[ CAS No. 76801-85-9 ] {[proInfo.proName]}

Name: 76801-85-9|(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one|97%
Brand: Ambeed
SKU: A273915
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Quality Control of [ 76801-85-9 ]

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Product Details of [ 76801-85-9 ]

CAS No. :	76801-85-9	MDL No. :	MFCD09038719
Formula :	C₃₇H₇₀N₂O₁₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	734.96	Pubchem ID :	-
Synonyms :	Desmethyl Azithromycin;Azaerythromycin A;Azaerythromycin

Safety of [ 76801-85-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 76801-85-9 ]

* 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 [ 76801-85-9 ]
Downstream synthetic route of [ 76801-85-9 ]

[ 76801-85-9 ] Synthesis Path-Upstream 1~8

1
[ 342371-84-0 ]
[ 76801-85-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: With hydrogen; acetic acid In methanol at 40 - 45℃; Stage #2: With sodium hydroxide In water	Example-2; [93][94] Preparation of 9-deoxo-9a-aza-9a-homoerythromycin A; [95][96] To a mixture of 6,9-imino ether (II) (70.Og) in methanol (700ml) was added acetic acid till pH 5 to 6 is obtained. PtO₂ (7.Og) in water was added to the above mixture and reduced under hydrogenation condition at hydrogen pressure 8 to 9 kg at 4O⁰C to 45⁰C for about 4 to 5 hours. After completion of the reaction the reaction mixture was filtered through hyflobed, washed with methanol. The combined filtrate was distilled under vacuum to evaporate methanol. D. M. water (700ml) was added to the remaining filtrate. The pH of the solution was adjusted to 11 to 12 using aq. Sodium hydroxide solution. The solid precipitated was filtered, suck dried and then dried in oven to give 9-deoxo-9a-aza-9a-homo erythromycin A (III) (55.0g).[97] Yield: 85percent
84.4%	Stage #1: Heating Stage #2: at 8℃;	50 g of erythromycin A-9 oxime was added to a 500 ml three-necked flask equipped with stirring,Followed by adding 200 ml of purified water,12.0 g sodium bicarbonate, the reaction temperature is controlled at about 5 ,Add another 15mlMethylsulfonyl chloride,With the addition of methyl sulfonyl chloride reaction solution gradually thinning,Until fully clarified,After the incubation reaction for 2 ~ 3 hr,A solution of 5.0percent sodium borohydride in 100 ml,While 36percent acetic acid solution was added dropwise,Control the pH between 6 to 8,2 to 6 hours drop finished,After heating for 1 to 2 hours,Add 15g of gulonic acid,Hydrolysis temperature control at about 8 ,With 10percent hydrochloric acid pH1.5 ~ 2.5,Hydrolysis 8min, adding 100ml acetone,Plus 30percent of the liquid alkali pH 10 ~ 11,With the addition of crystals to the liquid caustic soda,Cooling to 0 ~ 10 , filtration,Dried up azithromycin42.2 g (yield 84.4percent).
70.3%	at 0 - 20℃; for 24 h;	Under 0 ° C ice bath conditions,0.1 g b (0.1435 mmol),0.088 g sodium borohydride (2.333 mmol)Dissolved in 1.2ml of anhydrous methanol,Stirring reaction 4h, then remove the ice bath,Continue to react at room temperature for 20h,After the reaction is completed, carbon dioxide is introduced into a white solid to form,Filtered, the filter cake was washed with a small amount of methanol, distilled under reduced pressure methanol, a white solid.DCM was added to dissolve the white solid,The organic phase is washed twice with 10percent sodium bicarbonate, the layers are separated and the organic phase is added with 100 ml of water and the pH is adjusted to 2-3 (preferably 2.5) with 1 mol / L hydrochloric acid under stirring.After stirring for 20 minutes, the pH is adjusted to 6-7 (preferably 6.5) with 10percent sodium hydroxide and the organic layer discarded.The aqueous layer was added with 20 ml of DCM, the pH was adjusted to 11 with 10percent sodium hydroxide, stirred for 15 minutes, separated to give a DCM solvent,Drying in vacuo gave a white solid (III-1) (see Figure 1) in a yield of 70.6percent

Reference： [1] Patent: WO2009/156938, 2009, A2, . Location in patent: Page/Page column 8
[2] Patent: CN106632543, 2017, A, . Location in patent: Paragraph 0003; 0025-0026
[3] Organic and Biomolecular Chemistry, 2008, vol. 6, # 22, p. 4120 - 4124
[4] Patent: CN106478541, 2017, A, . Location in patent: Paragraph 0022; 0047

2
[ 1357466-70-6 ]
[ 76801-85-9 ]

Yield	Reaction Conditions	Operation in experiment
57.4 g	Stage #1: With sodium hydroxide In dichloromethane at 10℃; Stage #2: With sodium tetrahydroborate In dichloromethane at 10℃;	85g of erythromycin A 9-oxime thiocyanate, 500ml of dichloromethane was added to 1000ml reaction flask then adjust PH9 ~ 11 by adding 20percent sodium hydroxide and after all the solid was dissolved the stratification was carried out . the upper aqueous layer was again extracted with dichloromethane and the combined the dichloromethane layers. Dichloromethane was concentrated by evaporation and 250ml of water was added. cooled to below 10 ° C, then methanesulfonyl chloride 25g was added and the incubation reaction was carried out until erythromycin A9-oxime was complete. With 20percent sodium hydroxide adjusted pH3 ~ 7, cooling to below 10 ° C, sodium borohydride 7g was added and Insulation reaction is completed. Then dichloromethane 1000ml was added , adjust pH0. 5 ~ 2. 5 with 10percent hydrochloric acid , incubation at 0 ~ 10 ° C and stirred for 20 minutes. Then, adjusted pH9 ~ 11 by adding 20percent sodium hydroxide, allowed to stand to separate the layers and the aqueous layer was extracted with 100ml of dichloromethane then the combined dichloromethane layer and 200ml of water was added. Concentrated under reduced pressure to remove dichloromethane, cooled to 0 ~ 5 ° C, washed the filter and drying was carried out to obtain 57. 4g products, purity 94.6percent by HPLC , moisture

Reference： [1] Patent: CN103772456, 2016, B, . Location in patent: Paragraph 0029-0030
[2] Patent: CN107141324, 2017, A,

3
[ 944124-75-8 ]
[ 76801-85-9 ]

Reference： [1] Patent: WO2007/80507, 2007, A2, . Location in patent: Page/Page column 11

4
[ 111321-02-9 ]
[ 76801-85-9 ]

Reference： [1] Tetrahedron Letters, 2000, vol. 41, # 18, p. 3371 - 3375
[2] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 13, p. 4498 - 4510
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 2792 - 2804

5
[ 13127-18-9 ]
[ 76801-85-9 ]

Reference： [1] Chemical Communications, 2018, vol. 54, # 6, p. 654 - 657
[2] Patent: CN106478541, 2017, A,

6
[ 227948-37-0 ]
[ 76801-85-9 ]

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 2792 - 2804

7
[ 114-07-8 ]
[ 76801-85-9 ]

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 2792 - 2804
[2] Patent: CN106478541, 2017, A,

8
[ 7704-67-8 ]
[ 76801-85-9 ]

Reference： [1] Patent: CN107141324, 2017, A,

[ 76801-85-9 ] Synthesis Path-Downstream 1~46

1
[ 111321-02-9 ]
[ 76801-85-9 ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 3371 - 3375
[2]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 4498 - 4510
[3]Journal of Medicinal Chemistry,2011,vol. 54,p. 2792 - 2804

2
[ 292638-85-8 ]
[ 76801-85-9 ]
[ 96779-85-0 ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 3371 - 3375

3
[ 287727-89-3 ]
[ 76801-85-9 ]
9a-aza-9a-[(3'-deoxythymidin-3'-yl)aminocarbonyl]-9-deoxo-9a-homoerythromycin A [ No CAS ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 3371 - 3375

4
[ 501-53-1 ]
[ 76801-85-9 ]
[ 352032-78-1 ]

Yield	Reaction Conditions	Operation in experiment
96.9%		In a low-temperature reaction tank, add 20g to a three-necked flask at a temperature of -10-0 As shown in formula IDemethyl azithromycin, dissolved in 320mL of dichloromethane, then cooled to 3 C, stirred, slowly add 4.7g CBZ-Cl dropwise after 10 minutes, then slowly add 2.7g triethylamine dropwise Stability, stirring at 3 for 2h, thin layer chromatography monitoring the end of the reaction, the reaction is complete. Add 150mL of distilled water, adjust pH = 2 with 3N HCl, separate the liquid, extract the organic phase with acidic aqueous phase, combine the aqueous phases, extract the aqueous phase with petroleum ether and dichloromethane twice, and add 150mL of 2 to the aqueous phase Chloromethane, pH = 9 adjusted with 5N NAOH, liquid separation, the aqueous phase was extracted with 50mL of dichloromethane again, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and dried in vacuo to give 22.9g of white powdery solid, yield 96.9%
84.57%	In dichloromethane; at 0 - 5℃; for 1h;	2L reaction flask in three 800mL dichloromethane added, cooled to 0-5 'C, stirring, 50g (0.068moL) Compound 1 (State of the Import and Export Company, batch number: 20091101), and stirred until dissolved. 20111008) 28.8g (24mL; 0.moL) 60mL 0-5C Take benzyl chloroformate (Xinyi Huili Fine Chemical Co., lot number: 20111008) 28.8g (24mL; 0. should moL) was dissolved in dichloromethane to 60mL, constant infusion, to control the temperature at 0-5 C. lh 50'C 50g2, 84.57% Drop was completed, at this temperature for lh, the reaction was concentrated by rotary evaporation under reduced pressure Bi 50'C to dryness to give a pale yellow solid compound 2 50g, Yield: 84.57%
84.1%	In dichloromethane; at 0 - 5℃; for 12h;Large scale;	In this embodiment, The principle of synthesizing Cbz-dihydro-erythromycin alcohol is as follows: The specific reaction conditions are as follows: Add 50 ml of glass kettle to dichloromethane (43.42 kg). dihydro-erythromycin (2.5 kg, 3.4 mol) was heated to reflux for 4 hours. Check the water content of the solution to less than 0.05%, distill off part of dichloromethane (22.16 kg), cool, add fresh dichloromethane (5 kg) and cool to 0-5 C, add benzyl chloroformate (698.8 g, 4.075 mol), after the addition, the temperature is 0-5 C for 10 hours.High performance liquid chromatography for the determination of dihydro-erythromycin (ensuring that the content of dihydrogalomycin is less than 1%),Continue to add dropwise benzyl chloroformate (139 g, 0.815 mol) and stir at 0-5 C for 2 hours. The content of the raw material dihydro-erythromycin was checked by high performance liquid chromatography. Add deionized water (10 kg) and check pH 6-7,Add 10% sodium carbonate solution (800 ml), check pH 9-10, separate the liquid, wash with organic layer deionized water (8 kg x 2), dry anhydrous sodium sulfate (700 g), and dilute dichloromethane under reduced pressure. The solution was added with isopropanol (4.5 kg), cooled to 0-5 C, and trifluoroacetic acid (783.5 g, 6.82 mol) was added dropwise with stirring to precipitate a large white solid.After stirring at 0-5 C for 1 hour, it was filtered, and the filter cake was washed with isopropyl alcohol (1 kg) and dried under vacuum at 30 C for three days. The white solid was 2.7 kg, the yield was 67%, and the purity was 88.7% by high performance liquid chromatography. Sample preparation for analysis:Cbz-dihydro-erythromycin alcohol (200 g) was added isopropanol (400 ml), heated to 80 C with stirring, kept for 10 minutes, cooled to 0 C, filtered, and the filter cake was washed with isopropyl alcohol (100 ml) Dry at 40 C for 24 hours under vacuum. Obtained 168.6 g of white solid. The yield was 84.1%, and the purity by HPLC was 97.1%.

