[ CAS No. 702-82-9 ]

Name: 702-82-9|3-Aminoadamantan-1-ol|95% (contains <6%H2O)
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Product Details of [ 702-82-9 ]

CAS No. :	702-82-9	MDL No. :	MFCD01821204
Formula :	C₁₀H₁₇NO	Boiling Point :	266.8°C at 760 mmHg
Linear Structure Formula :	-	InChI Key :	-
M.W :	167.25 g/mol	Pubchem ID :	658645
Synonyms :

Calculated chemistry of of [ 702-82-9 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	47.79
TPSA :	46.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.94 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.81
Log Po/w (XLOGP3) :	0.53
Log Po/w (WLOGP) :	1.03
Log Po/w (MLOGP) :	1.52
Log Po/w (SILICOS-IT) :	1.35
Consensus Log Po/w :	1.25

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.21
Solubility :	10.3 mg/ml ; 0.0615 mol/l
Class :	Very soluble
Log S (Ali) :	-1.07
Solubility :	14.2 mg/ml ; 0.0846 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.22
Solubility :	9.99 mg/ml ; 0.0597 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.72

Safety of [ 702-82-9 ]

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

Application In Synthesis of [ 702-82-9 ]

* 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 [ 702-82-9 ]
Downstream synthetic route of [ 702-82-9 ]

[ 702-82-9 ] Synthesis Path-Upstream 1~8

1
[ 880-52-4 ]
[ 5001-18-3 ]
[ 702-82-9 ]
[ 778-10-9 ]

Reference： [1] Russian Journal of Organic Chemistry, 2017, vol. 53, # 7, p. 971 - 976[2] Zh. Org. Khim., 2017, vol. 53, # 7, p. 959 - 964,5

2
[ 665-66-7 ]
[ 702-82-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	at 0 - 10℃; for 2 h;	To a round bottom flask containing 1, amantadine hydrochloride (100 mg,0.53 mmol) a mixture of concentrated sulfuric acid (2 ml, 37.1 mmol) andconcentrated nitric acid (0.2 ml, 4.46 mmol) was added at 0°C. Themixture was left to stir for two hours at 10 °C. Ice-cold water was thencarefully added to the reaction mixture, following this addition the reactionmixture was made basic using solid sodium hydroxide until precipitation couldbe seen. The solution was thereafter filtered and the wet solid collected anddissolved in DCM and left to stir for 30 minutes. Next, the solid was removedfrom the solution by filtration and washed with DCM. The DCM-solutioncontaining 2 was concentrated to afford compound 2 (70 mg, yield 81percent).
48%	Stage #1: at 0 - 20℃; for 48 h; Stage #2: at 80℃; for 1 h; Cooling with ice	To an ice-cooled mixture of sulfuric acid (96percent, 12.33 mL, 231 mmol) and nitric acid (65percent, 1.2 mL, 26.5 mmol) was added 1-aminoadamantane hydrochloride (1 g, 6.61 mmol) portion wise. The mixture was stirred at rt for 2 days, ice-water (6 mL) was added to the reaction mixture. The solution was stirred in an ice-water bath for 30 min; KOH (35 g, 0.62 mol) was added in small portions over 1 h at such a rate to keep the temperature below 80 °C. The resulting white paste was mixed with CH₂Cl₂ (300 mL) and vigorously stirred for 1 h. The solid was filtered off, and the mother liquor was evaporated to dryness under reduced pressure to provide 5 (527 mg, 3.15 mmol) in 48percent yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 4.33 (s, 1H), 2.08 (s, 2H), 1.49-1.42 (m, 5H), 1.38-1.35 (m, 9H). ¹³C NMR (100 MHz, DMSO-d₆): δ 67.7, 54.0, 44.8, 44.1, 34.8, 30.5. HRMS calcd for C₁₀H₁₈NO 168.1383, found 168.1380.
48%	Stage #1: With sulfuric acid; nitric acid In water at 20℃; for 48 h; Cooling with ice Stage #2: With potassium hydroxide In water at 80℃; for 1 h;	To an ice-cooled mixture of sulfuric acid 96percent (12.33 mL, 231 mmol) and nitric acid 65percent (1.2 mL, 26.5 mmol) was added 1-aminoadamantan HCl (1g, 6.61 mmol) portionwise. The mixture was stirred at rt for 2 days. Ice-water (6 mL) was added to the reaction and solution was placed in an ice-water bath and allowed to stir for 30 minutes. KOH (35 g, 0.62 mol) was added in small portions over 1 h. During this addition, the reaction was never allowed to exceed 80 °C. The resulting white paste was mixed with DCM (300 mL) and vigorously stirred for 1 h. After filtration the organic layer is separated and solvents were removed under reduced pressure to provide 5 (527 mg, 3.15 mmol) in 48percent yield as a white solid. HRMS calcd for C₁₀H₁₈NO 168.1383, found 168.1380.

3.2 g	Stage #1: With sulfuric acid; nitric acid In water for 3 h; Cooling with ice Stage #2: With potassium hydroxide In water for 2 h; Cooling with ice	38 ml of 98percent concentrated sulfuric acid with 4 ml of 65percent concentrated nitric acid in mixed under ice bath cooling, the mixed acid in to the adding 3 . 75 g amantadine hydrochloride, stirring in ice bath reaction 3 hours; 60 g adding crushed ice, stirring 0.5 hours; then adding solid potassium hydroxide, to adjust the pH value to 12 - 13, the reaction under ice bath 2 hours; and filtering, the filtrate concentrated hydrochloric acid to adjust the pH value to 8 - 9, concentrated to dry; adding 80 ml anhydrous ethanol reflux 1 hour, cool, filtered, the filtrate is concentrated to dry; then adding 10 ml of the mixed liquid (acetone: ethyl acetate=3:1) reflux 1 hour, placed under ice bath, filtered, shall be 3 - amino adamantanol mellow solid 3.2 g,
58 g	at 0 - 20℃; for 13.5 h;	(1) To a three-mouth flask, equipped with thermometer and tail gas absorption device, add 170 ml trifluoroacetic acid, and 800 ml fuming sulfuric acid. Under ice-bath cooling, under stirring slowly drop 56 ml 65percent concentrated nitric acid, stirring 30min, When temperature drop to 0 °C, in 30min divided 8 times add 76g amantadine hydrochloride, After stirring 3 hours, remove ice-bath. Control temperature to 20 °C, stirring 10 hours, to the reaction solution is added to the reaction solution in the ice cubes one by one for clarification, the reaction liquid is moved to the stirring in ice bath 30min, after the reaction liquid into white, removed ice, stirring under batchwise by adding 89percent potassium hydroxide to neutralize, to the solution is strongly alkaline to continue after the stirring, the absorption of the generation of a white solid; (2) the one step on the resulting white to the absorption of the solid filtered, washing the resulting solid with chloroform, extraction, the filtrate, anhydrous sodium sulfate drying, filtering, and steaming and, after removal of a part of the solvent in the standstill or put into the refrigerator, crystallization, extraction, to obtain white solid 3-amino-1-adamantanol, methanol is recrystallized to obtain fine 58g, purity 99percent or more.

