate dimer(0.0005mmo),They were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes,Phenyldiazo 2a (0.10 mmol) was weighed and dissolved in dry dichloromethane (1.0 mL), and slowly added dropwise to the reaction system (about 1 hour), and stirring was continued for half an hour.The solvent was removed by rotary evaporation to give a crude product. The rapamycin analog I-k was obtained by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4).The yield was 79%.

Reference： [1]Patent: CN109776571,2019,A .Location in patent: Paragraph 0062-0065

60
[ 391-12-8 ]
[ 22979-35-7 ]
[ 53123-88-9 ]
C₆₉H₉₁F₃N₂O₁₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%		Weigh rapamycin (0.05mmol), isatin 3m (0.10mmol) and rhodium octanoate dimer(0.0005mmo),They were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes,Phenyldiazo 2a (0.10 mmol) was weighed and dissolved in dry dichloromethane (1.0 mL), and slowly added dropwise to the reaction system (about 1 hour), and stirring was continued for half an hour.The solvent was removed by rotary distillation to give a crude product. The rapamycin analog I-m was obtained by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4).The yield was 86percent.

Reference： [1]Patent: CN109776571,2019,A .Location in patent: Paragraph 0070-0073

61
[ 774-47-0 ]
[ 22979-35-7 ]
[ 53123-88-9 ]
C₆₈H₉₀F₂N₂O₁₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		Weigh rapamycin (0.05mmol), isatin 3n (0.10mmol) and rhodium octanoate (0.0005mmo),They were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes,Phenyldiazo 2a (0.10 mmol) was weighed and dissolved in dry dichloromethane (1.0 mL), and slowly added dropwise to the reaction system (about 1 hour), and stirring was continued for half an hour.The solvent was removed by rotary evaporation to give a crude product. The rapamycin analog I-n was obtained by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4).The yield was 90%.

Reference： [1]Patent: CN109776571,2019,A .Location in patent: Paragraph 0074-0077

62
[ 2058-74-4 ]
[ 22979-35-7 ]
[ 53123-88-9 ]
C₆₉H₉₄N₂O₁₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%		Weigh rapamycin (0.05mmol), isatin 3p (0.10mmol) and rhodium octanoate dimer(0.0005mmo),They were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes,Phenyldiazo 2a (0.10 mmol) was weighed and dissolved in dry dichloromethane (1.0 mL), and slowly added dropwise to the reaction system (about 1 hour), and stirring was continued for half an hour.The solvent was removed by rotary evaporation to give a crude product; and the rapamycin analog I-p1 was obtained by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4).The yield was 74%.

Reference： [1]Patent: CN109776571,2019,A .Location in patent: Paragraph 0085-0088

63
[ 574-17-4 ]
[ 22979-35-7 ]
[ 53123-88-9 ]
C₇₀H₉₄N₂O₁₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%		Weigh rapamycin (0.05mmol), isatin 3q (0.10mmol) and rhodium octanoate dimer(0.0005mmo),They were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes,Phenyldiazo 2a (0.10 mmol) was weighed and dissolved in dry dichloromethane (1.0 mL), and slowly added dropwise to the reaction system (about 1 hour), and stirring was continued for half an hour.The solvent was removed by rotary distillation to give a crude product. The rapamycin analog I-q was obtained by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4).The yield was 89%.

Reference： [1]Patent: CN109776571,2019,A .Location in patent: Paragraph 0089-0092

64
[ 91-56-5 ]
[ 53123-88-9 ]
[ 219564-79-1 ]
C₆₈H₉₁FN₂O₁₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%		Weigh rapamycin (0.05mmol), isatin 3a (0.10mmol) and rhodium octanoate dimer(0.0005mmo),They were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes,Phenyldiazo 2b (0.10 mmol) was weighed and dissolved in dry dichloromethane (1.0 mL), and slowly added dropwise to the reaction system (about 1 hour), and stirring was continued for half an hour.The solvent was removed by rotary evaporation to give a crude product. The rapamycin analog I-b was obtained by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4).The yield was 87%.