	In dichloromethane; toluene; at -5 - 55℃;Inert atmosphere; Large scale;	Into 1000L reactor into 40kgTA04, 100kg toluene, stirring 20 ~ 30min, 55 C concentrated to no distillate. Cooled to about 25 C under nitrogen, vacuum suction 900Kg dichloromethane, open the stirring, the system was cooled under nitrogen to -5 ~ 5 C, was added dropwise to the system 22kg benzyl chloroformate and 66Kg dichloromethane The solution. A total of about 1.5h, the addition was completed. Insulation 0 ~ 5 C, 2 ~ 3h, the conversion of raw materials is completed. (HPLC monitoring raw material conversion) temperature T <35 C, the reaction mixture was concentrated to dry oily, low temperature 0 ~ 10 C preservation
		Put 29Kg TA04 into the 500L reactor.160Kg methylene chloride, stirring 20 ~ 30min,5 Kg of anhydrous sodium sulfate was added thereto, and the mixture was stirred and dried for 1 to 2 hours. The entire mixture was filtered by suction and concentrated to substantially no fraction. Transfer the concentrated system to a 1000-liter reactor, add 660 Kg of methylene chloride, turn on the stirring, and reduce the temperature of the system to -5 to 5C while protecting the nitrogen.A solution of 16 Kg/33 Kg of benzyl chloroformate and methylene chloride was added dropwise to the system.A total of 1.5h was added dropwise.Insulation 0 ~ 5 C, 2 ~ 4h, the conversion of raw materials is completed. (HPLC monitoring of raw material conversion), temperature control T ? 30 C, the reaction mixture was concentrated to 250 Kg. Low temperature 0 ~ 10 C preservation.
29.1 g	In dichloromethane; at 0 - 10℃; for 3.33333h;Inert atmosphere;	25 g of dihydroerythromycin and 350 mL of dichloromethane were added to a 1L three-necked flask, stirred, and dissolved. Nitrogen was filled in the flask for protection, and the temperature was cooled to 0 to 10 C. by an ice-salt water bath. A mixed solution of 12.2 mL of carbobenzoxy chloride and 50 mL of dichloromethane was added dropwise over 20 minutes, during which the internal temperature was kept between 0 and 10 C. The reaction was traced by TLC+HPLC until the reaction was completed, and the duration of the reaction was 3 hours. 125 mL of saturated NaHCO3 aqueous solution was added to quench the reaction. The organic layer was separated from the water layer, and 50 mL of dichloromethane was added to the water layer for one more extraction. The organic layers were combined, washed with 100 mL of saturated sodium bicarbonate solution once, and dried with anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure at a temperature between 35 and 40 C., and drained with an oil pump to give 29.1 g of a bubble compound represented by formula V, MS(ESI)868.53.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2771 - 2774
[2]Patent: CN111004299,2020,A .Location in patent: Paragraph 0033-0037
[3]Patent: CN102993250,2016,B .Location in patent: Paragraph 0264-0272
[4]Patent: CN109293628,2019,A .Location in patent: Paragraph 0038-0050
[5]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1955 - 1958
[6]Patent: CN107400152,2017,A .Location in patent: Paragraph 0059; 0060
[7]Patent: CN107501364,2017,A .Location in patent: Paragraph 0047; 0060
[8]Patent: US2019/23681,2019,A1 .Location in patent: Paragraph 0066

5
[ 76801-85-9 ]
[ 111247-94-0 ]

Yield	Reaction Conditions	Operation in experiment
61%		Azaerythromycin (50g, 13.61 mmol) was suspended in water (500 mL) and a 35% w/w aqueous solution of formaldehyde (19.3 mL) was charged. Formic acid (12.3 mL) was then charged to the slurry. The solution was heated to reflux for 30 hours. The reaction mixture was allowed to cool down to room temperature and washed twice with ethyl acetate. The aqueous layer was basified to pH 11 by addition of a concentrated aqueous solution of sodium hydroxide, and extracted twice with ethyl acetate. The combined organic extracts were washed with water (500mL), dried and concentrated to give an off-white solid. The solid was reslurried in MTBE, then collected by filtration and washed with MTBE. After drying the product was obtained as a white powder (24.56g, 61% yield).
6.3 g	With hydrogenchloride; In water; at 20℃; for 6h;pH 1 - 2;	Example 4(1) 15 g of the obtained erythromycin obtained in the method of Example 2 was dissolved in water, stirred and dissolved at 20 C, and 4 mol / LHydrochloric acid to adjust the pH value to 1 ~ 2, reaction 6h, after the completion of the reaction with 20% concentration of sodium hydroxide solution to adjust the pH to 8 ~ 9,Extracted three times with an appropriate amount of methylene chloride, and the filtrate was collected and concentrated to give 10.2 g of TUM as a crude product in 87% yield.(2) 10.2 g of TUM was placed in a three-necked flask equipped with a spherical condenser tube, and a mixed solution of acetone and petroleum ether100mL, the volume ratio of acetone and petroleum ether is 6: 1, stirring at 60 for 2h, then cooling to 0 ~ 5 recrystallization 6h,The resulting product was dried by filtration. According to this method and then recrystallization 2 times, the resulting solid in a vacuum drying oven at 50 5h, obtainedTUM pure 6.3g, the yield

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 4498 - 4510
[2]Patent: WO2012/131396,2012,A1 .Location in patent: Page/Page column 19
[3]European Journal of Medicinal Chemistry,2007,vol. 42,p. 138 - 145
[4]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 556 - 566
[5]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 853 - 856
[6]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 321 - 332
[7]Patent: CN104119413,2016,B .Location in patent: Paragraph 0048; 0049

6
[ 76801-85-9 ]
9-deoxo-9-dihydro-3'-N-oxide-9a-aza-9a-homoerythromycin A [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.3%	With dihydrogen peroxide; In methanol; water; at 0 - 20℃; for 2h;	To a solution of theta-deoxo-theta-dihydro-thetaa-aza-thetaa-homoerythromycin A (20 g, 27.21 mmol) in MeOH (80 ml) at O0C, a 30% water solution of H2O2 (30 ml) was added dropwise over 30 min. The reaction mixture was stirred for an additional 1.5 hour at room temperature. After detection of complete transformation the reaction mixture was poured into ice water (400 ml) and DCM (200 ml). A saturated water solution of Na2S2O3 (150 ml) was added to remove excess of H2O2. The layers were separated and the water layer extracted with DCM (2 x 200 ml). Combined organic layers were evaporated under reduced pressure and the residue was precipitated from DCM-diisopropylether yielding the title product (21.5 g, 94.3 % yield); MS (ES+) m/z 751.6 [M+H]+.13C NMR (125 MHz, pyridine)/delta: 177.3, 101.9, 96.2, 82.8, 77.6, 77.4, 76.9, 75.8, 73.2, 73.0, 72.8, 72.2, 71.9, 65.5, 65.0, 56.2, 55.8, 50.8, 48.6, 44.7, 42.3, 41.9, 34.2, 33.8, 29.1 , 27.2, 21.3, 20.8, 20.5, 20.4, 18.3, 16.6, 14.1 , 13.5, 10.4, 8.8.

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3595 - 3605
[2]Patent: WO2007/125414,2007,A2 .Location in patent: Page/Page column 46

7
[ 292638-85-8 ]
[ 76801-85-9 ]
[ 955955-02-9 ]

Yield	Reaction Conditions	Operation in experiment
53.7%	In chloroform; at 60℃; for 48h;Heating / reflux;	To a solution of 9-deoxo-9-dihydro-9a~aza-9a-homoerythromycin A (4.0 g, 5.44 mmol) in CHCI3 (80.0 mL) methyl acrylate (24.5 ml_, 272.1 mmol) was added. Reaction mixture was stirred under reflux (60 0C) for 2 days. After evaporation of organic solvent crude title product (4.58 g) was obtained.Crude product was purified using Solid Phase Extraction (SPE) technique on a LC-Si (2 g) cartridge with the FlashMaster Il instrument and gradient system for eluation: CH2CI2/(Me0H : NH4OH = 9 : 1.5) in which MeOH : NH4OH = 9 : 1.5 was increased from 0 to 12% giving after evaporation of solvent yellowish the title product as powder (2.4 g,53.7%); MS (ES+) m/z 821.5 [M+H]+.

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1389 - 1401
[2]Patent: WO2007/125414,2007,A2 .Location in patent: Page/Page column 48

8
[ 107-13-1 ]
[ 76801-85-9 ]
[ 92627-70-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	at 80℃; for 24h;	9-Deoxo-9-dihydro-9a-aza-9a-homoerythromycin A 9 (100 g; 136 mmol) was dissolved in acrylonitrile (300 ml) and the reaction mixture was heated at 80 C for 24 h. The solvent was evaporated under reduced pressure to afford the desired product 10 (106 g) in 99% yield as a white foam. This compound was used for the next step without previous purification.LC/MS (area %): 95%, MS(ES) m/z: [MH]+ 788.2 (calcd: 788.02).
41%	for 7h;Heating / reflux;	A mixture of intermediate 11 (16 g, 21.7 MMOL), obtained from erythromycin A oxime as described in the literature (Djokic S. et AL., J. Chem. Soc. Perkin Trans. , 1986,1881), in acrylonitrile (160 ML) was refluxed for 7 h and evaporated under vacuum from the acrylonitrile in excess to give a solid raw product. Purification by flash chromatography (SILICA, ELUENT CH2CI2/MEOH/NH3 90/5/0.5) gave intermediate 12 (6. 9 g, YIELD 41 %).
	at 85℃; for 22h;	The suspension of <strong>[76801-85-9]9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A</strong> (45 g, 61.23 mmol) in acrylonitrile (166 mL, 2.52 mol) was warmed up to 85 0C and stirred about 22 hours. After cooling the solvent was evaporated under reduced pressure. The residue was suspended three times with toluene and evaporated under reduced pressure giving the title compound (51.24 g); MS (ES+) m/z 788.03 [M+Hf.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 1692 - 1701
[2]Organic and Biomolecular Chemistry,2008,vol. 6,p. 4120 - 4124
[3]Patent: WO2004/39821,2004,A1 .Location in patent: Page 32-33
[4]European Journal of Medicinal Chemistry,2009,vol. 44,p. 3459 - 3470
[5]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 321 - 332
[6]Patent: WO2007/125414,2007,A2 .Location in patent: Page/Page column 51

9
[ 50-00-0 ]
[ 76801-85-9 ]
[ 83905-01-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With formic acid; In acetone; at 30 - 55℃; for 4h;	Into 500 ml three-neck flask was added desmethyl Azithromycin (I) (50 g, 0.07 mol), acetone 175 ml, room temperature stirring to dissolve. 30-40 C. Add dropwise anhydrous formic acid (8.5 g, 0.18 mol), 37% formaldehyde (7.3 g, 0.09 mol). Heating to 50 - 55 C, maintain temperature react for 4 h, TLC monitoring reaction finishes.To a room temperature, adding 175 ml de-ionized water, 10 wt % sodium hydroxide aqueous solution to adjust the pH=12 - 13, dropwise 175 ml de-ionized water, stirring crystallization 2 h. Filtering, for 100 ml water washing 2 times, drying, be azithromycin 47.5 g, yield 95%, purity 98.8% (HPLC see Figure 4 and table 4 shown).
87%		Example 1C; Preparation of Azithromycin dihydrate; To the 300 ml of acetone, 100 gm <strong>[76801-85-9]9-Deoxo-9a-aza-9a-homoerythromycin A</strong> (prepared according to Example IB) was added. The mixture of 17.49 ml of formic acid and 17.49 ml of formaldehyde was EPO <DP n="14"/>prepared. This mixture was added to <strong>[76801-85-9]9-Deoxo-9a-aza-9a-homoerythromycin A</strong> solution within 5 to 6 hours at 40 C. The reaction was monitored for 2 hours at 40 to 45 C. The pH of the reaction mixture was adjusted to 11 to 11.5 by adding sodium hydroxide solution. The charcoal treatment was given to reaction mixture. The acetone layer was separated from the reaction mixture. To the acetone layer, 650 ml water was added within 12 hour while stirring. The mixture was stirred at 20 C for 12 hours. After the completion of reaction, Azithromycin dihydrate was filtered and washed with water. Azithromycin dihydrate was dried at 65 C. The yield and purity of the Azithromycin dihydrate was 87 % and 98 %.
77%	With formic acid; In water; ethyl acetate; for 2h;Heating / reflux;	6.48 g of a compound of formula III obtained according to example 4 are dissolved in 58 ml of ethyl acetate and 0.6 ml of formic acid and 1.30 ml of 37% aqueous formaldehyde are added to the solution obtained. The mixture obtained is refluxed for ca. 2 hours. HPLC analysis shows the formation of azithromycin. [00106] Yield: 77%.of theory.