Reference： [1] Pharmaceutical Chemistry Journal, 1990, vol. 24, # 1, p. 35 - 39[2] Khimiko-Farmatsevticheskii Zhurnal, 1990, vol. 24, # 1, p. 29 - 31
[3] Tetrahedron Letters, 2017, vol. 58, # 15, p. 1456 - 1458
[4] Journal of Medicinal Chemistry, 2016, vol. 59, # 3, p. 947 - 964
[5] European Journal of Medicinal Chemistry, 2015, vol. 92, p. 554 - 564
[6] Patent: EP2966062, 2016, A1, . Location in patent: Paragraph 0063; 0069
[7] Patent: WO2011/101861, 2011, A1, . Location in patent: Page/Page column 17
[8] Patent: CN105523985, 2016, A, . Location in patent: Paragraph 0049; 0050; 0051; 0052; 0053
[9] Patent: CN106432026, 2017, A, . Location in patent: Paragraph 0033; 0034; 0035
[10] Patent: CN103804204, 2017, B, . Location in patent: Paragraph 0020; 0021; 0022
[11] Patent: CN105949070, 2016, A, . Location in patent: Paragraph 0022-0024

3
[ 768-94-5 ]
[ 702-82-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: With sulfuric acid; nitric acid In water at 5 - 25℃; Stage #2: at 0 - 40℃; for 1 h;	Example 1: Preparation of 3-amino-adamantan-l-ol (0099) In a clean and dry 5.0 L 4 necks RBF equipped with liquid addition funnel, TP. Charged cone, sulphuric acid (300 mL, 2 V) and cooled the reaction mass to 5-10 °C. To the cooled mass 1-adamantyl amine (150 g, 1 eq.) was added lot wise at 5-10 °C. After complete addition, stirred the reaction mass to get clear (slightly hazy) solution and maintained the reaction mass at 5-15 °C. Meanwhile a nitrating mixture was prepared by adding 150 mL of 65-70 percent nitric acid to 450 mL cone, sulphuric acid maintaining temperature at 0-10 °C). The nitrating mixture was added to the reaction mass maintaining reaction temperature at 20 ± 5 °C. After the addition was over, stirred the reaction mass at 20 ± 5°C for 3 to 5 h. Completion of the reaction was confirmed by GC. The reaction mass was cooled to 0 - 5 °C and added water (150 mL, I V) to the reaction mass maintaining 0-20 °C and again cooled reaction mass to 5-10 °C. Second lot of water (300 mL, 2 V) was added to the reaction mass maintaining 5-20 °C. The reaction mass was cooled again to 5-10 °C and added third lot of water (1050 mL, 7 V) to the reaction mass maintaining 5-20 °C. After complete addition of water the reaction mass was cooled to 0-5 °C and added 50 percent NaOH solution maintaining 0- 40 °C and stirred for 1 h at 35-40 °C. Filtered the solid obtained and washed the cake with water (150 mL, IV). Wet weight: 1 185 g. The wet cake was dried under reduced pressure at 60-70 °C. Mixed the above dried solid with IPA (750 mL, 5 V w.r.t. adamantly amine) and heated at 50 - 60°C and maintained for 1 h. Then cooled reaction mass to 20-25°C and maintained at 20-25°C for 1 h. Filtered the solid obtained and wash with IPA (150 mL, 1 V). Distilled around 600 mL, 4 - 4.5 V of IPA from reaction mass under reduced pressure and cooled the residual reaction mass to 40-45°C. Added cyclohexane (1200 mL, 8 V) to reaction mass and heated to 50-55°C. Applied 200-250 Torr vacuum slowly to the reaction mass and distilled cyclohexane (900 mL, 6 V) from reaction mass under reduced pressure. Filtered the solid and wash with cyclohexane (150 mL, IV) Unload solid and dry it for 10-12 h under reduced pressure at 60°C. Yield range: 90percent; GC purity > 98percent; melting point: 265°C; 1H NMR (CDC1₃, 400 MHz) δ: 1.35-1.48 (m, 14H, 6xCH₂, l NH₂); 2.08 (brs, 2H, 2*CH); 4.36 (s, ΙΗ, ΟΗ).
81%	at 0 - 10℃; for 2 h;	To a round bottom flask containing compound 13 (100mg, 0.53mmol) a mixture of concentrated sulfuric acid (2mL, 37.1mmol) and concentrated nitric acid (0.2mL, 4.46mmol) was added at 0°C. The mixture was left to stir for two hours at 10°C. Ice-cold water was then carefully added to the reaction mixture, following this addition the reaction mixture was made basic using solid sodium hydroxide until precipitation could be seen. The solution was thereafter filtered, and the wet solid collected and dissolved in DCM and left to stir for 30min. Next, the solid was removed from the solution by filtration and washed with DCM. The DCM-solution containing 14 was concentrated in vacuo to afford compound 14 (70mg, yield 81percent). ¹H NMR (CDCl₃ 300MHz) δ: 2.24–2.16 (m, 2H), 1.62–1.58 (m, 4H), 1.54–1.50 (m, 2H), 1.49–1.43(m, 6H). ¹³C NMR (CDCl₃, 75.4MHz) δ: 69.6 (HOC), 53.9, 50.5, 44.9, 44.2, 34.9, 31.1 (aliphatic C).

Reference： [1] Patent: WO2015/128718, 2015, A1, . Location in patent: Page/Page column 15
[2] Tetrahedron, 2018, vol. 74, # 24, p. 2905 - 2913
[3] Russian Journal of Organic Chemistry, 2009, vol. 45, # 8, p. 1137 - 1142

4
[ 243145-00-8 ]
[ 702-82-9 ]

Yield	Reaction Conditions	Operation in experiment
19.5g	With sodium methylate In methanol at 30℃; for 0.5 h;	Added in the reaction bottle 96percent - 98percent concentrated sulfuric acid 300 ml (5.28mol) stirring cooling to 5 °C the following, is dripped slowly into the 68percent nitric acid 30 ml (0.41mol), and ice in batches under cooling by adding amantadine hydrochloride 24g (0.13mol). The temperature is increased to 25 °C stirring reaction 10hr. Lowering the temperature to the reaction liquid 15 °C the following, under stirring sodium methoxide methanol solution slowly adding 400 ml (25percent, 1 . 80mol), pH > 14, the 30 °C stirring for 30 min, solid inorganic salt worry eliminates, filtrate water 100 ml, stirring and heating to reflux 1hr, filtering, the filtrate concentrated under reduced pressure, obtaining white crystalline 3-hydroxy-1-amantadine (2) (19.5g, 89.4percent).