Reference： [1]Patent: CN109776571,2019,A .Location in patent: Paragraph 0026-0029

65
[ 91-56-5 ]
[ 53123-88-9 ]
[ 93961-29-6 ]
C₆₈H₉₁ClN₂O₁₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		Weigh rapamycin (0.05mmol), isatin 3a (0.10mmol) and rhodium octanoate dimer(0.0005mmo),They were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes,Phenyldiazo 2c (0.10 mmol) was weighed into dry dichloromethane (1.0 mL), slowly added dropwise to the reaction system (about 1 hour), and stirring was continued for half an hour.The solvent was removed by rotary evaporation to give a crude product. The rapamycin analog I-c was obtained by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4).The yield was 85%.

Reference： [1]Patent: CN109776571,2019,A .Location in patent: Paragraph 0030-0033

66
[ 1011528-25-8 ]
[ 91-56-5 ]
[ 53123-88-9 ]
C₆₈H₉₁FN₂O₁₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		Weigh rapamycin (0.05mmol), isatin 3a (0.10mmol) and rhodium octanoate dimer(0.0005mmo),They were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes,Phenyldiazo 2d (0.10 mmol) was weighed and dissolved in dry dichloromethane (1.0 mL), and slowly added dropwise to the reaction system (about 1 hour), and stirring was continued for half an hour.The solvent was removed by rotary evaporation to give a crude product. The rapamycin analog I-d was obtained by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4).The yield was 70%.

Reference： [1]Patent: CN109776571,2019,A .Location in patent: Paragraph 0034-0037

67
[ 91-56-5 ]
[ 53123-88-9 ]
[ 384365-49-5 ]
C₆₉H₉₄N₂O₁₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		Weigh rapamycin (0.05mmol), isatin 3a (0.10mmol) and rhodium octanoate dimer(0.0005mmo), theThey were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes,Phenyldiazo 2e (0.10 mmol) was weighed and dissolved in dry dichloromethane (1.0 mL), and slowly added dropwise to the reaction system (about 1 hour), and stirring was continued for half an hour.The solvent was removed by rotary evaporation to give a crude product, which was obtained by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4) to give the rapamycin analog I-e.The yield was 75%.

Reference： [1]Patent: CN109776571,2019,A .Location in patent: Paragraph 0038-0041

68
[ 343-69-1 ]
[ 22979-35-7 ]
[ 53123-88-9 ]
40-O-(1-(3-hydroxy-2-oxo-6-(trifluoromethyl)indolin-3-yl)-2-methoxy-2-oxo-1-phenylethoxy)rapamycin [ No CAS ]
40-O-(1-(3-hydroxy-2-oxo-6-(trifluoromethyl)indolin-3-yl)-2-methoxy-2-oxo-1-phenylethoxy)rapamycin [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2019,vol. 2019,p. 2914 - 2918

69
[ 391-12-8 ]
[ 22979-35-7 ]
[ 53123-88-9 ]
40-O-(1-(3-hydroxy-2-oxo-7-(trifluoromethyl)indolin-3-yl)-2-methoxy-2-oxo-1-phenylethoxy)rapamycin [ No CAS ]
40-O-(1-(3-hydroxy-2-oxo-7-(trifluoromethyl)indolin-3-yl)-2-methoxy-2-oxo-1-phenylethoxy)rapamycin [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2019,vol. 2019,p. 2914 - 2918

70
[ 774-47-0 ]
[ 22979-35-7 ]
[ 53123-88-9 ]
40-O-(1-(5,6-difluoro-3-hydroxy-2-oxoindolin-3-yl)-2-methoxy-2-oxo-1-phenylethoxy)rapamycin [ No CAS ]
40-O-(1-(5,6-difluoro-3-hydroxy-2-oxoindolin-3-yl)-2-methoxy-2-oxo-1-phenylethoxy)rapamycin [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2019,vol. 2019,p. 2914 - 2918