		Example - Preparation of azithromycin Monohydrate <strong>[76801-85-9]9-Deoxo-9a-aza-9a-homoerythromycin A</strong> (73.5g - 0.1 mole) was dissolved in 250 ml acetonitrile.. To this solution, formic acid (19 ml, 0.5 mole) followed by formaldehyde (37%, 20 ml, 0.25 mole) were added and refluxed for 24 hours.. The PH of the reaction mixture was adjusted with alkali (NaOH solution) to 10.5 and filtered to remove particles.. To the filtered acetonitrile solution, an equal volume of water was added to precipitate azithromycin monohydrate as cube shaped crystals.. The crystals were filtered and dried under vacuum at 50C to give 65g of azithromycin monohydrate having water content of 5% (water content measured by the Karl Fischer titration method).. This sample of azithromycin monohydrate crystals has a characteristic solid state (KBr pellet) IR spectrum (Fig 1) and a characteristic X-ray diffraction pattern (Fig 2). In the process described above reductive methylation is carried out in acetonitrile (solvent) and Azithromycin monohydrate crystals are directly precipitated from the reaction mixture without the need for conducting any extraction procedure. All patent, patent applications, articles, publications, textbooks and any other references cited in this application are incorporated herein by reference in their entirety for all purposes.
	With formic acid; In ethanol; at 78℃; for 4h;Industry scale;	Azaerythromycin (100 kg) (Ercros Ind., Madrid, Spain) and 95% ethanol (500 L) were combined to form a mixture in a 1,000-L reaction vessel. The mixture was then stirred. Paraformaldehyde (10.4 kg) and formic acid (15 kg) were added, and the mixture was heated at a reflux temperature (i.e., 78 C.) for about 4 hours. When thin-layer chromatography (TLC) indicated the disappearance of azaerythromycin, about 200 L of ethanol was removed by distillation under vacuum. At about 25-30 C., water (300 kg) and 25% ammonium hydroxide (40 kg) were added to bring the pH to above 9. Then, more water (300 kg) was added. The mixture was further stirred at room temperature for about 6 hours. The precipitate was filtered and washed with water, providing about 105 kg of crude, wet azithromycin (contained 24.74% water (w/w)).
		(b); The pH of the chloroform extract was adjusted to 5.0 to 5.5 with formic acid (17.0 g) and formaldehyde (17.0 g) and the resultant mixture was refluxed for 10 hr. After completion of the reaction, water (500 ml) was added and pH brought to 4.0 with hydrochloric acid. The pH of the reaction mixture was adjusted to 8.0 using sodium hydroxide solution and the aqueous layer was extracted with chloroform. The chloroform extract was concentrated to dryness. The residue obtained was dissolved <n="13"/>in methylene chloride (750.0 ml), filtered and concentrated ana dried under reduced pressure. The solid so obtained was dissolved in acetonitrile (750.0 ml). The acetonitrile was partially distilled out (600.0 ml) under vaccum. The slurry obtained was cooled to 10-25C and filtered to get anhydrous azithromycin. Yield: 45.0 g. Purity: 99.0 %.
	With formic acid; In chloroform; for 10h;pH 5 - 5.5;Heating / reflux;Product distribution / selectivity;	Example 4: Preparation of azithromycin; The Cyclic amine of formula III obtained from example 1, was dissolved in chloroform (1 Litre) and adjusted to pH 5.0 to 5.5 with methylating mixture i.e. formic acid (17.0 g) and formaldehyde (17.0 g) and refluxed for 10 hr. The resultant mass was subjected to process as exemplified in example 3 (b), to get the title compound.
		Example-3; [100][101] Preparation of Azithromycin; [102][103] <strong>[76801-85-9]9-Deoxo-9a-aza-9a-homoerythromycin A</strong> (III) (73.5g) was dissolved in acetone(250ml). To this solution formic acid (19ml) followed by formaldehyde (37%, 20ml) were added and refluxed for 24 hrs. The pH of the reaction mixture was adjusted with alkali to 10.5 and filtered to remove particles. To the filtered acetone solution equal volume of water was added to precipitate azithromycin (IV). The crystals were filtered and dried under vacuum at 5O0C to give the title product (65g).
	With formic acid; triethylamine; In acetone; at 46 - 48℃; for 8h;	Experiment 1. Preparation of azithromycin from Aza-azithromycinIn a 100 L reactor, 10 Kg of aza-azithromycin was dissolved in 30 L of acetone. Formaldehyde 37% (2.22 Kg), formic acid 85% (2.65 Kg) and triethyl amine (50 mL) were added and the clear solution was heated at 46-480C. The mixture was stirred at 46-48C for 8 hours then cooled to less than 35C and 30 L of water was added. The clear solution was transferred via a Buchner filter to a 200 L reactor. The pH was adjusted with ammonia solution of 7% (20 L) to 9.5-9.7. Water (60 L) was added over 2 hours. After stirring the suspension for 1 hour, the crude azithromycin (9.5 Kg, 93%) was obtained.

Reference： [1]Patent: CN107141324,2017,A .Location in patent: Paragraph 0101; 0102; 0103
[2]Patent: WO2007/15265,2007,A2 .Location in patent: Page/Page column 12-13
[3]Patent: US6703372,2004,B1 .Location in patent: Page/Page column 11
[4]Organic and Biomolecular Chemistry,2008,vol. 6,p. 4120 - 4124
[5]Chemical Communications,2018,vol. 54,p. 654 - 657
[6]Patent: EP1400528,2004,A1 .Location in patent: Page 5
[7]Patent: US2006/63725,2006,A1 .Location in patent: Page/Page column 4
[8]Patent: WO2007/80507,2007,A2 .Location in patent: Page/Page column 11-12
[9]Patent: WO2007/80507,2007,A2 .Location in patent: Page/Page column 13
[10]Patent: WO2009/156938,2009,A2 .Location in patent: Page/Page column 8
[11]Patent: WO2011/15219,2011,A1 .Location in patent: Page/Page column 15

10
[ 50-00-0 ]
[ 76801-85-9 ]
azithromycin dihydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%		To the 300 ml of acetone, 100 gm <strong>[76801-85-9]9-Deoxo-9a-aza-9a-homoerythromycin A</strong> (prepared according to Example IB) was added. The mixture of 17.49 ml of formic acid and 17.49 ml of formaldehyde was prepared. This mixture was added to <strong>[76801-85-9]9-Deoxo-9a-aza-9a-homoerythromycin A</strong> solution within 5 to 6 hours at 40 C. The reaction was monitored for 2 hours at 40 to 45 C. The pH of the reaction mixture was adjusted to 11 to 11.5 by adding sodium hydroxide solution. The charcoal treatment was given to reaction mixture. The acetone layer was separated from the reaction mixture. To the acetone layer, 650 ml water was added within 12 hour while stirring. The mixture was stirred at 20 C for 12 hours. After the completion of reaction, Azithromycin dihydrate was filtered and washed with water. Azithromycin dihydrate was dried at 65 C. The yield and purity of the Azithromycin dihydrate was 87 % and 98 %.
76.7%		100g (0. 136G moles) of azaerythromycin A was dissolved in 300ML of acetone under stirring at room temperature. Formic acid (85%, 15.6g, 0. 288G moles) and formaldehyde solution (37%, 14. 10G, 0. 1737G moles) were added and resulting mixture was heated at 50- 55C for 8 hrs. The mixture was then cooled to room temperature and stirred with 16ML of 30% aqueous NAOH solution. The aqueous layer was separated and acetone layer containing material was filtered through polishing filter and the clear filtrate was heated to 38 to 40C. The first portion of water (70ML) was added to this in about 1 hr maintaining a temperature of 38 to 40C followed by stirring for 2hrs at the same temperature to allow abundant formation of crystals. The second portion of water (380ML) was then added in about 2 hrs and thereafter maintained for 8-10 hrs at 38-40C. The resulting crystals were cooled to 10 to 15C, maintained for 2hrs and recovered by filtration. The crystals were washed with 50ML X 2 of chilled water and dried under vacuum at 45 to 50C till constant weight furnishing 80gms of azithromycin dihydrate in 80% w/w yield from azaerythromycin A (74.9% of theoretical) with a moisture content of 4. 7%. EXAMPLE 2 Example 1 was repeated except that the second portion of water used in the CRYSTALLIZATION PROCESS CONTAINED LOML OF LIQ. ammonia (i. e. 370MLOFWATER+ 10MLOFLIQ. ammonia). Thus, 82g of azithromycin dihydrate was obtained in 82% w/w yield from azaerythromycin A (76.7% of theoretical).
73 - 74.9%		EXAMPLE 3 100g (0.136g moles) of azaerythromycin A was dissolved in 400mL of chloroform under stirring at room temperature. Formic acid (85%, 15.6g, 0. 288G. moles) and formaldehyde solution (37%, 14. 10G, 0. 1737G moles) were added and the resulting mixture was heated at 50-55C for 10HRS. The mixture was then cooled to room temperature and washed with 25ML X 2 of 10% aq. NAOH solution. The chloroform layer was separated, dried over anhydrous magnesium sulphate and distilled off completely under reduced pressure till dryness. This was further chased with 100mL of acetone till dryness. The residual product was cooled to room temperature and dissolved in 300ML of acetone and the resulting solution was filtered through polishing filter and crystallization was carried out as per the procedure given in Example 1 to get 78g of azithromycin dihydrate in 78%. w/w from azaerythromycin A (73% of theoretical). EXAMPLE 4 The procedure described in Example 3 was repeated but using methylene dichloride as a solvent during the reaction (20 hrs/reflux conditions) to furnish 80g of azithromycin dihydrate in 80% w/w yield from azaerythromycin A (74.9% of theoretical). EXAMPLE 5 100g (0. 136G moles) of azaerythromycin A was dissolved in 400mL of chloroform under stirring at room temperature. Formic acid (85%, 15.6g, 0.288g. moles) and formaldehyde solution (37%, 14. 10G, 0. 1737G moles) were added and the resulting mixture was heated at 50-55C for 10hrs. The mixture was then cooled to room temperature and washed with 25mL X 2 of 10% aq. NAOH solution. The chloroform layer was separated. Mixture of Hydrochloric acid and water (20ML Con HC1 + 380ML water) added to the chloroform layer, stir for 15 minutes and separate the aqueous layer. The aqueous layer was washed with 200 ml chloroform. The aqueous layer cool to 25-30C and adjust the aqueous layer pH to 9. 5-10.00 by using 30% aqueous NAOH solution. The resulting solid was extracted with chloroform. The chloroform layer was washed with 100 ml water. Chloroform layer dried over anhydrous magnesium sulphate and distilled off completely under reduced pressure till dryness. This was further chased with 100mL of acetone till dryness. The residual product was cooled to room temperature and dissolved in 300mL of acetone and the resulting solution was filtered through polishing filter and crystallization was carried out as per the procedure given in Example 1 to get 78g of azithromycin dihydrate in 78% w/w from azaerythromycin A (73% of theoretical). EXAMPLE 6 The procedure described in Example 5 was repeated but using methylene dichloride as a solvent during the reaction (20 hrs/reflux conditions) to furnish 80g of azithromycin dihydrate in 80% w/w yield from azaerythromycin A (74.9% of theoretical). SCHEME H H HO OH H3 H3 Ho OH CH3 CH3 0 0 H3C"CH3 H3C OCH3 'cl CH3 + H (\|) H3 9-deoxo-9a-aza-9a-homoerythromycin (azaerythromycin A) Step-1 Formic acid I Formaldehyde CH 3 cl 3 OH OH v H3C/. H3c",//0 OCH3 1 CH3 wCH3 o OH Single () ) Step (Current Hygroscopic azithromycin monohydrate (= Azithromycin Crude) invention) Step-2 Crystallization cl HgC-CH W 3C/t CH3 C ? XCH3 OH QH 3 H3c,/, , CH 3 OH , g3 C/ss, u I I O H3 CH3 H CH3 CH3 H Ici 3 Non-hygroscopic azithromycin dihydrate