Reference： [1] Patent: CN105439873, 2016, A, . Location in patent: Paragraph 009; 0019; 0020

5
[ 67496-92-8 ]
[ 702-82-9 ]

Reference： [1] Patent: EP915077, 1999, A1,

6
[ 665-66-7 ]
[ 702-82-9 ]

Reference： [1] Patent: US5395846, 1995, A,

7
[ 880-52-4 ]
[ 5001-18-3 ]
[ 702-82-9 ]
[ 778-10-9 ]

Reference： [1] Russian Journal of Organic Chemistry, 2017, vol. 53, # 7, p. 971 - 976[2] Zh. Org. Khim., 2017, vol. 53, # 7, p. 959 - 964,5

8
[ 702-82-9 ]
[ 1032564-18-3 ]

Reference： [1] Patent: WO2011/101861, 2011, A1,
[2] Patent: WO2011/101861, 2011, A1,
[3] Patent: WO2015/128718, 2015, A1,
[4] Patent: CN107033054, 2017, A,

[ 702-82-9 ] Synthesis Path-Downstream 1~31

1
[ 665-66-7 ]
[ 702-82-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sulfuric acid; nitric acid; at 0 - 10℃; for 2h;	To a round bottom flask containing 1, <strong>[665-66-7]amantadine hydrochloride</strong> (100 mg,0.53 mmol) a mixture of concentrated sulfuric acid (2 ml, 37.1 mmol) andconcentrated nitric acid (0.2 ml, 4.46 mmol) was added at 0 C. Themixture was left to stir for two hours at 10 C. Ice-cold water was thencarefully added to the reaction mixture, following this addition the reactionmixture was made basic using solid sodium hydroxide until precipitation couldbe seen. The solution was thereafter filtered and the wet solid collected anddissolved in DCM and left to stir for 30 minutes. Next, the solid was removedfrom the solution by filtration and washed with DCM. The DCM-solutioncontaining 2 was concentrated to afford compound 2 (70 mg, yield 81%).
48%		To an ice-cooled mixture of sulfuric acid (96%, 12.33 mL, 231 mmol) and nitric acid (65%, 1.2 mL, 26.5 mmol) was added 1-aminoadamantane hydrochloride (1 g, 6.61 mmol) portion wise. The mixture was stirred at rt for 2 days, ice-water (6 mL) was added to the reaction mixture. The solution was stirred in an ice-water bath for 30 min; KOH (35 g, 0.62 mol) was added in small portions over 1 h at such a rate to keep the temperature below 80 C. The resulting white paste was mixed with CH2Cl2 (300 mL) and vigorously stirred for 1 h. The solid was filtered off, and the mother liquor was evaporated to dryness under reduced pressure to provide 5 (527 mg, 3.15 mmol) in 48% yield as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 4.33 (s, 1H), 2.08 (s, 2H), 1.49-1.42 (m, 5H), 1.38-1.35 (m, 9H). 13C NMR (100 MHz, DMSO-d6): delta 67.7, 54.0, 44.8, 44.1, 34.8, 30.5. HRMS calcd for C10H18NO 168.1383, found 168.1380.
48%		To an ice-cooled mixture of sulfuric acid 96% (12.33 mL, 231 mmol) and nitric acid 65% (1.2 mL, 26.5 mmol) was added 1-aminoadamantan HCl (1g, 6.61 mmol) portionwise. The mixture was stirred at rt for 2 days. Ice-water (6 mL) was added to the reaction and solution was placed in an ice-water bath and allowed to stir for 30 minutes. KOH (35 g, 0.62 mol) was added in small portions over 1 h. During this addition, the reaction was never allowed to exceed 80 C. The resulting white paste was mixed with DCM (300 mL) and vigorously stirred for 1 h. After filtration the organic layer is separated and solvents were removed under reduced pressure to provide 5 (527 mg, 3.15 mmol) in 48% yield as a white solid. HRMS calcd for C10H18NO 168.1383, found 168.1380.

		Example-1: Preparation of l-aminoadamantane-3-ol compound of formula-2:A mixture of concentrated nitric acid (35.25 grams) and concentrated sulfuric acid (460 grams) was added to <strong>[665-66-7]amantadine hydrochloride</strong> (25 grams) at 0C and stirred for 2 hours at 8-12 C and then the reaction mixture was poured into ice-cold water. The reaction mixture was basified with sodium hydroxide, filtered and washed with water. Methylene chloride (1200 ml) was added to the wet solid and stirred for 30 minutes. The solid was removed by filtration and washed with methylene chloride. The filtrate was distilled under reduced pressure and the obtained compound was recrystallized from cyclohexane to get the title compound.
	With sulfuric acid; water; nitric acid; at 0 - 20℃; for 14h;	The 3-amino-adamantanol was prepared by pouring 46.94 g of concentrated sulfuric acid into a three-0.7 g of water was added dropwise,Magnetic stirring, adding batches of <strong>[665-66-7]amantadine hydrochloride</strong> total l0g.Then lower the temperature of the reaction solution to 0 5 C,7.75 g of fuming nitric acid was slowly added dropwise,Dropping process more obvious heat,Keeping the temperature of the reaction solution at 0-5 C;The reaction solution was at this temperatureAfter 2 h of reaction,Then raise the temperature to 20 C,The reaction was continued for 12 h.[0053] Upon completion of the reaction,Ice water bath,50% K0H solution adjusted pH ? 12,The insoluble matter was filtered off,The filtrate was concentrated,A small amount of toluene with water,It was then refluxed in toluene for 1.5 h,The supernatant was crystallized,Filtration,The filter cake was dried to give 8.2 g of crude material,The yield was 85%The purity was 97.5%.
3.2 g		38 ml of 98% concentrated sulfuric acid with 4 ml of 65% concentrated nitric acid in mixed under ice bath cooling, the mixed acid in to the adding 3 . 75 g <strong>[665-66-7]amantadine hydrochloride</strong>, stirring in ice bath reaction 3 hours; 60 g adding crushed ice, stirring 0.5 hours; then adding solid potassium hydroxide, to adjust the pH value to 12 - 13, the reaction under ice bath 2 hours; and filtering, the filtrate concentrated hydrochloric acid to adjust the pH value to 8 - 9, concentrated to dry; adding 80 ml anhydrous ethanol reflux 1 hour, cool, filtered, the filtrate is concentrated to dry; then adding 10 ml of the mixed liquid (acetone: ethyl acetate=3:1) reflux 1 hour, placed under ice bath, filtered, shall be 3 - amino adamantanol mellow solid 3.2 g,
58 g	With sulfuric acid; nitric acid; trifluoroacetic acid; at 0 - 20℃; for 13.5h;	(1) To a three-mouth flask, equipped with thermometer and tail gas absorption device, add 170 ml trifluoroacetic acid, and 800 ml fuming sulfuric acid. Under ice-bath cooling, under stirring slowly drop 56 ml 65% concentrated nitric acid, stirring 30min, When temperature drop to 0 C, in 30min divided 8 times add 76g <strong>[665-66-7]amantadine hydrochloride</strong>, After stirring 3 hours, remove ice-bath. Control temperature to 20 C, stirring 10 hours, to the reaction solution is added to the reaction solution in the ice cubes one by one for clarification, the reaction liquid is moved to the stirring in ice bath 30min, after the reaction liquid into white, removed ice, stirring under batchwise by adding 89% potassium hydroxide to neutralize, to the solution is strongly alkaline to continue after the stirring, the absorption of the generation of a white solid;(2) the one step on the resulting white to the absorption of the solid filtered, washing the resulting solid with chloroform, extraction, the filtrate, anhydrous sodium sulfate drying, filtering, and steaming and, after removal of a part of the solvent in the standstill or put into the refrigerator, crystallization, extraction, to obtain white solid 3-amino-1-adamantanol, methanol is recrystallized to obtain fine 58g, purity 99% or more.
		Use, to the reaction solution storage tank 1 added concentrated sulfuric acid, while slowly adding <strong>[665-66-7]amantadine hydrochloride</strong>, and chilled water to the temperature below 20 C, stir, slowly dropping concentrated nitric acid, dropwise addition was completed and warmed to room temperature , Stirred for 2h. The reaction liquid was obtained.At the same time in the reaction vessel 3 with a stirring blade added sodium hydroxide, and dissolved in water, while cooling into the chilled water.Open the bottom of the reaction liquid storage tank valve so that the reaction solution flows into the ultrasonic device 4 in the first ultrasound device ultraUnder the action of sound, the hydrochloric acid bubble generated by the reaction between <strong>[665-66-7]amantadine hydrochloride</strong> and concentrated acid is shattered and broken, and then the reaction liquid with the bubbles removed is pumped into the top of the reaction vessel by a magnetic pump to open the nozzle switch at the top of the reaction kettle and open the liquid flow control valve Control the flow rate, the reaction solution can be sprayed to the reaction dad, open the motor connected to the stirring paddle, stirring the liquid in the reaction dad to control the temperature <40 C, after spraying, stirred at room temperature for 1 hour to obtain 3- Amino-1-adamantanol, opening the switch valve under the reaction vessel to flow the mixed solution into the second ultrasonic device 8, and using the ultrasonic device to crush the air bubbles in the mixed solution into the centrifugal device, centrifuging and drying , Packaging can be the target product 3-amino-1-armandol.After the reaction is completed, the catheter on the nozzle and magnetic separation of the chestnut and connected to the chestnut, the water can be sprayed into the reactor using the nozzle, at the same time, as the nozzle can be rotated 360 degrees to complete the reactor cleaning, The top of the reactor can be cleaned.