71
[ 7693-46-1 ]
[ 53123-88-9 ]
40(R)-O-(4-nitrophenyl)carbonate rapamycin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.2%	With pyridine; In dichloromethane; at -78℃; for 2h;	To a solution of rapamycin (30.10 g, 32.92 mmol, 1.0 equiv) in DCM (148.9 mL) was added pyridine (29.6 mL, 367 mmol, 11.1 equiv). The solution was cooled to -78 C and then p-nitrophenyl chloroformate (12.48 g, 61.92 mmol, 1.9 equiv) was added. The reaction was stirred at -78 C for 2 h. To the reaction mixture was then added DCM and the solution was then poured into H2O. The aqueous layer was extracted with DCM and the combined organic layers were dried over MgSO4, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (050% EtOAc/hexanes) to provide the product (23.1 g, 59.2% yield) as a white solid. LCMS (ESI) m/z: [M + Na] calcd for C58H82N2O17: 1101.55; found 1101.6.

Reference： [1]Patent: WO2019/212990,2019,A1 .Location in patent: Paragraph 00716

72
[ 7693-46-1 ]
[ 53123-88-9 ]
40(R)-O-(4-nitrophenyl)thiocarbonate rapamycin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64.4%	With pyridine; In dichloromethane; at -20℃; for 48h;	To a solution of rapamycin (4.00 g, 4.38 mmol, 1.0 equiv) in DCM (20 mL) at -78 ^C was added pyridine (4.0 mL, 49 mmol, 11.2 equiv), followed by a solution of O-(4- nitrophenyl)chlorothiocarbonate (1.19 g, 5.47 mmol, 1.3 equiv) in DCM (8.0 mL). The reaction mixture was warmed to -20 ^C and stirred for 48 h. Hexane (40 mL) was then added and the resulting suspension was purified by silica gel chromatography (15/25/60 EtOAc/DCM/hexane then 20/25/55 EtOAc/DCM/hexane) to provide the product (3.09 g, 64.4% yield) as an off-white solid. LCMS (ESI) m/z: [M + Na] calcd for C58H82N2O16S: 1117.53; found 1117.5.

Reference： [1]Patent: WO2019/212990,2019,A1 .Location in patent: Paragraph 00725

73
[ 5579-66-8 ]
[ 53123-88-9 ]
(21E,23E,25E,26E,48R,49S,50R,51R,53S,55S,58S,59R,60R,69R)-59,69-dihydroxy-57-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-58-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-60-methoxy-48,49,50,51,61,62-hexamethyl-80,81-dioxa-70-azatricyclohexatriaconta-21,23,25⁽⁶¹⁾,26⁽⁶²⁾-tetraene-63,64,65,66,67-pentone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With toluene-4-sulfonic acid; In tetrahydrofuran; at 25℃; for 2h;	To a solution of rapamycin (0.5 g, 0.547 mmol) and 4-methylbenzenesulfonic acid (0.47 g, 2.73 mmol) in THF (15 mL) was added 2-[2-[2-[2-[2-[2-[2-[2-[2-(2- hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol (2.51 g, 5.47 mmol) and the mixture stirred at 25 C for 2 h. The reaction was then poured into a cold aqueous NaHCO3 solution which was then extracted with EtOAc. The organic layer was then dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (CH3CN:pure water = 7:3) to provide (21E,23E,25E,26E,48R,49S,50R, 51R,53S,55S,58S,59R,60R,69R)-59,69-dihydroxy-57-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2- hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-58- [(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-60-methoxy- 48,49,50,51,61,62-hexamethyl-80,81-dioxa-70-azatricyclohexatriaconta-21,23,25(61),26(62)- tetraene-63,64,65,66,67-pentone (I-98: 115 mg, 15% yield) as a thick oil. ESI-MS (EI+, m/z): 1362.9 [M+Na]+. 1H NMR (500 MHz, CDCl3) d 6.40- 5.83 (m, 4H), 5.55-5.35 (m, 2H), 5.32 - 5.03 (m, 2H), 4.31- 4.10 (m, 1H), 3.93 (dd, J = 70.7, 6.3 Hz, 1H), 3.78- 3.15 (m, 53H), 2.97- 2.41 (m, 5H), 2.32 (s, 2H), 2.15- 1.55 (m, 18H), 1.52- 1.16 (m, 10H), 1.14- 0.81 (m, 18H), 0.73- 0.58 (m, 1H).