Reference： [1]Patent: WO2007/29266,2007,A2 .Location in patent: Page/Page column 11
[2]Patent: WO2005/3144,2005,A1 .Location in patent: Page 7
[3]Patent: WO2005/3144,2005,A1 .Location in patent: Page 7-8

11
C₇₀H₁₂₈BN₄O₂₆^(1-)*Na⁽¹⁺⁾ [ No CAS ]
[ 76801-85-9 ]

Yield	Reaction Conditions	Operation in experiment
	With Amberlite IRA-743; sulfuric acid; water; for 0.5h;pH 2.8;	EXAMPLE 2 [00099] 1.98 g of an intermediate borate compound obtained according to example 1 are suspended in 34 ml of water. 20% sulphuric acid is added to the suspension obtained and a pH of 2.8.is adjusted. 22 g of an ion resin containing hydroxy groups (Amberlite IRA-743) are added to the mixture obtained and the mixture obtained is stirred for ca. 30 minutes, the resin is filtrated off and washed with water. The pH of the filtrate obtained is adjusted to a basic pH with 20% sodium hydroxide. The mixture obtained is extracted with ethyl acetate, the organic phase is dried and evaporated off. [00100] Yield: 1.22 g of a compound of formula III in pure form.

Reference： [1]Patent: US6703372,2004,B1 .Location in patent: Page/Page column 11

12
[ 620161-75-3 ]
[ 76801-85-9 ]
[ 823803-04-9 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid;tris-(dibenzylideneacetone)dipalladium(0); n-butyl-diphenylphosphane; In tetrahydrofuran; for 4h;Heating / reflux;	To a solution of desmethyl azithromycin (14.7g, 20 mmol), the compound from step la (6.92 g, 24 mmol) and dppb (512 mg, 1.2 mmol) in THF (200 ML), is added acetic acid (1.14, 20 mmol) and Pd2 (dba) 3 (550 mg, 0.5 mmol) under nitrogen. The mixture is refluxed for 4 hours, diluted with ethyl acetate (250 ML). washed with saturated NAHC03 (200 MLX2) and brine (200 ml), and dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (SiOz, 2M NH3 in METHANOL/CH2CI2 = 5/95) to give the title compound (11 g). MS (ESI) m/z 787.55 (M+H) + 3C NMR (CDCI3) : 8 177.1, 145.6, 114.3, 103.2, 95.8, 84.4, 83.7, 79.6, 78.3, 77.2, 74.3, 74.2, 74.0, 73.2, 71.3, 69.6, 69.0, 66.0, 65.9, 64.5, 54.5, 53.7, 49.7, 45.4, 42.6, 41.2, 40.6, 35.4, 29.2, 27.2, 22.3, 21.9, 21.7, 21.2, 18.6, 16.7, 16.1, 11. 1, 9.8, 7.6.
		Example 5.; Formation of 9a-11 3-carbon bridged azithromvcin; To a solution of desmethyl azithromycin (14.7g, 20 mmol), the compound from step 3a (6.92 g, 24 mmol) and dppb (512 mg, 1.2 mmol) in THF (200 ml), is added acetic acid (1.14, 20 mmol) and Pd2 (dba) 3 (550 mg, 0.5 mmol) under nitrogen. The mixture is refluxed for 4 hours, diluted with ethyl acetate (250 ml), washed with saturated NaHC03 (200 mlX2) and brine (200 ml), and dried over anhydrous Na2S04. The solvent was removed in vacuo, and the residue was purified by flash chromatography (Si02, 2M NH3 in methanol/CH2C12 = 5/ 95) to give the title compound (11 g). MS (ESI) m/z 787.55 (M+H) + 13C NMR (CDCl3) : 8 177.1, 145.6, 114.3, 103.2, 95.8, 84.4, 83.7, 79.6, 78. 3, 77.2, 74.3, 74.2, 74.0, 73.2, 71.3, 69.6, 69.0, 66.0, 65.9, 64.5, 54.5, 53.7, 49.7, 45.4, 42.6, 41.2, 40.6, 35.4, 29.2, 27.2, 22.3, 21.9, 21.7, 21.2, 18.6, 16.7, 16.1, 11.1, 9.8, 7.6.

Reference： [1]Patent: WO2005/30227,2005,A1 .Location in patent: Page/Page column 56
[2]Patent: WO2005/80408,2005,A1 .Location in patent: Page/Page column 32

13
[ 115580-32-0 ]
[ 76801-85-9 ]
[ 823803-03-8 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid;tris-(dibenzylideneacetone)dipalladium(0); 1,4-di(diphenylphosphino)-butane; In tetrahydrofuran; for 5h;Heating / reflux;	Example 4. Formation of 9a-11 2-Carbon Bridged Azithromycin Derivatives; To a solution of desmethyl azithromycin (2.94g, 4 mmol), BocOCH2CH=CHCH2OBoc (1.5g, 5.2 mmol) and dppb (171 mg, 0.4 mmol) in THF (50 ml) and acetic acid, was added Pd2 (dba) 3 (183 mg, 0.2 mmol) under nitrogen. The mixture was refluxed for 5 hours and subsequently concentrated in vacuo. The residue was purified by flash chromatography (SiO2 hexane: acetone/2 : 1) to give a mixture of stereoisomers (2.4g). MS (ESI) m/z: 787.87 (M+H). 13C-NMR (100 MHz, CDC13) : 8 175.9, 136.1, 116.6, 103.5, 96.9, 84. 9,81. 1,78. 7,78. 3,77. 2, 76.3, 74.1, 73.4, 73.0, 71.3, 68.9, 66.0, 65.8, 64.2, 56.6, 49.8, 49.6, 45.0, 41.9, 40.6, 39.6, 35.6, 29.1, 27.1, 27.0, 21. 8, 21.6, 18. 9, 17.1, 15.5, 10.9, 9.9, 5.5.

Reference： [1]Patent: WO2005/80408,2005,A1 .Location in patent: Page/Page column 31-32

14
[ 2937-50-0 ]
[ 76801-85-9 ]
2'-O-allyloxycarbonyl-9-deoxy-9a-allyloxycarbonyl-9a-aza-9a-homoerythromycin A [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In tetrahydrofuran; water; at 0 - 3℃; for 1.66667h;	a) 2'-O-Allyloxycarbonyl-9-deoxy-9a-allyloxycarbonyl-9a-aza«9a-homoerythromycin ATo an ice-cooled mixture of 9-deoxy-9a-aza-9a-homoerythromycin A (S. Djokic et al. in DE 3012533), (109.3 g) and potassium carbonate (82.2 g) in THF (500 ml_) and water (250 ml_), with overhead stirring, was added allyl chloroformate (34.7 ml_) dropwise, keeping the internal temperature below 30C. Additional allyl chloroformate (15.8 mL) was added after 20 min. Further allyl chloroformate (7.89 mL) was added after a further 30 min. After 50 min the organic layer was separated, washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The aqueous layer was re-extracted with Et2O (500 mL) (x3) and the organic extracts combined, dried (Na2SO4), filtered, and concentrated in vacuo. These Et2O extracts were combined with the first organic extracts to give the title compound as a white solid (140 g); ESMS m/z 903.8 [M+H]+.

Reference： [1]Patent: WO2006/50940,2006,A1 .Location in patent: Page/Page column 79

15
[ 7732-18-5 ]
[ 76801-85-9 ]
azithromycin Monohydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With formaldehyd; formic acid; In ethanol; chloroform;	PREPARATION 1 Hygroscopic Azithromycin Monohydrate Substantially following the methylation procedure of Kobrehel et al., U.S. Pat. No. 4,517,359; and the crystallization procedure of Bright, U.S. Pat. No. 4,474,768; <strong>[76801-85-9]9-deoxo-9a-aza-9a-homoerythromycin A</strong> (previously called 11-aza-10-deoxo-10-dihydroerythromycin A; 100 g, 0.218 mol) was dissolved with stirring in 400 ml CHCl3. Formic acid (98%; 10.4 ml, 0.436 mol) and formaldehyde (37%; 16.4 ml, 0.349 mol) were added over 4-5 minutes, and the mixture heated at reflux for 20 hours. The mixture was cooled to ambient temperature, diluted with 400 ml H2 O and adjusted to pH 10.5 with 50% NaOH. The aqueous layer was separated and extracted 2*100 ml with fresh CHCl3. The organic layers were combined, stripped in vacuo to 350 ml, twice diluted with 450 ml of ethanol and restripped to 350 ml, and finally diluted with 1000 ml H2 O over a 1 hour period, pausing for 15 minutes as a slurry began to develop after the addition of about 250 ml of H2 O. Title product was recovered by filtration and dried in air at 50 C. for 24 hours, 85 g; mp 136 C.; differential thermal analysis (heating rate 20 C./minute) shows an endotherm at 142 C.; thermal gravimetric analysis (heating rate 30 C./minute) shows a 2.6% weight loss at 100 C. and a 4.5% weight loss at 150 C.; water content 3.92%; ethanol content 1.09%. Anal. Calcd. for C38 H72 N2 O12 (corrected for ethanol and water content): C, 58.46; H, 9.78; N, 3.74; Alkoxy, 4.67. Found: C, 58.40; H, 9.29; N, 3.50; Alkoxy, 4.52.