Reference： [1]Pharmaceutical Chemistry Journal,1990,vol. 24,p. 35 - 39
Khimiko-Farmatsevticheskii Zhurnal,1990,vol. 24,p. 29 - 31
[2]Tetrahedron Letters,2017,vol. 58,p. 1456 - 1458
[3]Journal of Medicinal Chemistry,2016,vol. 59,p. 947 - 964
[4]European Journal of Medicinal Chemistry,2015,vol. 92,p. 554 - 564
[5]Patent: EP2966062,2016,A1 .Location in patent: Paragraph 0063; 0069
[6]Patent: WO2011/101861,2011,A1 .Location in patent: Page/Page column 17
[7]Patent: CN105523985,2016,A .Location in patent: Paragraph 0049; 0050; 0051; 0052; 0053
[8]Patent: CN106432026,2017,A .Location in patent: Paragraph 0033; 0034; 0035
[9]Patent: CN103804204,2017,B .Location in patent: Paragraph 0020; 0021; 0022
[10]Patent: CN105949070,2016,A .Location in patent: Paragraph 0022-0024

2
[ 702-82-9 ]
[ 207557-35-5 ]
[ 274901-16-5 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate; potassium iodide; In tetrahydrofuran; butanone; at 40℃; for 3h;	3-aminoadamantanol (3g,18mmol), potassium carbonate(10g,72.5mmol) and potassium iodide (0.25g,1.5mmol) wereadded to the solution of 2-butanone (21mL) and heated to 40C. Then the compound 5 (3g,16.5mmol) dissolved in 22mLTHF and added to the reaction mixture dropwise within 1.5h. After the addition, the reaction mixture was stirred at 40C for 1 h and then heated up to reflux for 30 minutes. Thenthe hot mixture was filtered and concentrated under vacuum.The resultant precipitate was filtered and dried to afford thetarget product. (Yield 82%); HPLC Purity 99.17%; mp 148-150 C (150C [8]); IR (KBr, cm-1): 3293, 2915, 2848,2241, 1656, 1405; 1HNMR (400 MHz, d6-DMSO) : 1.41-1.49 (m, 14H, CH2), 1.97-2.02 (m, 2H, OH, NH), 3.44-3.63(m, 2H, COCH2), 4.70-4.73 (t, 1H, CHCN), 2.10-2.14 (m,4H, CH2), 3.26-3.32 (t, 2H, NCH2); 13C NMR (75 MHz, d6-DMSO): 22.07 (C4), 34.22 (C3), 38.79 (C6?), 39.00 (C5),39.21 (C10?), 39.43 (C9?), 39.64 (C8?), 39.85 (C4?), 40.06(C2?), 44.62 (C2?), 47.09 (C5?), 47.09 (C7?), 47.16 (C2),52.72 (C1?), 68.39 (C3?), 120.03 (CN), 171.32 (C=O); MSm/z 304.2 [M+1], 305.2 [M+2].
82%	With potassium carbonate; potassium iodide; In tetrahydrofuran; butanone; at 40℃; for 3h;Reflux;	3-Aminoadamantanol (3 g,18 mmol), 2-butanone (21 mL),potassium carbonate (10 g, 72.5 mmol) and potassium iodide(0.25 g, 1.5 mmol) were added to a 150 mL three-neck roundbottom flask which was equipped with a condenser pipe, athermometer and a constant pressure funnel. The mixture washeated to 40 C under stirring and then the compound 4 (3 g,16.5 mmol) dissolved in 22 mL THF was added dropwise for 1.5 h. After dropped over, the reaction mixture was stirred at 40 C for 1 h and then heated up to reflux for 0.5 h. The reactionwas monitored by TLC (5 % CH3OH-CH2Cl2). After completing the reaction, the hot mixture was filtered and the filtercake was washed with hot 2-butanone (3 × 20 mL). The collected filtrate was concentrated under vacuum and stirred underslowly cooling. After the mixture became viscous, it was stirredin the ice-bath. The resulting white crystalline solid was filteredand washed with ethyl acetate (3 × 20 mL) and then dried at45 C under vacuum to afford the target compound of vildagliptin (4.1 g, 82 %). HPLC purity 99.17 %, m.p. 148-150 C, IR(KBr, nu max , cm -1 ): 3293, 2915, 2848, 2241, 1656, 1405; 1 H NMR (400 MHz, DMSO-d6) 1.41-1.49 (m, 14H, CH 2 ), 1.97-2.02(m, 2H, OH, NH), 3.44-3.63 (m, 2H, COCH 2 ), 4.70-4.73 (t,1H, CHCN), 2.10-2.14 (m, 4H, CH 2 ), 3.26-3.32 (t, 2H, NCH 2 );13 C NMR (75 MHz, DMSO-d 6 ) delta 22.07, 34.22, 38.79, 39,39.21, 39.43, 39.64, 39.85, 40.06, 44.62, 47.09, 47.09, 47.16,52.72, 68.39, 120.03, 171.32; MS m/z 304.2 [M + 1], 305.2[M + 2] 13 .
82.2%	With potassium carbonate; potassium iodide; In acetone; at 50 - 55℃; for 3h;	In the 2L reaction flask, 138.6 g of 3-amino-1-adamantanol was added.105.7g of potassium carbonate,5.3g potassium iodideAnd 900ml acetone,Stir and heat to 50-55C,Intermediate 2 in 110g was added dropwise in 1hMixed with 600 ml acetone,Stirred and incubated for 2 h, TLC detected the reaction was complete.Filter and rinse the filter cake with 300 ml hot acetone.The combined filtrate and washings were concentrated under reduced pressure at 35-45[deg.] C. to a remaining amount of about 770 ml, cooled to 0-10[deg.] C., and incubated for 2 hours while stirring.The filter cake was washed with 100ml of acetone, 40 ~ 50 cake was dried in vacuo 4h, to give a crude vildagliptin 173.5g, a yield of 89.8%. The 3L reaction flask was filled with 170g of crude product and 1870ml of acetone.Stir and heat to 50-55C,Stir until the solids are completely dissolved,Add 8.5g of activated carbon, heat and stir for 0.5h.Heat filtered and washed with 80 ml acetone.The filtrate was stirred and lowered to a temperature of 10-20C.Stir and stir for 2h.After filtration, the filter cake was washed with 80 ml of acetone, and the filter cake was vacuum dried at 40-50 C. for 4 hours to obtain 139.8 g of Vildagliptin with a yield of 82.2%. The content of 3-amino-1-adamantanol was 0.03%. 0.02%, no isomers detected, purity 99.8%.