Reference： [1]Patent: WO2019/241789,2019,A1 .Location in patent: Paragraph 00447-00448

74
[ 2358-54-5 ]
[ 53123-88-9 ]
(21E,23E,25E,26E,33R,34S,35R,36R,38S,40S,42R,43S,44R,45R,54R)-44,54-dihydroxy-43-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-45-methoxy-33,34,35,36,46,47-hexamethyl-42-[2-(2,2,2-trifluoroethoxy)ethoxy]-65,66-dioxa-56-azatricyclohexatriaconta-21,23,25⁽⁴⁶⁾,26⁽⁴⁷⁾-tetraene-48,49,50,51,52-pentone [ No CAS ]
(21E,23E,25E,26E,33R,34S,35R,36R,38S,40S,42S,43S,44R,45R,54R)-44,54-dihydroxy-43-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-45-methoxy-33,34,35,36,46,47-hexamethyl-42-[2-(2,2,2-trifluoroethoxy)ethoxy]-65,66-dioxa-56-azatricyclohexatriaconta-21,23,25⁽⁴⁶⁾,26⁽⁴⁷⁾-tetraene-48,49,50,51,52-pentone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 8 mg 2: 16 mg	With toluene-4-sulfonic acid In tetrahydrofuran at 0 - 35℃; Inert atmosphere;	46.1-46.2 Step 1: Synthesis of (21E,23E,25E,26E,33R,34S,35R,36R,38S,40S,43S,44R,45R,54R)- 44,54-dihydroxy-43-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1- methyl-ethyl]-45-methoxy-33,34,35,36,46,47-hexamethyl-42-[2-(2,2,2-trifluoroethoxy) ethoxy]-65,66-dioxa-56-azatricyclohexatriaconta-21,23,25(46),26(47)-tetraene- 48,49,50,51,52-pentone (I-77): A solution of rapamycin (0.3 g, 0.313 mmol) and 2-(2,2,2-trifluoroethoxy)ethanol (0.9 g, 6.26 mmol) in THF (9 mL) was cooled to 0°C and p-TsOH (0.27 g, 1.57 mmol) was added. The resulting mixture was stirried at 35 °C for 5h under N2 then poured into ice cold NaHCO3 and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with water (30 mL), brine (30 mL), dried, filtered, and concentrated. The residue was purified via reverse phase chromatography (C18, CH3CN:H2O = 57:43) to provide (21E,23E,25E,26E,33R,34S,35R,36R,38S,40S,43S,44R,45R,54R)-44,54-dihydroxy-43- [(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-45- methoxy-33,34,35,36,46,47-hexamethyl-42-[2-(2,2,2-trifluoroethoxy)ethoxy]-65,66-dioxa- 56-azatricyclohexatriaconta-21,23,25(46),26(47)-tetraene-48,49,50,51,52-pentone (I-77: 0.063 g, 19% yield) as a white solid. ESI-MS (EI+, m/z): 1092.3 [M+Na]+. 1H NMR (400 MHz, CDCl3) d 6.55- 5.88 (m, 4H), 5.72- 5.03 (m, 4H), 4.78 (s, 1H), 4.63- 4.34 (m, 1H), 4.32- 4.09 (m, 1H), 4.00- 2.81 (m, 21H), 2.77- 2.43 (m, 3H), 2.41- 2.17 (m, 2H), 2.18- 1.93 (m, 3H), 1.93- 1.54 (m, 18H), 1.54- 1.14 (m, 10H), 1.13- 0.79 (m, 16H), 0.78- 0.63 (m, 1H). 