Reference： [1]Patent: US4963531,1990,A

16
[ 76801-85-9 ]
azithromycin Monohydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With formaldehyd; formic acid; In ethanol; chloroform; water;	PREPARATION 1 Hygroscopic Azithromycin Monohydrate Substantially following the methylation procedure of Kobrehel et al., U.S. Patent 4,517,359; and the crystallization procedure of Bright, U.S. Patent 4,474,768; <strong>[76801-85-9]9-deoxo-9a-aza-9a-homoerythromycin A</strong> (previously called 11-aza-10-deoxo-10-dihydroerythromycin A; 100 g, 0.218 mol) was dissolved with stirring in 400 ml CHCl3. Formic acid (98%; 10.4 ml, 0.436 mol) and formaldehyde (37%; 16.4 ml, 0.349 mol) were added over 4-5 minutes, and the mixture heated at reflux for 20 hours. The mixture was cooled to ambient temperature, diluted with 400 ml H2O and adjusted to pH 10.5 with 50% NaOH. The aqueous layer was separated and extracted 2 x 100 ml with fresh CHCl3. The organic layers were combined, stripped in vacuo to 350 ml, twice diluted with 450 ml of ethanol and restripped to 350 ml, and finally diluted with 1000 ml H2O over a 1 hour period, pausing for 15 minutes as a slurry began to develop after the addition of about 250 ml of H2O. Title product was recovered by filtration and dried in air at 50C for 24 hours, 85 g; mp 136C; differential thermal analysis (heating rate 20C/minute) shows an endotherm at 142C; thermal gravimetric analysis (heating rate 30c/minute) shows a 2.6% weight loss at 100C and a 4.5% weight loss at 150C; water content 3.92%; ethanol content 1.09%. Anal. Calcd. for C38H72N2O12 (corrected for ethanol and water content): C, 58.46; H, 9.78; N, 3.74; Alkoxy, 4.67. Found: C, 58.40; H, 9.29; N, 3.50; Alkoxy, 4.52.
	With formaldehyd; formic acid; In ethanol; chloroform; water;	PREPARATION 1 Hygroscopic Azithromycin Monohydrate Substantially following the methylation procedure of Kobrehel et al., U.S. Pat. No. 4,517,359; and the crystallization procedure of Bright, U.S. Pat. No. 4,474,768; <strong>[76801-85-9]9-deoxo-9a-aza-9a-homoerythromycin A</strong> (previously called 11-aza-10-deoxo-10-dihydroerythromycin A; 100 g, 0.218 mol) was dissolved with stirring in 400 ml CHCl3. Formic acid (98%; 10.4 ml, 0.436 mol) and formaldehyde (37%; 16.4 ml, 0.349 mol) were added over 4-5 minutes, and the mixture heated at reflux for 20 hours. The mixture was cooled to ambient temperature, diluted with 400 ml H2O and adjusted to pH 10.5 with 50% NaOH. The aqueous layer was separated and extracted 2*100 ml with fresh CHCl3. The organic layers were combined, stripped in vacuo to 350 ml, twice diluted with 450 ml of ethanol and restripped to 350 ml, and finally diluted with 1000 ml H2O over a 1 hour period, pausing for 15 minutes as a slurry began to develop after the addition of about 250 ml of H2O. Title product was recovered by filtration and dried in air at 50 C. for 24 hours, 85 g; mp 136 C.; differential thermal analysis (heating rate 20 C./minute) shows an endotherm at 142 C.; thermal gravimetric analysis (heating rate 30 C./minute) shows a 2.6% weight loss at 100 C. and a 4.5% weight loss at 150 C.; water content 3.92%; ethanol content 1.09%. Anal. Calcd. for C38H72N2O12 (corrected for ethanol and water content): C, 58.46; H, 9.78; N, 3.74; Alkoxy, 4.67. Found: C, 58.40; H, 9.29; N, 3.50; Alkoxy, 4.52.

Reference： [1]Patent: EP307128,1989,A2
[2]Patent: US6268489,2001,B1

17
C₃₇H₆₆N₂O₁₂ [ No CAS ]
[ 76801-85-9 ]

Yield	Reaction Conditions	Operation in experiment
91.5%		Example IB; Hydrogenation of 6,9-Imino ether to 9-Deoxo-9a-aza-9a-homoerythromycin A; To the 650 ml of methanol, 100 gm of 6,9-Imino ether (prepared according to example IA) was added. The methanolic solution of 6,9-Imino ether was filtered after Charcoal treatment. The filtrate was chilled to 5 to 60C. To this mixture, 70% perchloric acid solution was added to adjust the pH of the reaction mixture to 5.5. 20 gm of Pt/C catalyst was added to the reaction mixture. The reaction mixture was flushed with N2 and then with H2. The hydrogenation was carried out at temperature of 42 C and pressure of 14 kg/cm2 with stirring for 3 hours. The reaction was monitored by HPLC. The speetaj: catalyst was filtered from the reaction mixture. Methanol was distilled out from the reaction mixture to obtain residue. 700 ml of water was added to the residue. The pH of the residue was adjusted with 5 % aqueous sodium hydroxide solution to 12-12.5. The precipitated 9-Deoxo-9a-aza-9a- homoerythromycin A was filtered and washed with water. The product thus obtained was dried at 65 C. The yield and purity of 9-Deoxo-9a-aza-9a-homoerythromycin A was 91.5 % and 91%. The Pt/C catalyst comprised reactivated Pt/C catalyst along with fresh Pt/C catalyst in the ratio of 98:2.

Reference： [1]Patent: WO2007/15265,2007,A2 .Location in patent: Page/Page column 12

18
C₃₇H₆₆N₂O₁₂ [ No CAS ]
[ 76801-85-9 ]

Yield	Reaction Conditions	Operation in experiment
86.6 - 91.5%		To the 650 ml of methanol, 100 gm of 6,9-Imino ether (prepared according to example IA) was added. The methanolic solution of 6,9-Imino ether was filtered after Charcoal treatment. The filtrate was chilled to 5 to 6C. To this mixture, 70% perchloric acid solution was added to adjust the pH of the reaction mixture to 5.5. 20 gm of Pt/C catalyst was added to the reaction mixture. The reaction mixture was flushed with N2 and then with H2. The hydrogenation was carried out at temperature of 42 C and pressure of 14 kg/cm2 with stirring for 3 hours. The reaction was monitored by HPLC. The spent catalyst was filtered from the reaction mixture. Methanol was distilled out from the reaction mixture to obtain residue. 700 ml of water was added to the residue. The pH of the residue was adjusted with 5 % aqueous sodium hydroxide solution to 12-12.5. The precipitated 9-Deoxo-9a-aza- 9a-homoerythromycin A was filtered and washed with water. The product thus obtained was dried at 65 C. The yield and purity of 9-Deochio-9a-aza-9a-homoerythromycin A was 86.6 % and 91%.Example IB(B) EPO <DP n="12"/>Hydrogenation of 6,9-Imino ether to 9-Deoxo-9a-aza-9a-homoerythromycin A(Using Pt/c catalyst comprising reactivated Pt/C catalyst along with the fresh catalyst in the ratio of 98:2)To the 650 ml of methanol, 100 gm of 6,9-Imino ether (prepared according to example IA) was added. The methanolic solution of 6,9-Imino ether was filtered after Charcoal treatment. The filtrate was chilled to 5 to 6C. To this mixture, 70% perchloric acid solution was added to adjust the pH of the reaction mixture to 5.5. 20 gm of Pt/C catalyst comprising reactivated catalyst along with fresh catalyst in the ratio of 98:2 was added to the reaction mixture. The reaction mixture was flushed with N2 and then with H2. The hydrogenation was carried out at temperature of 42 C and pressure of 14 kg/cm2 with stirring for 3 hours. The reaction was monitored by HPLC. The spent catalyst was filtered from the reaction mixture. Methanol was distilled out from the reaction mixture to obtain residue. 700 ml of water was added to the residue. The pH of the residue was adjusted with 5 % aqueous sodium hydroxide solution to 12-12.5. The precipitated 9-Deoxo-9a-aza-9a- homoerythromycin A was filtered and washed with water. The product thus obtained was dried at 65 C. The yield and purity of 9-Deoxo-9a-aza-9a-homoerythromycin A was 91.5 % and 91%.9-Deoxo-9a-aza-9a-homoerythromycin A was characterized by IR (Refer Figure 1 of the Accompanying drawing).

Reference： [1]Patent: WO2007/29266,2007,A2 .Location in patent: Page/Page column 10-11

19
[ 944124-75-8 ]
[ 76801-85-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1: Preparation of cyclic amine (Formula III):; 6,9-Imino ether (Formula-II) (100 g) was suspended in water (1.0 lit). The reaction mixture was cooled to 0-5C. To, the resulting reaction mixture, chilled aqueous solution of sodium borohydride (18.0 g in 200ml water) was added at a temperature between 0-5C while maintaining the pH between 6.0 -8.0 with formic acid. After completion of the borohydride addition, the reaction mixture was stirred at 0-5C for 1 hour and then at room temperature for 10 hours. It was then extracted with chloroform at pH 9.5. The chloroform layer was concentrated under vacuum and the residue so obtained was treated with water (1.0 lit) and malic acid (75 g). The pH of the resultant mixture was further adjusted to 2.5 with hydrochloric acid. The product was extracted in chloroform (500 ml x 2) after adjusting the pH to about 9.5 and 10.0 with sodium hydroxide solution, whereby the compound of Formula III separated out from the reaction mass, which was isolated and dried. Yield: 78.0 g.; Example 2: Preparation of anhydrous azithromycin:; (a); 6,9-Imino ether (Formula-II) (100 g) was suspended in water (1.0 lit). The reaction mixture was cooled to 0-50C .To the resulting reaction mixture, chilled aqueous solution of sodium borohydride (18.0 g in 200ml water) was added at temperature between 0-50C while maintaining the pH between 6.0 -8.0 with formic acid. After completion of borohydride addition, the reaction mixture was stirred at 0-50C for 1 hr and then at room temperature for 10 hrs. After completion, the "reaction mass is extracted with chloroform at pH 9.5. Chloroform layer was concentrated under vacuum and the residue was treated with water (1.0 lit) and malic acid (75 g). The pH of resultant mixture further adjusted to 2.5 with hydrochloric acid. The product was extracted in chloroform (500 ml x 2) after adjusting the pH 9.5 to 10.0 with sodium hydroxide solution. The chloroform extracts were combined and taken for next step.

Reference： [1]Patent: WO2007/80507,2007,A2 .Location in patent: Page/Page column 11

20
[ 123-91-1 ]
[ 50-00-0 ]
[ 64-18-6 ]
[ 76801-85-9 ]
C₄H₈O₂*C₃₈H₇₂N₂O₁₂*H₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		<strong>[76801-85-9]9-Deoxo-9a-aza-9a-homoerythromycin A</strong> (9a-DeMet) [(1] mole), formic acid (1.8 to 2.5 mole/mole 9a-DeMet) and formalin (1 to 1.5 mole formaldehyde/mole 9a-DeMet) were added to 1,4-dioxane (4 to 8 [1/KG] 9a-DeMet). The mixture was heated to about [60C] and stirred at this temperature for 4 hours. Whilst maintaining this temperature, activated carbon was added to the reaction mixture. The mixture was filtered, and the carbon remaining on the filter was washed with 1,4-dioxane (0.5 to 2 1/kg of the 9a-DeMet substrate). The combined 1,4-dioxane solution (both the filtrate and the wash) was then added to a previously prepared amount of water (10 to 20 [1/KG] 9a-DeMet) at temperature of about 25 to [30 C.] The resulting mixture was alkalized stepwise with 10% [NAOH] solution to a pH 9.8, and then stirred at room temperature for 2 hours. The precipitate was a crystalline isostructural pseudopolymorph of the general Formula la (S = 1,4-dioxane). The precipitate was filtered, washed with an aqueous 1,4-dioxane solution (10% v/v) and dried at room temperature under atmospheric pressure to constant weight. A minimum of 0.4 mole of the pseudopolymorph was thus prepared. The pseudopolymorph la obtained was analogous in form to that prepared in Example 1.