80%		A 250 mL three-neck round bottom flask, equipped witha condenser pipe, thermometer, constant pressure funnel was charged with 3-aminoadamantanol (6.0 g, 0.036 mol), 2-butanone (42 mL), K2CO3 (20 g, 0.145 mol) and KI (0.5g,0.003 mol). The mixture was mildly heated about 40 Cwith stirring. Then compound 9 (6.0 g, 0.0329 mol) was dissolvedin 42 mL THF at about 45 C. After dissolving, themixed solution was dropped in the stirring suspension for 1.5h, which was kept at temperature about 38-42 C. Afterdropped over, the reaction mixture was stirred at 38-42 Cfor 1h, then heated up to reflux (approx, 70-75 C) for 30min. The reaction was monitored by TLC (5% MeOHCH2Cl2).Subsequently, the hot suspension was filtered, thefiltration cake was washed with 3x15 mL of hot 2-butanone.The obtained clear filtrate was concentrated to about 50 mLunder vacuum, then was stirred under slow cooling. After awhile, the solution became cloudy due to separation of theproduct. The suspension was stirred at the ice-bath. Then,filtration followed and the cake was washed with 2x15 mLethyl acetate, then was dried out to give the white crystallinepowder of vildagliptin. (8.0 g, yield 80%); HPLC Purity99.17%. mp 148-150 C (lit [16] 150 C), IR (KBr, cm-1):3293, 2915, 2848, 2241, 1656, 1405; 1H NMR (300 MHz,d6-DMSO) 1.41-1.49 (m, 14H, CH2), 1.97-2.02 (m, 2H,OH, NH), 3.44-3.63 (m, 2H, COCH2), 4.70-4.73 (t, 1H,CHCN), 2.10-2.14 (m, 4H, CH2), 3.26-3.32 (t, 2H, NCH2);13C NMR (75 MHz, d6-DMSO) 22.07, 34.22, 38.79, 39.00,39.21, 39.43, 39.64, 39.85, 40.06, 44.62, 47.09, 47.09, 47.16,52.72, 68.39, 120.03, 171.32; MS m/z 304.2 [M+1], 305.2[M+2].
80.2%	With tetra-(n-butyl)ammonium iodide; potassium carbonate; In acetonitrile; at 60℃;	A method for producing vildagliptin,Comprising the following steps: 3-amino-1-adamantanol (20 g, 0.120 mol),Potassium carbonate (20 g, 0.464 mol),Tetrabutylammonium iodide (2 g, cat) was added to 150 mL of acetonitrile,A solution of (S) - (2-chloroacetyl chloride) -2-cyanopyrrolidine (20 g, 0.116 mol) in 150 mL of acetonitrile was slowly added dropwise at 60 C (2 to 3 hours)After completion of the dropwise addition,The reaction was maintained at 60 C for 6 hours,filter,The filtrate was dried,To give an oil,300 mL of dichloromethane was added,1 OOmL water,Extraction washing,The organic phase was washed with saturated brine,dry,filter,Drying,To give an oil,After vacuum dryingTo obtain 28 g of a pale yellow product,Purity 96%Yield: 80.2%.
78.3%	With potassium carbonate; potassium iodide; In acetone; at 60 - 65℃; for 5h;	Acetone (1000 ml), 3-amino-1-adamantanol (100 g), potassium iodide (4.87 g), Potassium carbonate (123 g), and the mixture was heated to 60 to 65 C. A solution of (S)-1-(2-chloroacetyl)pyrrole-2-carbonitrile (77.4 g) in acetone (500 ml) was slowly added dropwise over 5h. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in methylene chloride (500 ml), Silica gel (38.7 g) was added and the mixture was stirred at 30 to 40 C for 30 minutes. The residue was washed with dichloromethane (100 ml * 2). The filtrate was combined and concentrated under reduced pressure to a volume of about 200 ml. The mixture was crystallized by adding toluene (400 ml). The system slowly cooled to 0 ~ 5 , filtration, cold toluene (50ml * 2) washing, dried in vacuo to give the product (106.8 g, yield 78.3% HPLC purity 99.95%, GC (formula II content) 0.05%).
73.3%	With triethylamine; In N,N-dimethyl-formamide; at 20 - 30℃; for 20h;Industrial scale;	(1) To a 250 mL reaction bottle was added 80.0 g of N, N-dimethylformamide, 13.8 g (0.08 mmol) of(S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile, 13.4 g (0.08 mmol) of 3-amino-Alcohol, 8.1 g (0.08 mmol) of triethylamine, and keeping the temperature at 20 to 30 C. The reaction mixture was stirred for 20 hours to obtain a reaction solution.(2) Extraction: The reaction solution was distilled at 60-70 C under reduced pressure, and the temperature was lowered to 30 C or less. To the mixture was added 120.0 g of methylene chlorideAnd 60.0 g of a half-saturated aqueous solution of ammonium chloride, 40 ml of a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was stirred and the layers were separated. The methylene chloride layerWashed once with 50.0 g of water to obtain an organic phase extract;(3) Drying: The organic phase extract is added with 8g of anhydrous magnesium sulfate and dried for 1-2 hours, then filtered, concentrated under reduced pressure, concentratedShrink to no fraction, to obtain concentrated liquid;(4) Crystallization: 100 g of ethyl acetate was added to the concentrated solution, and the temperature was increased to be completely dissolved, followed by cooling and crystallization for 2 hours,Drying,Vildagliptin finished 17.8g, yield 73.3%,
72.4%	With triethylamine; potassium iodide; In acetonitrile; at 75 - 80℃; for 3h;	In a 2L three-neck flask, 116.3 g (0.6954 moL) of 3-aminoadamantanol was added.70.2 g (0.6954 moL) of triethylamine, 4.8 g (0.02891 moL) of potassium iodide and 650.0 g of acetonitrile,Heat to 75-80C with stirring.100.0 g (0.5793 moL) of (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile (dissolved in 500.0 g of acetonitrile) are added dropwise.2h drop is completed,Stir at 75-80 C for 1 h; TLC test is complete, and the reaction system is cooled to 20-30 C.The filter cake was rinsed with 400 g acetonitrile.Combine the filtrate and remove the solvent under reduced pressure (60C, -0.09--0.1MPa) to obtain an almost white solid.Add 211.0 g of a mixed solvent of ethanol and butanone in a mass ratio of 1:1 and heat to reflux to dissolve.Cool down to 20-30C, stir and crystallize for 1h, continue cooling to -5-5C,The crystals were stirred for 1 h. Filtration, 43g of butanone at 0C, and drying under reduced pressure (60C, -0.09--0.1MPa),127.3 g of white solid powder was obtained (yield 72.4%, HPLC purity 99.10%, Ia content 0.87%),Structural confirmation,
68%	With potassium carbonate; In acetonitrile; at 82 - 85℃;	In a clean round bottom flask, (100gm) of 1-amino-3-adamantol in l000ml of acetonitrile were charged. 239.8gm of potassium carbonate was charged to the above flask. The reaction mass was heated to 82-85C. The compound of formula III (4x25gm), was charged after 60-90 mm intervals. After completion of reaction, the reaction mass was cooled to 65-70C. The reaction mass was filtered and the solid was washed with 500m1 acetonitrile and suck dried. Theacetonitrile was distilled out from filtrate under vacuum at 50-55C. Ethyl acetate was charged to the residue and the slurry stirred at 50-55C for 30-45 minutes. The slurry was cooled to 20-30C and stirred for 60-90 minutes. The solid was filtered and washed with ethyl acetate and suck dried, The wet cake was suspended in IPA and heated to 80-85C to get a clear solution. The clear solution was charcoalised and filtered through hyflo. The filtrate was distilled oUt undervacuum to get final volume to 5Volume. The reaction mass was cooled to -5 to 5C and stirred for 60-90 minutes. The solid was filtered and washed with IPA and suck dried. The solid was dried under vacuum at 50-55C. 105 to 120gm of solid was obtained (yield 59-68%, HPLC purity >98%)
61.3%		Compound (S)-1-(2-chloroacetyl) pyrrolidine-2-carbonitrile (12.1 g, 70.3mmol) is added to dichloromethane (200mL), stir for 10 minutes, hydroxyl adamantanamine (12.7 g, 66.8mmol) is slowly added to the above solution, the resulting solution is stirred at room temperature for 10 minutes, Potassium carbonate (19. 3g, 140mmol) is added to the reaction solution, the reaction is stirred for 4 hours.The reaction solution has been filtered, the filter cake is washed with dichloromethane (50mL), combined filtrates. Rotate the solvent to get dryness, the residual oil is added to ethyl acetate to dissolve. The resulting ethyl acetate solution is washed with water (50mL X 2), dry over anhydrous sodium sulfate for 2 hours. The desiccant has been removed; and dried then obtained the crude compound 6 (21.2g).Vildagliptin crude (21. 2g) is added into the reactor which is containing 100mL 2-butanone. The mixture is heated to reflux (95 C) and stirred for 30 minutes. The mixture is filtered into a preheated (75 C) reactor; the filter cake is washed with using hot 2-butanone (100mL). The filtrate is heated to reflux for 30 minutes, slowly cool down at room temperature. Let stand overnight. The system is cooled with an ice water bath for 1 hour. The resulting suspension is filtered, the filter cake is washed twice with 2-butanone.The filter cake has been dried, and obtained target product Vildagliptin 12. 4g(white crystal), 61.3%.
41%	With potassium carbonate;N-benzyl-N,N,N-triethylammonium chloride; In acetonitrile; at 45℃; for 16h;Inert atmosphere;	Example 3Preparation of vildagliptin (I)A 500 mL reactor, inertized with Ar, is charged with 15.60 g (93.3 mmol, 1.15 equiv. ) of 3-amino-l-adamantole, 22.42 g (162.2 mmol, 2 equiv.) of K2CO3, and 3.70 g (16.2 mmol, 0.2 equiv.) of benzyl triethyl ammonium chloride. 150 mL of acetonitrile are added and the reaction mixture is vigorously stirred. One half of a solution prepared by dissolving 14.0Og (81.1 mmol, 1 equiv.) of (S)-l-(2- chloroacetyl) pyrrolidin-2-carbo-nitrile in 50 mL of acetonitrile is slowly added. The reaction mixture is stirred at 450C and after 2 hours, one 1/4 of the solution of (S) -1- (2-chloroacetyl) pyrrolidin-2-carbo-nitrile as above is added. After another 2 hours of stirring, the last H of the solution of (S) -1- (2-chloroacetyl) pyrrolidin-2- carbo-nitrile is added. The reaction mixture is stirred at 45C for 12 hours, the solid phase is filtered off and the volatile components of the liquid phase are evaporated under reduced pressure. The residue is dissolved in 200 mL of dichloromethane and washed with 100 mL of water. The aqueous phase is washed twice with 100 mL of dichloromethane. The combined organic phases are dried over anhydrous Na2SO4, filtered and the solvent is evaporated under educed pressure. The crude vildaglitpine obtained is re-crystallized from 2-butanone (70 inL) . 10.2 g of white crystals with a melting point of 149-1500C and a purity of 99.8% as determined by HPLC are obtained (41% yield).