100 mg of (21E,23E,25E,26E,33R,34S,35R,36R,38S,40S,43S,44R,45R,54R)- 44,54-dihydroxy-43-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1- methyl-ethyl]-45-methoxy-33,34,35,36,46,47-hexamethyl-42-[2-(2,2,2-trifluoroethoxy) ethoxy]-65,66-dioxa-56-azatricyclohexatriaconta-21,23,25(46),26(47)-tetraene- 48,49,50,51,52-pentone was purified via prep chiral HPLC and the resulting epimers purified via silica gel chromatography (hexane:DCM:EtOAc:MeOH = 3:3:1:0.3) to provide (21E,23E,25E,26E,33R,34S,35R,36R,38S,40S,42S,43S,44R,45R,54R)-44,54-dihydroxy-43- [(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-45- methoxy-33,34,35,36,46,47-hexamethyl-42-[2-(2,2,2-trifluoroethoxy)ethoxy]-65,66-dioxa- 56-azatricyclohexatriaconta-21,23,25(46),26(47)-tetraene-48,49,50,51,52-pentone (I-71: 16 mg, 16% yield) and (21E,23E,25E,26E,33R,34S,35R,36R,38S,40S,42S,43R,44R,45R,54R)- 44,54-dihydroxy-43-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1- methyl-ethyl]-45-methoxy-33,34,35,36,46,47-hexamethyl-42-[2-(2,2,2- trifluoroethoxy)ethoxy]-65,66-dioxa-56-azatricyclohexatriaconta-21,23,25(46),26(47)- tetraene-48,49,50,51,52-pentone (I-70: 8 mg, 8% yield) as a white solid. Chiral separation method: I-71: ESI-MS (EI+, m/z): 1092.4 [M+Na]+.1H NMR (400 MHz, CDCl3) d 6.41- 6.20 (m, 2H), 6.13 (dd, J = 15.1, 9.7 Hz, 1H), 5.93 (dd, J = 22.9, 10.3 Hz, 1H), 5.58- 5.45 (m, 1H), 5.41 (d, J = 9.8 Hz, 1H), 5.27 (d, J = 5.2 Hz, 1H), 5.19- 5.03 (m, 1H), 4.78 (s, 1H), 4.19 (dd, J = 13.9, 5.9 Hz, 1H), 3.95- 3.63 (m, 10H), 3.63- 3.53 (m, 2H), 3.52- 3.25 (m, 11H), 3.24- 3.01 (m, 3H), 2.72 (dd, J = 16.8, 5.8 Hz, 2H), 2.58 (dd, J = 16.8, 6.3 Hz, 1H), 2.31 (t, J = 23.5 Hz, 2H), 2.15- 1.40 (m, 18H), 1.27 (ddd, J = 32.5, 16.2, 6.3 Hz, 8H), 1.15- 0.81 (m, 18H), 0.70 (dt, J = 17.8, 9.0 Hz, 1H). I-70: ESI-MS (EI+, m/z): 1092.4 [M+Na]+. 1H NMR (400 MHz, CDCl3) d 6.43- 5.90 (m, 4H), 5.56- 5.08 (m, 5H), 4.33- 3.99 (m, 3H), 3.95- 3.63 (m, 8H), 3.62- 3.02 (m, 18H), 2.89- 1.97 (m, 12H), 1.76 (dd, J = 31.4, 24.8 Hz, 8H), 1.40 (ddd, J = 39.2, 29.5, 12.0 Hz, 9H), 1.14- 0.79 (m, 18H), 0.76- 0.61 (m, 1H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2019/241789, 2019, A1 Location in patent: Paragraph 00536-00541