Reference： [1]Patent: WO2004/9608,2004,A2 .Location in patent: Page 25

21
[ 342371-84-0 ]
[ 76801-85-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium borohydride; In methanol; at 0 - 5℃; for 2h;	Add a erythromycin A 6,9-imino ether (40g, 55mmoL) to a 500mL three-necked flask, add 200mL methanol and stir to dissolve, cool to 0 C, and add (8.9g, 165mmol) KBH4 and (1.99g, 5.5mmoL), control temperature is not higher than 5 ,The reaction was stirred for 2h. 200 mL of water was added to the reaction mixture, and the solution was adjusted to pH = 3 with 10% hydrochloric acid.After stirring for 30 minutes, add 100 mL of isobutyl acetate and 45 g of IRA-743 resin, and then adjust the pH = 9.5 with 20% sodium hydroxide solution. After stirring for 15 minutes, collect the resin by filtration.The filtrate was left to separate and separated, and the organic layer was separated.It was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 38.2 g of a white foamy solid with a yield of 93%.
85%		Example-2; [93][94] Preparation of 9-deoxo-9a-aza-9a-homoerythromycin A; [95][96] To a mixture of 6,9-imino ether (II) (70.Og) in methanol (700ml) was added acetic acid till pH 5 to 6 is obtained. PtO2 (7.Og) in water was added to the above mixture and reduced under hydrogenation condition at hydrogen pressure 8 to 9 kg at 4O0C to 450C for about 4 to 5 hours. After completion of the reaction the reaction mixture was filtered through hyflobed, washed with methanol. The combined filtrate was distilled under vacuum to evaporate methanol. D. M. water (700ml) was added to the remaining filtrate. The pH of the solution was adjusted to 11 to 12 using aq. Sodium hydroxide solution. The solid precipitated was filtered, suck dried and then dried in oven to give 9-deoxo-9a-aza-9a-homo erythromycin A (III) (55.0g).[97] Yield: 85%
84.4%		50 g of erythromycin A-9 oxime was added to a 500 ml three-necked flask equipped with stirring,Followed by adding 200 ml of purified water,12.0 g sodium bicarbonate, the reaction temperature is controlled at about 5 ,Add another 15mlMethylsulfonyl chloride,With the addition of methyl sulfonyl chloride reaction solution gradually thinning,Until fully clarified,After the incubation reaction for 2 ~ 3 hr,A solution of 5.0% sodium borohydride in 100 ml,While 36% acetic acid solution was added dropwise,Control the pH between 6 to 8,2 to 6 hours drop finished,After heating for 1 to 2 hours,Add 15g of gulonic acid,Hydrolysis temperature control at about 8 ,With 10% hydrochloric acid pH1.5 ~ 2.5,Hydrolysis 8min, adding 100ml acetone,Plus 30% of the liquid alkali pH 10 ~ 11,With the addition of crystals to the liquid caustic soda,Cooling to 0 ~ 10 , filtration,Dried up azithromycin42.2 g (yield 84.4%).

70.3%

With methanol; sodium tetrahydroborate; at 0 - 20℃; for 24h;

Under 0 C ice bath conditions,0.1 g b (0.1435 mmol),0.088 g sodium borohydride (2.333 mmol)Dissolved in 1.2ml of anhydrous methanol,Stirring reaction 4h, then remove the ice bath,Continue to react at room temperature for 20h,After the reaction is completed, carbon dioxide is introduced into a white solid to form,Filtered, the filter cake was washed with a small amount of methanol, distilled under reduced pressure methanol, a white solid.DCM was added to dissolve the white solid,The organic phase is washed twice with 10% sodium bicarbonate, the layers are separated and the organic phase is added with 100 ml of water and the pH is adjusted to 2-3 (preferably 2.5) with 1 mol / L hydrochloric acid under stirring.After stirring for 20 minutes, the pH is adjusted to 6-7 (preferably 6.5) with 10% sodium hydroxide and the organic layer discarded.The aqueous layer was added with 20 ml of DCM, the pH was adjusted to 11 with 10% sodium hydroxide, stirred for 15 minutes, separated to give a DCM solvent,Drying in vacuo gave a white solid (III-1) (see Figure 1) in a yield of 70.6%

Reference： [1]Patent: CN110684056,2020,A .Location in patent: Paragraph 0006-0007
[2]Patent: WO2009/156938,2009,A2 .Location in patent: Page/Page column 8
[3]Patent: CN106632543,2017,A .Location in patent: Paragraph 0003; 0025-0026
[4]Organic and Biomolecular Chemistry,2008,vol. 6,p. 4120 - 4124
[5]Patent: CN106478541,2017,A .Location in patent: Paragraph 0022; 0047

22
[ 76801-85-9 ]
[ 620169-48-4 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 10 3'-lambda/-Demethyl-<strong>[76801-85-9]9-deoxo-9a-aza-9a-homoerythromycin A</strong> theta-Deoxo-thetaa-aza-thetaa-homoerythromycin A (400 g, 0.54 mol) and Trizma base (326 g, 2.69 mol; also known as 2-amino-2(hydroxylmethyl)-1 ,3-propa?ediol) were stirred in acetonitrile (6 L) under nitrogen. Then, iodine (612 g, 2.42 mol) was added in portions keeping the reaction mixture temperature not higher than 25 0C. The reaction mixture was stirred at room temperature for 2 hours, N-iodosuccinimide (67.2 g, 0.30 mol) was added and stirring continued overnight. Then acetonitrile was removed in vacuo, brown solid residue was dissolved in ethyl acetate (3 L) and stirred with 1 M aqueous potassium carbonate solution (3 L) and 12.5% sodium sulphite solution (3 L). The aqueous phase was separated and the pH adjusted from 9 to 10 by the addition of 1 M aqueous potassium carbonate (3 L) The obtained mixture was stirred for 1 hour resulting in formation of white precipitate, which was collected by filtration, washed with water (2 L) and dried overnight at 50 0C under vacuum. This material was slurried in dichloromethane (700 mL) for 1 hour, solid was collected by filtration, washed with dichloromethane (300 mL) and dryed at 50 C under vacuo overnight to afford title product (150 g) as a white solid, MS (ES+) m/z : 721.5 [M+H]+.

Reference： [1]Patent: WO2009/130189,2009,A1 .Location in patent: Page/Page column 39

23
[ 1304028-65-6 ]
[ 76801-85-9 ]
9a,11-O-{N'-[4-(3-methoxy)biphenyl]carbonimidoyl}-9-deoxo-9a-aza-9a-homoerythromycin A [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With triethylamine; In acetonitrile; at 60℃;	General procedure: To a solution of 1-4 in acetonitrile (c 0.03 g/ml), triethylamine (3 equiv), the corresponding isothiocyanate (3 equiv), and P-Mukaiyama reagent (1.18 mol/g, 1.5 equiv) were added and the reaction mixture shaken at 60 C overnight. The reaction mixture was cooled to room temperature and the P-Mukaiyama reagent separated by filtration. After evaporation of the solvent, the crude product was purified on the Flashmaster personal-solid phase extraction techniques (SPE 10 g). Solvent system gradient (98-93% CH2Cl2/(CH3OH/NH4OH = 9:1.5)) and 10 ml/min flow rate was used. Combining and evaporating the chromatographically homogenous fractions gave the final products 25-33.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 556 - 566

24
[ 2253-73-8 ]
[ 76801-85-9 ]
9a,11-O-(N'-isopropropylcarbonimidoyl)-9-deoxo-9a-aza-9a-homoerythromycin A [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With triethylamine; In acetonitrile; at 60℃;	General procedure: To a solution of 1-4 in acetonitrile (c 0.03 g/ml), triethylamine (3 equiv), the corresponding isothiocyanate (3 equiv), and P-Mukaiyama reagent (1.18 mol/g, 1.5 equiv) were added and the reaction mixture shaken at 60 C overnight. The reaction mixture was cooled to room temperature and the P-Mukaiyama reagent separated by filtration. After evaporation of the solvent, the crude product was purified on the Flashmaster personal-solid phase extraction techniques (SPE 10 g). Solvent system gradient (98-93% CH2Cl2/(CH3OH/NH4OH = 9:1.5)) and 10 ml/min flow rate was used. Combining and evaporating the chromatographically homogenous fractions gave the final products 25-33.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 556 - 566

25
[ 622-78-6 ]
[ 76801-85-9 ]
[ 166036-09-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine; In acetonitrile; at 60℃; for 3h;	General procedure: To the solution of compound 1-4 in acetonitrile (c 0.05 g/ml), benzyl isothiocyanate (3 equiv) and triethylamine (3 equiv) were added. The reaction mixture was stirred at 60 C for 3 h. After removal of the solvent under reduced pressure, a crude residue was obtained which was used as-is for further reactions. Purification of the crude products by solid phase extraction techniques (SPE), solvent system gradient (98-95% CH2Cl2/(CH3OH/NH4OH = 9:1.5)), afforded pure products 17 to 20 for the purpose of structure confirmation.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 556 - 566

26
[ 551-06-4 ]
[ 76801-85-9 ]
9a,11-O-[N'-(1-naphthyl)carbonimidoyl]-9-deoxo-9a-aza-9a-homoerythromycin A [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With triethylamine; In acetonitrile; at 60℃;	General procedure: To a solution of 1-4 in acetonitrile (c 0.03 g/ml), triethylamine (3 equiv), the corresponding isothiocyanate (3 equiv), and P-Mukaiyama reagent (1.18 mol/g, 1.5 equiv) were added and the reaction mixture shaken at 60 C overnight. The reaction mixture was cooled to room temperature and the P-Mukaiyama reagent separated by filtration. After evaporation of the solvent, the crude product was purified on the Flashmaster personal-solid phase extraction techniques (SPE 10 g). Solvent system gradient (98-93% CH2Cl2/(CH3OH/NH4OH = 9:1.5)) and 10 ml/min flow rate was used. Combining and evaporating the chromatographically homogenous fractions gave the final products 25-33.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 556 - 566

27
[ 76801-85-9 ]
[ 92594-46-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 1692 - 1701
[2]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 321 - 332
[3]Patent: WO2007/125414,2007,A2

28
[ 123-38-6 ]
[ 76801-85-9 ]
[ 92594-48-4 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2792 - 2804

29
[ 76801-85-9 ]
[ 111247-95-1 ]

Yield	Reaction Conditions	Operation in experiment
60.1%	With hydrogenchloride; In water; at 50℃; for 10h;	1.5 g of III-1 (2.0535 mmol)Dissolved in 120ml of hydrochloric acid,The reaction was stirred at 50 C for 10 hours,Add 10% sodium hydroxide in an ice bath, adjust the pH to 9, a large number of white solid precipitated, extracted with DCM 3 times, combined organicPhase, DCM was evaporated under reduced pressure, dried under vacuum,A white solid (III-4) (see Figure 1) was obtained in a yield of 60.1%

Reference： [1]Patent: CN106478541,2017,A .Location in patent: Paragraph 0022; 0050
[2]Structural Chemistry,2012,vol. 23,p. 1785 - 1796

30
[ 76801-85-9 ]
C₃₇H₆₈N₂O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		80.1 g of the compound of formula (I) (1-IPLC assay 85 %) were dissolved in 1 L of CH2C12 and the solvent was removed under reduced pressure. The residue was redissolved in 1 L of fresh CH2C12 and 167 mL of anhydrous DMSO were added while stirring under a nitrogen atmosphere. After cooling to -78 00, 38 mL of TFA were added dropwise over a period of 15 mm while stirring, with the temperature not exceeding -75 CC. The reaction mixture was stirred for additional 50 mm at -78 00. Next, 85 mL of Et3N were added dropwise over a period of 30 mm with the temperature not exceeding -75 00 The reaction mixture was stirred for additional 30 ruin at -78 C. Next, 250 mL of H20 were added and the mixture was gradually warmed up to room temperature. Then it was stored at -20 00 overnight. The layers were separated and the organic phase was washed with 3 x 250 mL of H20. The solvent was removed under reduced pressure to afford 77.482 g (f-IPLC assay 72 %, yield 82 %) of the compound of formula (II)HPLC purity: 71.05 area %

Reference： [1]Patent: WO2015/14907,2015,A1 .Location in patent: Page/Page column 22; 23

31
[ 76801-85-9 ]
(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[[2,6-dideoxy-3-C-methyl-3-Ο-methyl-4-C-[(propylamino)methyl]-α-L-ribohexopyranosyl]oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylohexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one [ No CAS ]

Reference： [1]Patent: WO2015/14907,2015,A1
[2]Patent: CN102786569,2016,B
[3]Patent: CN107501364,2017,A
[4]Patent: CN107501364,2017,A
[5]Patent: CN107501364,2017,A
[6]Patent: CN107501364,2017,A
[7]Patent: CN111004299,2020,A