36%	With potassium carbonate; In Isopropyl acetate; for 4h;Heating / reflux;Product distribution / selectivity;	EXAMPLE 24; This example illustrates the synthesis of the compound of formula (I) in accordance with embodiments of the invention.Into a 100 mL rounded reaction vessel were charged 3 g (17.37 mmol) of 1-chloroacetyl-2-cyanopyrrolidine, 3.22 g (19.82 mmol) of 1-amino-3-adamantanol, 2.78 g (20.1 mmol) of potassium carbonate, and 30 mL isopropyl acetate. The mixture was refluxed for 4 h, cooled to room temperature, and the salts were filtered and washed with acetonitrile. The mother liquors were evaporated to dryness to obtain an oil which was aged in MEK from which a white solid crystallizes at 0-5 C. The solid was filtered washing the cake with MEK and dried at 40 C. in a vacuum oven until constant weight.Yield: 36%. Assay: 99.21%. HPLC purity: 97.55% of vildagliptin (measured according to Example 2). HPLC chiral purity: more than 99.99% of vildagliptin (measured according to Example 7).
31.4%	With sodium carbonate; sodium iodide; In acetonitrile;Inert atmosphere; Reflux;	A solution of 9.12 g of 3-amino-1-adamantanol, 7.24 g of (s) - (1) - (2-chloroacetyl) -pyrrolidine-2-carbonitrile and 4.51 g of sodium carbonate were successively added to a 100- 0.33 g of sodium iodide was added thereto. After replacing the nitrogen gas several times, 60 ml of acetonitrile was added, and the mixture was heated to reflux and the reaction was stirred.After completion of the reaction by TLC, the reaction mixture was concentrated in vacuo and the resulting residue was partitioned with 30 ml of water and 30 ml of ethyl acetate. The aqueous phase was extracted twice with 20 ml of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate after the solvent was evaporated under reduced pressure to give the crude product 5.2 g, HPLC measured Vildagliptin: compounds of formula VII The crude product was purified by column chromatography on silica gel and recrystallized from a 8: 1 by volume mixture of ethyl acetate / methanol to give 2.0 g of a white solid (vildagliptin) in a yield of 31.4%, HPLC: 99.2%
		A 4. 51 reactor, equipped with a mechanical stirrer, is charged with 733 G of potassium carbonate, 194 g 3-hydroxyaminoadamantane, 8.0 G potassium iodide and 880 G 2-butanone. The suspension is heated to about 35 C. At this temperature 937 G solution of step b) (crude (S)-1-CHLOROACETYL-PYRROLIDINE-2-CARBONITRILE) is added within 1.5 h. The addition funnel is rinsed with 20 G 2-butanone. After stirring for an additional 1 h, the suspension is warmed to about IT 70 C for 30 min. The warm suspension is filtered and the filter cake is rinsed three times with warm 331 G 2-butanone. The filtrate is concentrated at about JT (jacket temperature) 60 C under reduced pressure (about 20 mbar). Step (d) At about JT 60 C 8.8 G 1, 8-diazabicyclo [5.4. 0] undec-7-ene and 44 G isopropanol is added and stirred for 30 min. at IT about 60 C. The resulting suspension is cooled to about IT 40 C and at JT 40 C 814 G t-butylmethylether is added. The suspension is cooled to about IT 20 C and stirred for at least 2 h at this temperature, then cooled to ABOUT-10C-0 C, stirred for 1 h and filtered. The filtration"cake"is washed twice with 168 G of a cold (about-10 C) 1: 1 (v: v) mixture of isopropanol and t-butylmethylether. The crude product (247 g) is dried under reduced pressure at about JT 55 C.
	With potassium carbonate; potassium iodide; In tetrahydrofuran; at 60 - 65℃; for 5h;Product distribution / selectivity;	ExampIe-22: Preparation of Vildagliptin compound of formula-1:, To a mixture of l-aminoadamantane-3-ol (26 grams), (S)-(l)-(2-chloroacetyl) pyrrolidine-2-carbonitrile (22.8 grams) in tetrahydrofuran (300 ml) added potassiumicarbonate (64.3 grams) and potassium iodide (0.774 grams). The mixture was heated to 60-65 and stirred for 5 hours. After completion, the reaction mixture was cooled to 25-30 C and filtered. The filtrate was distilled under reduced pressure. 2-butanone (20 ml), methyl tertiary butyl ether (80 ml) was added to the residue at 25-30 C, and stirred for 45 minutes. The solid obtain was filtered, washed with methyl tertiary butyl ether and then dried to get the title compound.Yield: 34 grams.
100 g		Example 1 : Preparation of vildagliptin To the (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile (100 gm) was added FontWeight="Bold" FontSize="10" isopropyl acetate (400 ml) and dimethylformamide (400 ml) at room temperature and then heated to 40C for 15 minutes to provide a solution. A mixture of 3-hydroxy-l- aminoadamantane (100 gm), 2-butanone (700 ml), potassium iodide (5 gm) and potassium carbonate (400 gm) were added to the solution. The reaction mixture was maintained for 1 hour at room temperature and then heated to 75 to 80C. The reaction mass was maintained for 1 hour at 75 to 80C, filtered and then concentrated to provide a residual solid. To the residual solid was added a mixture of diisopropyl ether (900 ml) and isopropyl acetate (100 ml) and then heated to 70C. The reaction mass was then cooled to room temperature and further cooled to 0 to 5C. The contents were maintained for 1 hour at room temperature and filtered. The solid thus obtained was dried to provide 100 gm of vildagliptin.
85 g	With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 10h;Inert atmosphere;	Dimethyl formamide (600 ml), (2S)-1-(chloroacetyl) pyrrolidine-2-carbonitrile (100 g), 3-Amino-1-hydroxyadamantane (106.5) and potassium carbonate (99.9g) were mixed under nitrogen atmosphere. The reaction mixture was heated at 40C for 10 hrs. The solid was filtered and washed with DMF (200 ml). The solvent was distilled completely under vacuum and charged Isopropyl Acetate (600 ml) into the semi solid mass. The reaction mass was stirred at 5-10C for 30 to 60 minutes. The solid was filtered and washed with Isopropyl Acetate (50 ml). Dried the material under vacuum at 50-55C to obtain crude Vildagliptin (150.0 gm), HPLC purity: 98.0.
175 g	In water; at 25 - 45℃;	To a solution of L-Prolinamide (100 gms) dissolved in DCM (1000 mL) was added triethyl amine (88.6 gms) and DMAP (1.07 gms) at 25-30C under N2 atmosphere and stirred for 15 min at 25-30C. This solution was added to a solution of chloroacetyl chloride (118.7 gms) in DCM (500 mL) under N2 atmosphere at -5 to 0C over 2-4 hr. Heated the reaction mass temperature to 10-15C and stirred until reaction completion, charged phosphorus oxychloride (201.5 gms) to the reaction mass at 0-5C, heated the reaction mass temperature to reflux and stirred for 6hr at same temperature. After reaction completion, allowed to cool to 5-15C and slowly added DM water (500 mL). Aqueous layer was separated and the organic layer was washed with DM water. To the organic layer, DM water (300 mL) was added at 25-30C and adjusted the reaction mass pH to 6.5-7.5 with -200 mL of sodium bicarbonate solution (-16 g of NaHC03 dissolved in 200 mL of DM Water). Separated the aqueous layer and concentrated the organic layer under vacuum at temperature of 30-40C to get residual mass. The residual mass was dissolved in DM Water (640 mL), charged l-aminoadamantane-3-ol (310.6 g) at 25-35C. Heated the reaction mass temperature to 40-45 C and stirred for 9 hr at the same temperature. After reaction completion, allowed to cool to 25-30C and charged DM water (900 mL) and DCM (1280 mL). Separated the organic layer and extracted the aqueous layer with DCM. The aqueous layer was separated and kept aside for l-aminoadamantane-3-ol recovery. The total organic layer was treated with P.S. 133 carbon, stirred for 30 rnins at 25-30C and filtered over hyflo bed. The resulting filtrate was concentrated under, vacuum at temperature 30-40C to get residual mass. To the residual mass, charged ethyl acetate (128 mL) and distilled completely under vacuum at 30-40C to get semi solid mass. Charged ethyl acetate (640 mL) to the obtained semi solid and refluxed for 1 hr. The reaction mass was allowed to cool to 25-30C and stirred for 2 hr. Filtered the reaction mass and washed with ethyl acetate (128 mL) to obtain wet cake. Again charged ethyl acetate (512 mL) to the obtained wet cake and refluxed for 1 hr. The reaction mass was allowed to cool to 25- 30C and stirred for 2 hr. Filtered the reaction mass and washed with ethyl acetate (128 mL) and then dried at 50-55C for 6 hr to provide 175 gms of crude vildagliptin. HPLC Purity: 99.66%. Dimer impurity content: <0.2%; R-isomer content (by chiral HPLC) : <0.1 %; l-aminoadamantane-3-ol content (by GC): <0.7%. DSC: 150.12C.
6.89 g	With potassium carbonate; In dichloromethane; for 5h;Reflux;	In 100 mL of dichloromethane, 4.32 g (25 mmol) of (S)-N-chloroacetyl-2-cyano-pyrrolidine and 4.68 g (28 mmol) of 3-amino-1-hydroxyadamantane were added. , 6.91g (50mmol) K2CO3, reflux reaction for 5 hours, adding steamed water,The liquid layer was separated, and the organic phase was concentrated, and then subjected to column chromatography to obtain 6.89 g (22.7 mmol) of vildagliptin, the yield was 91%, and the HPLC purity was 98.8%.