75
[ 3386-18-3 ]
[ 53123-88-9 ]
(21E,23E,25E,26E,46R,47S,48R,49R,51S,53S,56S,57R,58R,67R)-57,67-dihydroxy-55-[2-[2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-56-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-58-methoxy-46,47,48,49,59,60-hexamethyl-78,79-dioxa-68-azatricyclohexatriaconta-21,23,25⁽⁵⁹⁾,26⁽⁶⁰⁾-tetraene-61,62,63,64,65-pentone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	With toluene-4-sulfonic acid; In tetrahydrofuran; at 10 - 35℃; for 18h;Inert atmosphere;	To a solution of rapamycin (0.5 g, 0.547 mmol) in THF (15 mL) was added 4- methylbenzenesulfonic acid (0.47 g, 2.73 mmol) and <strong>[3386-18-3]nonaethylene glycol</strong> (2.27 g, 5.47 mmol) at 10 C. The reaction was stirred at 30C for 18 h under N2 then quenched with aq. NaHCO3 and extracted with EtOAc (60 mL× 3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (C18, CH3CN:H2O = 63:37) to provide (21E,23E,25E,26E,46R,47S,48R,49R,51S,53S,56S,57R,58R,67R)-57,67-dihydroxy-55-[2-[2- [2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]-56-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-58- methoxy-46,47,48,49,59,60-hexamethyl-78,79-dioxa-68-azatricyclohexatriaconta- 21,23,25(59),26(60)-tetraene-61,62,63,64,65-pentone (I-97: 111 mg, 16% yield) as a white solid. ESI-MS (EI+, m/z): 1318.9 [M+Na]+. 1H NMR (500 MHz, CDCl3) d 6.50- 5.79 (m, 4H), 5.64- 5.06 (m, 4H), 4.89 (d, J = 53.5 Hz, 1H), 4.51- 3.94 (m, 2H), 3.75- 3.18 (m, 46H), 3.02- 2.86 (m, 2H), 2.82- 2.61 (m, 3H), 2.39- 2.18 (m, 2H), 2.20- 1.91 (m, 6H), 1.78- 1.54 (m, 16H), 1.51- 1.19 (m, 11H), 1.09- 0.82 (m, 17H), 0.74- 0.62 (m, 1H).

Reference： [1]Patent: WO2019/241789,2019,A1 .Location in patent: Paragraph 00532-00533

76
[ 53123-88-9 ]
[ 6809-70-7 ]
(21E,23E,25E,26E,50R,51S,52R,53R,55S,57S,60S,61R,62R,71R)-61,71-dihydroxy-59-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-60-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-62-methoxy-50,51,52,53,63,64-hexamethyl-82,83-dioxa-72-azatricyclohexatriaconta-21,23,25⁽⁶³⁾,26⁽⁶⁴⁾-tetraene-65,66,67,68,69-pentone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With toluene-4-sulfonic acid In tetrahydrofuran at 0 - 20℃; for 2h;	45.1 Step 1: Synthesis of (21E,23E,25E,26E,50R,51S,52R,53R,55S,57S,60S,61R,62R,71R)- 61,71-dihydroxy-59-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-60-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3- methoxy-cyclohexyl]-1-methyl-ethyl]-62-methoxy-50,51,52,53,63,64-hexamethyl-82,83- dioxa-72-azatricyclohexatriaconta-21,23,25(63),26(64)-tetraene-65,66,67,68,69-pentone (I- 96): To a solution of rapamycin (0.2 g, 0.22 mmol) and 4-methylbenzenesulfonic acid (0.19 g, 1.09 mmol) in THF (6 mL) was added 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2- hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol (1.10 g, 2.19 mmol) at 0 °C and the reaction was stirred at 20 °C for 2 h then poured into sat. NaHCO3 (30 mL) and extracted with EtOAc (40 mL× 3). The combined organic layers were washed with water (40 mL), brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (C18, CH3CN: H2O = 51:49) to obtain (21E,23E,25E,26E,50R,51S,52R,53R,55S,57S,60S,61R,62R,71R)-61,71- dihydroxy-59-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-60-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3- methoxy-cyclohexyl]-1-methyl-ethyl]-62-methoxy-50,51,52,53,63,64-hexamethyl-82,83- dioxa-72-azatricyclohexatriaconta-21,23,25(63),26(64)-tetraene-65,66,67,68,69-pentone (I- 96: 61 mg, 20% yield) as a colorless oil. ESI-MS (EI+, m/z): 1408.0 [M+Na]+. 1H NMR (500 MHz, CDCl3) d 6.41- 5.84 (m, 4H), 5.61- 5.08 (m, 4H), 4.79 (s, 1H), 4.32- 4.05 (m, 1H), 3.89- 3.46 (m, 44H), 3.46- 3.16 (m, 12H), 2.98- 2.50 (m, 7H), 2.32 (s, 2H), 2.15- 1.89 (m, 4H), 1.82- 1.68 (m, 8H), 1.56- 1.16 (m, 14H), 1.12- 0.82 (m, 18H), 0.74- 0.56 (m, 1H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2019/241789, 2019, A1 Location in patent: Paragraph 00534-00535