32
[ 63697-96-1 ]
[ 76801-85-9 ]
(N¹⁰-(4-ethynylbenzyl))azithromycin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%		N10-Desmethylazithromycin 2 (2.72 g, 3.55 mmol) and 4-ethynylbenzaldehyde 6 39 (2.31 g, 17.75 mmol) were dissolved in anhydrous DMF (40 mL). Acetic acid (2.0 mL, 35.50 mmol) was added and the solution was stirred for 30 min and then sodium cyanoborohydride (465 mg, 7.10 mmol) was added to the reaction mixture. The mixture was then stirred at 70 C for 7 h after which it was cooled and the pH of the solution was raised to 8 by adding saturated aqueous NaHCO3 solution. The crude mixture was diluted into CH2Cl2 and was washed water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was purified by column chromatography (Silica gel, 5:1:1 EtoAc/hexane/triethylamine) to afford the title compound 7 as white solid (603 mg, 20%). 1H NMR (500 MHz, MeOH-d4) delta (ppm) 7.41 (s, 4H), 5.01 (m, 2H), 4.60 (d, J = 6.8 Hz, 1H), 4.20 (ddd, J = 24.8, 13.7, 6.6 Hz, 2H), 3.92 (d, J = 10.9 Hz, 1H), 3.73 (ddd, J = 37.9, 14.5, and 5.8 Hz, 4H), 3.45 (m, 1H), 3.38 (d, J = 11.2 Hz, 3H), 3.32 (m, 1H), 3.07 (dd, J = 11.5, and 7.2 HZ, 1H), 2.99 (m, 1H), 2.88 (dd, J = 14.7, and 8.4 Hz, 2H), 2.79 (m, 1H), 2.47 (d, J = 15.1 Hz, 1H), 2.40 (s, 6H), 2.19 (m, 1H), 2.11 (m, 1H), 1.96 (d, J = 21.6 Hz, 1H), 1.74 (m, 4H), 1.62 (m, 2H), 1.43 (m, 1H), 1.32 (m, 4H), 1.27 (m, 11H), 1.22 (m, 4H), 1.18 (d, J = 7.4 Hz, 3H), 1.14 (dd, J = 8.0, and 4.1 Hz, 3H), 0.94 (m, 3H), 0.89 (t, J = 7.3 Hz, 3H). 13C (125 MHz, MeOH-d4) delta (ppm) 178.7, 132.9, 130.7, 104.2, 97.6, 80.7, 79.4, 78.4, 76.9, 76.5, 74.5, 72.7, 69.4, 67.1, 65.6, 50.1, 46.6, 40.8, 36.3, 31.9, 23.2, 22.3, 21.9, 21.8, 19.1, 11.8, 10.8. HRMS (ESI) m+2/2z Calcd for C46 H78 O12 N2 [M+2H+]: 425.2772, found 425.2762.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 7543 - 7564

33
[ 1357466-70-6 ]
[ 76801-85-9 ]

Yield	Reaction Conditions	Operation in experiment
57.4 g		85g of erythromycin A 9-oxime thiocyanate, 500ml of dichloromethane was added to 1000ml reaction flask then adjust PH9 ~ 11 by adding 20% sodium hydroxide and after all the solid was dissolved the stratification was carried out . the upper aqueous layer was again extracted with dichloromethane and the combined the dichloromethane layers. Dichloromethane was concentrated by evaporation and 250ml of water was added. cooled to below 10 C, then methanesulfonyl chloride 25g was added and the incubation reaction was carried out until erythromycin A9-oxime was complete. With 20% sodium hydroxide adjusted pH3 ~ 7, cooling to below 10 C, sodium borohydride 7g was added and Insulation reaction is completed. Then dichloromethane 1000ml was added , adjust pH0. 5 ~ 2. 5 with 10% hydrochloric acid , incubation at 0 ~ 10 C and stirred for 20 minutes. Then, adjusted pH9 ~ 11 by adding 20% sodium hydroxide, allowed to stand to separate the layers and the aqueous layer was extracted with 100ml of dichloromethane then the combined dichloromethane layer and 200ml of water was added. Concentrated under reduced pressure to remove dichloromethane, cooled to 0 ~ 5 C, washed the filter and drying was carried out to obtain 57. 4g products, purity 94.6% by HPLC , moisture

Reference： [1]Patent: CN103772456,2016,B .Location in patent: Paragraph 0029-0030
[2]Patent: CN107141324,2017,A

34
[ 24424-99-5 ]
[ 76801-85-9 ]
(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-((3,4,6-trideoxy-3-(dimethylamino)-2-O-(tert-butoxycarbonyl)-β-D-xylo-hexopyranosyl)oxy)-1-oxa-6-(tert-butoxycarbonyl)azacyclopentadecan-15-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.3%	With dmap; In tetrahydrofuran; at -5 - 5℃; for 10.5h;Reflux;	250ml three-necked flask were added 15g (20.4mml) (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-((3,4,6-trideoxy-3-(dimethylamino)-beta-D-xylo-hexopyranosyl)oxy)-1-oxa-azacyclopentadecan-15-one 90ml of tetrahydrofuran, 1.2g 4-dimethylaminopyridine, temperature -5-5, thereto was slowly added dropwise 11.1g (51.0mml) di-tert-butyl dicarbonate dropwise after stirring for half an hour, warmed to reflux, the reaction was continued 10H, the reaction was completed, filtered, washed with 40ml of water was added to the system, the organic phase was dried, concentrated with n-hexane to force the crystals to give 19.1g product, yield 86.3 %.

Reference： [1]Patent: CN102786569,2016,B .Location in patent: Paragraph 0054; 0055

35
[ 13127-18-9 ]
[ 76801-85-9 ]

Reference： [1]Chemical Communications,2018,vol. 54,p. 654 - 657
[2]Patent: CN106478541,2017,A

36
[ 76801-85-9 ]
[ 371193-61-2 ]

Reference： [1]Patent: CN107400152,2017,A
[2]Patent: CN107400152,2017,A
[3]Patent: CN107501364,2017,A
[4]Patent: CN107501364,2017,A
[5]Patent: CN111004299,2020,A

37
[ 7704-67-8 ]
[ 76801-85-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: hydroxylamine hydrochloride; triethylamine / methanol / 52 h / 30 - 55 °C / pH 6.3 - 6.7 2.1: sodium hydrogencarbonate; p-toluenesulfonyl chloride / acetone / 4 h / 0 - 10 °C 3.1: phosphoric acid; potassium borohydride / water / 8 h / 0 - 5 °C / pH 7 - 9 3.2: 3 h / 0 - 5 °C / pH 2.5 - 3

Reference： [1]Current Patent Assignee: HEBEI UNIVERSITY OF SCIENCES AND TECHNOLOGY - CN107141324, 2017, A

38
erythromycin A 6,9-imino ether [ No CAS ]
[ 76801-85-9 ]

Yield	Reaction Conditions	Operation in experiment
		2. 1: Reduction80 g erythromycin A imino ether suspension in 320 ml water, stirring 10 min, cooling to 0-5 C. Add dropwise phosphoric acid to adjust the pH=7.0. Slowly add 16.7 wt % potassium borohydride aqueous solution 20 g. 1h addition complete. Maintain temperature stirring reaction 2h, pH=8.5-9.0. Add dropwise phosphoric acid, adjusting pH=7.0. Add dropwise 20 wt % potassium borohydride aqueous solution 10 g. Maintain temperature stirring reaction 2h, pH=8.0-8.5. Add dropwise phosphoric acid, adjusting pH=8.0. Continue to add dropwise 20 wt % potassium borohydride aqueous solution 10 g. Maintain temperature reaction 3 h, TLC monitoring. The end of the reaction. Add dropwise 10 wt % hydrochloric acid, adjust pH=5-6. Stirring until no gas is released. Add 800 ml dichloromethane. Add dropwise 10 wt % sodium hydroxide aqueous solution to adjust the pH=11-12. Stirring 0.5 h. Allow to stand to form layers. The water layer is 200 ml methylene chloride extraction. The combined methylene chloride level, remove the aqueous layer. The dichloromethane layer equally divided into two parts.2. 2: First hydrolysisTo step 2.1 one part methylene chloride layer, add 160 ml water. Cool to 0-5 C. Add dropwise 10 wt % hydrochloric acid to adjust water layer pH=2.5 - 3.0, Maintain temperature stirring reaction 1 h. TLC monitoring, borate {double to a Azithromycin borate (VI) and to a Azithromycin borate (VII)} basically disappears. The reaction under stirring [...] 5 wt % of sodium hydroxide aqueous solution 100 g in, room temperature stirring 1 h, static delamination, remove the aqueous layer.2. 3: Second hydrolysisThe above step organic phase was added 160 ml water, cooling to 0 - 5 C, 10 wt % hydrochloric acid to adjust the pH=2.5 - 3.0, maintain temperature stirring reaction 1h. TLC monitoring, borate {double to a Azithromycin borate (VI) and to a Azithromycin borate (VII)} disappears. The reaction under stirring [...] 5 wt % of sodium hydroxide aqueous solution 100 g in, room temperature stirring 1 h, static delamination, remove the aqueous layer.2.4: Preparation of desmethyl azithromycin (I) Second hydrolysis methylene chloride layer was added 160 ml water. Cool to 0-5 C. 10 wt % hydrochloric acid adjust the pH=2.5-3.0. Maintain temperature stirring reaction 1h. TLC monitoring borate {double to a Azithromycin borate (VI) and to a Azithromycin borate (VII)} disappears, static delamination. The fast is poured into the water layer 3 wt % sodium hydroxide aqueous solution 200 g in, stirring 0.5 h. 25 - 30 C decompression removing the residual dichloromethane, control pH=12 - 13. 20 - 25 C stirring crystallization 1 h, filtering, for 50 ml water washing 2 times, drying, to obtain desmethyl azithromycin (I) 35.3 g, yield 88.3%, purity 85%, borate {double to a Azithromycin borate (VI) and to a Azithromycin borate (VII)} has not detected (HPLC).Step 2.1 other part dichloromethane undergo same operation as above, have to obtain desmethyl azithromycin (I) 35.4 g, yield 88.5%, purity 87.0%, borate {double to a Azithromycin borate (VI) and to a Azithromycin borate (VII) and of} ? 0.5% (HPLC see Figure 3 and table 3 shown).

Reference： [1]Patent: CN107141324,2017,A .Location in patent: Paragraph 0058-0097

39
[ 147790-52-1 ]
[ 76801-85-9 ]
benzyl 6-[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-6-yl]hexanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.45 g	With sodium cyanoborohydride; acetic acid; In N,N-dimethyl-formamide; at 70℃; for 16h;	To a stirred solution of N-desmethyl-azithromycin (0.85 g, 1 .16 mmol), benzyl 6- oxohexanoate (0.64 g, 2.91 mmol) and CH3COOH (0.67 mL, 1 1.6 mmol) in DMF (30 mL) was added NaBHsCN (0.15 g, 2.32 mmol). The resulting mixture was heated at 70 C for 16 h. On cooling the reaction was quenched with H2O (20 mL), saturated aqueous NaHCOs (10 mL) and diluted with DCM (30 mL). The organic layer was separated and the aqueous further extracted with DCM (2 x 30 mL). The combined organics were washed with saturated aqueous NaHCOs (50 mL) and brine (50 mL). After drying over Na2S04 the organics were concentrated under reduced pressure and the resulting residue purified by chromatography eluting with 5-7% MeOH/0.7 M NH3 in DCM to give benzyl 6- [(2R,3S,4R,5R,8R,10R,1 1 R,12S,13S,14R)-1 1 -[(2S,3R,4S,6R)-4-(dimethylamino)-3- hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4- methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,6,8, 10, 12,14-hexamethyl-15-oxo-1 -oxa-6- azacyclopentadecan-6-yl]hexanoate (0.45 g) as a white solid, which was used in the next step.
0.45 g	With sodium cyanoborohydride; acetic acid; In N,N-dimethyl-formamide; at 70℃; for 16h;	To a stirred solution of N-desmethyl-azithromycin (0.85 g, 1 .16 mmol), benzyl 6-oxohexanoate (0.64 g, 2.91 mmol) and CH3COOH (0.67 mL, 1 1 .6 mmol) in DMF (30 mL) was added NaBH3CN (0.15 g, 2.32 mmol). The resulting mixture was heated at 70 C for 16 h. On cooling the reaction was quenched with H2O (20 mL), saturated aqueousNaHCOs (10 mL) and diluted with DCM (30 mL). The organic layer was separated and the aqueous further extracted with DCM (2 x 30 mL). The combined organics were washed with saturated aqueous NaHCOs (50 mL) and brine (50 mL). After drying over Na2S04the organics were concentrated under reduced pressure and the resulting residue purified by chromatography eluting with 5-7% MeOH/0.7 M NH3in DCM to give benzyl 6-[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-6-yl]hexanoate (0.45 g) as a white solid, which was used in the next step.