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Yield	Reaction Conditions	Operation in experiment
65%	With sodium hydroxide; In 1,4-dioxane; water; at 20℃; for 16h;	a. ) TERT-BRTYL [3- (P R IMIDIN-2-VLAMINO)-1-ADAMANTVL] CARBAMATE; In general formula (V) the meaning of R and B are as defined above, Y represents tert- butoxycarbonyl group.; (i) TERT-BUTVL (3-HYDROXV-1-ADAMANTYL) CARBAMATE; 2.51 g (15 mmole) of 3-hydroxy-1-aminoadamantane (Pharm. Chem. J. (Engl. Trans.) 1990, 24, 35) are dissolved in the mixture of 15 ml OF DIOXANE, 15 ml of water and 15 ml of 1N sodium hydroxide solution, then under cooling and stirring 4.91 g (22.5 mmole) OF DI- TERT-BUTYL dicarbonate are added. The mixture is stirred at room temperature for 16 hours, the solution is evaporated, and the residue is dissolved in the mixture of 50 ml of ethyl acetate and 50 ml of water. Following extraction and separation of the phases, the organic phase is dried over sodium sulphate. After evaporation the white crystalline residue is treated with n-hexane, to obtain 2.61 g (65%) of product. M. p.: 131-132C. 1H-NMR. : (DMSO-d6) : 1.36 (s, 9H), 1.41 (s, 2H), 1.48 (d, 4H), 1.70 (d, 6H), 2.10 (bs, 2H), 4.43 (s, 1H), 6.41 (s, 1H).
	With triethylamine; In tetrahydrofuran; at 20℃;Cooling with ice;	8-2 (167 mg, 1 mmol) was dissolved in 2 ml of THF, 164 mg of di-tert-butyl dicarbonate was added under ice-cooling, and then 14 ml of triethylamine was gradually added dropwise to room temperature and allowed to react overnight. The THF was evaporated to dryness and extracted with 10 ml of ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give crude 8-3 (230 mg, 86%) as a white solid. The intermediate8-3 (1 eq) was dissolved in 3 ml of dichloroethane,DMAP (0.1 eq) was added,Dropping butanoyl chloride under stirring,After reaction for 2 h,The solvent was evaporated to dryness, and water was added thereto. The mixture was extracted with methylene chloride. The methylene chloride layer was washed with saturated brine and dried. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give Intermediate 8-4. The resulting intermediate 8-4 was dissolved directly in methylene chloride and trifluoroacetic acid was added with stirring. After 1 h, the reaction solution was dried to give intermediate 8-1.