77
[ 5117-19-1 ]
[ 53123-88-9 ]
(21E,23E,25E,26E,42R,43S,44R,45R,47S,49S,51S,52S,53R,54R,63R)-53,63-dihydroxy-51-[2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-52-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-54-methoxy-42,43,44,45,55,56-hexamethyl-74,75-dioxa-64-azatricyclohexatriaconta-21,23,25⁽⁵⁵⁾,26⁽⁵⁶⁾-tetraene-57,58,59,60,61-pentone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%	With toluene-4-sulfonic acid; In tetrahydrofuran; water; at 23℃;	A solution of rapamycin (0.5 g, 547 mmol) and 2-[2-[2-[2-[2-[2-[2-(2- hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol (0.2 g, 0.547 mmol, 3 mL) and p-toluenesulfonic acid hydrate (0.52 g, 2.73 mmol) in THF (15 mL) was stirred at room temperature for 3 hours, then quenched with EtOAc (30 mL × 3). The combined organic layers were washed with ice cold saturated NaHCO3 solution and concentrated. The resulting crude material was purified by reverse phase chromatography (CH3CN/pure water = 7:3) to obtain (21E,23E,25E,26E,42R,43S,44R,45R,47S,49S,51S,52S,53R,54R,63R)-53,63- dihydroxy-51-[2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]-52-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]- 54-methoxy-42,43,44,45,55,56-hexamethyl-74,75-dioxa-64-azatricyclohexatriaconta- 21,23,25(55),26(56)-tetraene-57,58,59,60,61-pentone (I-24: 0.13 g, 19%) as a white solid. MS (EI+, m/z): 1275.6[M+Na]+. 1H NMR (500 MHz, CDCl3) d 6.45- 5.80 (m, 4H), 5.57- 5.05 (m, 4H), 4.85- 4.08 (m, 2H), 3.90- 3.50 (m, 34H), 3.47- 3.24 (m, 13H), 2.97- 2.44 (m, 7H), 2.39- 2.06 (m, 2H), 2.03- 1.84 (m, 6H), 1.78- 1.58 (m, 13H), 1.53- 1.16 (m, 9H), 1.14- 0.78 (m, 18H), 0.67-0.53 (m, 1H).

Reference： [1]Patent: WO2019/241789,2019,A1 .Location in patent: Paragraph 00347-00348