Reference： [1]Patent: WO2018/193124,2018,A1 .Location in patent: Paragraph 00201
[2]Patent: WO2018/193117,2018,A1 .Location in patent: Paragraph 00251

40
[ 72359-96-7 ]
[ 76801-85-9 ]
(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-6-(8-chlorooctyl)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%	With sodium cyanoborohydride; acetic acid; In N,N-dimethyl-formamide; at 20 - 70℃; for 88h;	A room temperature solution of (2R,3S 4R 5R 8R 10R,1 1 R,12S,13S,14R)-1 1 - [(2S 3R 4S 6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3 4,10- trihydroxy-13-[(2R 4R,5S 6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}- 3,5,8,10,12,14-hexamethyl-1 -oxa-6-azacyclopentadecan-15-one (1 .05 g, 1.43 mmol), 8- chlorooctanal (prepared as described in Example 1 step (a)) (1 .16 g, 7.13 mmol) and CHsCOOH (0.82 mL, 14.26 mmol) in DMF (1 1 .04 mL, 143 mmol) was treated with NaBH3CN (0.18 g, 2.85 mmol). The resulting reaction mixture was heated at 70 C for 16 h. On cooling the reaction mixture was further stirred at room temperature. After 72 h the reaction mixture was partitioned between H20 (100 mL), saturated aqueous NaHC03 (100 mL) and DCM (200 mL). The layers were separated and the aqueous further extracted with DCM (2 x 150 mL). The combined organics were washed with saturated aqueous NaHCOs (200 mL) and brine (3 X 200 m) and concentrated in vacuo. The resulting residue was purified by column chromatography eluting with 0-10% MeOH containing 20% NH3 in DCM to give (2R,3S,4R,5R,8R,10R,1 1 R,12S,13S,14R)-6-(8-chlorooctyl)-1 1 -[(2S,3R,4S,6R)-4- (dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10-trihydroxy-13- [(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,8, 10,12, 14- hexamethyl-1 -oxa-6-azacyclopentadecan-15-one (0.12 g, 9%) as a colourless solid. LCMS (Method E) 882 [M+H]+; RT 2.1 1 min

Reference： [1]Patent: WO2018/193124,2018,A1 .Location in patent: Paragraph 00182-00183

41
(13-carboxytridecyl)triphenylphosphonium bromide [ No CAS ]
[ 76801-85-9 ]
{14-[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-6-yl]-14-oxotetradecyl}triphenylphosphonium hexafluorophosphate(V) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃;	General procedure: A1 - To a stirred solution of N-desmethyl-azithromycin (1 equivalent), the corresponding phosphonium acid (1 .1 equivalents) and HATU (1.2 equivalents) in DCM (10 mL) was added Nu,Nu-diisopropylethylamine (DIEA) (2 equivalents). After stirring at room temperature for 16 to 20 h the reaction mixture is concentrated, and the resulting residue diluted with 7M NH3 MeOH and stirred for a further 16 to 20 h. The reaction mixture is then concentrated under reduced pressure and diluted with EtOAc. The organic is washed sequentially with saturated aqueous NaHCC>3, NH4CI and brine. The organic is dried over Na2S04and concentrated under reduced pressure to give the crude product, which is purified by chromatography to give the desired final product

Reference： [1]Patent: WO2018/193117,2018,A1 .Location in patent: Paragraph 00230; 00231; 00239

42
[ 72359-96-7 ]
[ 76801-85-9 ]
C₄₅H₈₄N₂O₁₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium cyanoborohydride; acetic acid; In N,N-dimethyl-formamide; at 75℃;	Step 1 - To a stirred solution of N-desmethyl-azithromycin (1 equivalent), LG-I_2a- CHO (where LG presents a leaving group; l_2a is one carbon shorter than L2) (3.5 equivalents) and CH3COOH (10 equivalents) in DMF (10 ml.) is added NaBH3CN (2 equivalents). The resulting mixture is heated at 75 C for 90 min to 16 h. On cooling the reaction is quenched with H2O, saturated aqueous NaHC03 and diluted with DCM. The aqueous layer is extracted further with DCM and the combined organics washed with saturated aqueous NaHC03 and brine. After drying over Na2S04the organic is passed through a phase separator and concentrated under reduced pressure to give the crude product, which is purified by chromatography and used in step 2.

Reference： [1]Patent: WO2018/193117,2018,A1 .Location in patent: Paragraph 00233; 00234; 00245

43
{2-[2-(2-carboxyethoxy)ethoxy]ethyl}triphenylphosphonium bromide [ No CAS ]
[ 76801-85-9 ]
[2-(2-{3-[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-6-yl]-3-oxopropoxy}ethoxy)ethyl]triphenylphosphonium bromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15 mg	With 1-hydroxy-7-aza-benzotriazole; diisopropyl-carbodiimide; In dichloromethane; at 30℃; for 32h;	To a solution of N-desmethyl-azithromycin (0.2 g, 0.27 mmol), {2-[2-(2- carboxyethoxy)ethoxy]ethyl}triphenylphosphonium bromide (prepared as described in Example 23 step (b)) (0.27 g, 0.54 mmol) and 1 -hydroxy-7-azabenzotriazole (HOAt) (46 mg, 0.3 mmol) in DCM (10 mL) was added Nu,Nu'-diisopropylcarbodiimide (DIC) (47 muIota_, 0.3 mmol). The resulting reaction mixture was heated at 30 C. After 16 h further quantities of {2-[2-(2-carboxyethoxy)ethoxy]ethyl}triphenylphosphonium bromide (0.13 g, 0.27 mmol) and Nu,Nu'-diisopropylcarbodiimide (DIC) (47 muIota_, 0.3 mmol) were added and heating continued for a further 16 h. On cooling the reaction mixture was concentrated under reduced pressure and the resulting residue taken up in MeOH (20 mL) and heated at 50 C fori 6 h. On cooling the solvent was removed under reduced pressure and the resulting residue purified by chromatography eluting with 0-20% MeOH/0.7 M NH3 in DCM to give the title compound (15 mg) as a white solid.LC-MS (Method H) 1 151 [M]+; RT 6.66 min

Reference： [1]Patent: WO2018/193117,2018,A1 .Location in patent: Paragraph 00251

44
[ 7530-96-3 ]
[ 76801-85-9 ]
{11-[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-6-yl]-11-oxoundecyl}triphenylphosphonium chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.4 g		A stirred solution of (10-carboxydecyl)triphenylphosphonium bromide (431 mg, 0.82 mmol), 1 -hydroxy-7-azabenzotriazole (HOAt) (1 1 1 mg, 0.82 mmol), N,N- diisopropylethylamine (DIEA) (0.36 ml_, 2.04 mmol) and N,N'-diisopropylcarbodiimide (DIC) (127 muIota_, 0.82 mmol) in DCM (2 mL) was heated at 40 C. After 30 min the reaction mixture was added to a stirred solution of N-desmethyl-azithromycin (0.5 g. 0.68 mmol) in DCM (2 mL) at 40 C. Stirring at 40 C was continued overnight. On cooling to room temperature H2O (5 mL) and DCM (5 mL) were added and the mixture passed through a phase separator, washing with DCM (2 x 1 mL). The DCM fractions wee pooled and solvent removed under reduced pressure to give a residue, which was taken up in MeOH (5 mL) and heated at 60 C for 2 h. On cooling the solvent was removed under reduced pressure and the resulting residue taken up in THF (10 mL), which was washed with saturated aqueous NH4CI (10 mL). The separated aqueous phase was further extracted with THF (2 x 5 mL). The combined organic extracts were washed with brine (10 mL), dried over MgS04and solvent removed under reduced pressure. The resulting residue was purified by silica column chromatography eluting with 0-10% MeOH/0.7 M NH3 in DCM. The resulting product was partitioned between DCM (10 mL) and saturated aqueous NH4CI (10 mL). The separated organic phase was passed through a phase separator containing brine (5 mL). The collected solvent was evaporated under reduced pressure and the resulting residue taken up in MeOH (3 mL) and filtered through an Amberlite IRA-400(CI) ion exchange resin. The collected MeOH was recycled through the column 3 x, followed by a fresh volume of MeOH. The combined MeOH washings were concentrated under reduced pressure to give the title compound (0.4 g) as a white solid.LC-MS (Method D) 1 164 [M]+; RT 1 .93 min

Reference： [1]Patent: WO2018/193117,2018,A1 .Location in patent: Paragraph 00251

45
erythromycin 6,9-imino ether [ No CAS ]
[ 76801-85-9 ]

Yield	Reaction Conditions	Operation in experiment
17.1%	With platinum on carbon; hydrogen; In methanol; at 40 - 45℃; under 7500.75 Torr; for 4h;Autoclave;	20 g of erythromycin imine ether, dissolved in 140 g of methanol, adjusted to pH 4-5 with sulfuric acid, and added 3 g of 5% Pt/C,After transferring to the autoclave, the air was exhausted by a vacuum-nitrogen method, and then hydrogen gas was charged at a pressure of 1.0 MPa, and the temperature was raised to 40 to 45 C, and the temperature was maintained for 4 hours until the end of the reaction.The catalyst was removed by filtration, 100 g of methanol was recovered, and the temperature was lowered to 30 C, and a 10% aqueous sodium hydroxide solution was slowly added dropwise to adjust the pH to 10 to 12.The dropping time was controlled to about 2 hours, and after the dropwise addition was completed, 100 g of water was further added dropwise.The dihydrodaunorubicin wet product was obtained by filtration, and dried to obtain 17.1 g of dihydrodaunorubicin dihydrate, having a water content of 5.1% and a liquid phase content of 95.8%.

Reference： [1]Patent: CN109293719,2019,A .Location in patent: Paragraph 0026-0031

46
[ 1885-14-9 ]
[ 76801-85-9 ]
C₄₄H₇₄N₂O₁₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	In dichloromethane; at -5 - 0℃; for 3h;	Add the compound of formula I (100.00g) and dichloromethane (700.00g) to the reaction flask at room temperature, stir and reduce the temperature to -5.0 C, and add a mixture of phenyl chloroformate (22.36g) and dichloromethane (100.00g) dropwise The solution was kept at 0 C and stirred for 3 hours. After the reaction was completed, an aqueous sodium carbonate solution was added to separate the liquid to obtain an organic phase, which was concentrated to obtain the compound of formula II, which was used directly in the next step.Yield: 92%.

Reference： [1]Patent: CN110903335,2020,A .Location in patent: Paragraph 0045-0047

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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. 76801-85-9 ] {[proInfo.proName]}

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[ 76801-85-9 ] Synthesis Path-Upstream 1~8

[ 76801-85-9 ] Synthesis Path-Downstream 1~46

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