78
[ 4704-94-3 ]
[ 53123-88-9 ]
(21E,23E,25E,26E,31R,32S,33R,34R,36R,38S,41S,42R,43R,53S)-42,53-dihydroxy-40-[3-hydroxy-2-(hydroxymethyl)propoxy]-41-[(1S)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-43-methoxy-31,32,33,34,44,45-hexamethyl-65,66-dioxa-54-azatricyclohexatriaconta-21,23,25⁽⁴⁴⁾,26⁽⁴⁵⁾-tetraene-46,47,48,49,50-pentone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%	With toluene-4-sulfonic acid; In tetrahydrofuran; water; at 15℃; for 17h;	p-toluenesulfonic acid hydrate (0.31 g, 1.64 mmol) was added to a mixture of rapamycin (0.5 g, 0.547 mmol) and 2-(hydroxymethyl) propane-1,3-diol (0.58 g, 5.47 mmol) in THF (10 mL) at 15 C. The resulting mixture was stirred at 15 C for 17 hours then the reaction mixture was diluted with EtOAc (100 mL) and adjusted to pH 9 using saturated aqueous NaHCO3 solution (about 50 mL). The organic layer was concentrated under vacuum. The residue was purified by reverse phase chromatography (CH3CN/pure water = 3:2). The solvent was removed by lyophilization, yielding (21E,23E,25E,26E,31R,32S, 33R,34R,36R,38S,41S,42R,43R,53S)-42,53-dihydroxy-40-[3-hydroxy-2-(hydroxymethyl) propoxy]-41-[(1S)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-43- methoxy-31,32,33,34,44,45-hexamethyl-65,66-dioxa-54-azatricyclohexatriaconta- 21,23,25(44),26(45)-tetraene-46,47,48,49,50-pentone (I-31: 0.054 g, 9% yield) as a white solid. MS (EI+, m/z): 1010.4 [M+Na]+. 1H NMR (500 MHz, CDCl3) d 6.37-5.96 (m, 4H), 5.56- 5.15 (m, 4H), 4.86-4.17 (m, 2H), 3.85-3.47 (m, 10H), 2.96-2.91 (m, 2H), 2.75-2.58 (m, 3H), 2.35-2.22 (m, 3H), 2.11-1.94 (m, 6H), 1.84-1.46 (m, 23H), 1.35-1.12 (m, 9H), 1.11-0.88 (m, 18H), 0.67-0.65 (m, 1H).

Reference： [1]Patent: WO2019/241789,2019,A1 .Location in patent: Paragraph 00367-00368

79
[ 57641-67-5 ]
[ 53123-88-9 ]
(21E,23E,25E,26E,34R,35S,36R,37R,39R,41S,44S,45R,46R,55S)-43-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]-45,55-dihydroxy-44-[(1S)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-46-methoxy-34,35,36,37,47,48-hexamethyl-65,66-dioxa-56-azatricyclohexatriaconta-21,23,25⁽⁴⁷⁾,26⁽⁴⁸⁾-tetraene-49,50,51,52,53-pentone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With toluene-4-sulfonic acid; In tetrahydrofuran; water; at 23℃; for 2.0h;	<strong>[57641-67-5]2-[2-(2-bromoethoxy)ethoxy]ethanol</strong> (0.12 g, 0.547 mmol, 2 mL) was added to a solution of rapamycin (0.5 g, 0.547 mmol) and p-toluenesulfonic acid hydrate (0.5 g, 2.73 mmol) in THF (7 mL) at room temperature and the resulting mixture was stirred for 2 hours. Ice cold NaHCO3 aqueous solution was then added and the mixture was extracted with EtOAc (30 mL × 3). The organic phase was then dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by reverse phase chromatography (CH3CN/pure water = 7:3) to obtain (21E,23E,25E,26E,34R,35S,36R,37R, 39R,41S,44S,45R,46R,55S)-43-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]-45,55-dihydroxy-44- [(1S)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-46-methoxy-34,35, 36,37,47,48-hexamethyl-65,66-dioxa-56-azatricyclohexatriaconta-21,23,25(47),26(48)- tetraene-49,50,51,52,53-pentone (0.2 g, 33.4% yield, 1HNMR shows a rapamycin impurity) as a white solid. MS (EI+, m/z): 1116.4 [M+Na] +.

Reference： [1]Patent: WO2019/241789,2019,A1 .Location in patent: Paragraph 00335; 00337

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P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 53123-88-9 ] {[proInfo.proName]}

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[ 53123-88-9 ] Synthesis Path-Upstream 1~6

[ 53123-88-9 ] Synthesis Path-Downstream 1~79

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