Reference： [1]Molecular Diversity,2017,vol. 21,p. 547 - 564
[2]Patent: WO2005/21536,2005,A2 .Location in patent: Page/Page column 18-19
[3]Patent: CN106146338,2016,A .Location in patent: Paragraph 0146-0148

4
2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid [ No CAS ]
[ 702-82-9 ]
C₂₂H₂₇N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With 2-chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;	Synthesis of Compound 48 To a magnetically stirred solution of 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (0.66 gram, 0.00306 mol) in dichloromethane (35 ml) was successively added diisopropylethylamine (DIPEA) (3.1 ml), CIP (2-chloro-1,3-dimethylimidazolinium hexafluorophosphate). (2.55 gram) and 3-hydroxyadamantane amine (0.612 gram, 0.00366 mol). The resulting mixture was reacted at 20 C. for 16 hours and subsequently concentrated in vacuo. The resulting residue was taken up in dichloromethane and washed with 5% aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (dichoromethane/methanol=98/2 (v/v)) to give N-(3 hydroxyadamant-1-yl)-2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxamide (0.75 gram, 67% yield). Rf (silica gel/dichoromethane/methanol=98/2 (v/v))~0.6. Melting point: 215-220 C.

Reference： [1]Patent: US2006/194779,2006,A1 .Location in patent: Page/Page column 22

5
[ 702-82-9 ]
[ 108-24-7 ]
[ 778-10-9 ]

Yield	Reaction Conditions	Operation in experiment
79.91%	With pyridine; at 0℃; for 1h;	Example 20(2S)-l-[2-(3-{2-[(2S)-2-Cyanopyrrolidin-l-yl]-2-oxoethylamino}-l- adamantylamino) acetyl] pyrr olidine-2-carbonitrileStep 1: Nl-(3-Hydroxy-l-adamantyl)acetamide: To a stirred suspension of Intermediate 1 (700 mg, 4.19 mmol) in pyridine (10 ml) was added acetic anhydride (514 mg, 5.03 mmol) at 0 C. Stirring was continued for 1 h. The reaction mixture was poured onto ice cold water, acidified with IN HCl and extracted into dichloromethane (2 x 50 ml). The combined organic extracts were washed with water, brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to afford the product as an off-white solid (406 mg, 79.91 %); IR (KBr) 3285, 2919, 2851, 1657, 1555 cm4; 1H NMR (300 MHz, CDCl3) delta 1.64-1.69 (m, 8H), 1.90-1.93 (m, 5H), 1.98 (s, 3H), 2.26 (s, 2H), 5.21 (brs, IH).

Reference： [1]Patent: WO2006/90244,2006,A1 .Location in patent: Page/Page column 54

6
[ 702-82-9 ]
[ 98-58-8 ]
[ 908290-97-1 ]

Yield	Reaction Conditions	Operation in experiment
31.6%	With triethylamine; In dichloromethane; at 0℃; for 2h;	Example 6 iV-(3-{2-[(2S)-2-Cyanopyrrolidin-l-yl]-2-oxoetIiylammo}-l-(4-fluorophenyl- sulfonamido)adamantane EPO <DP n="38"/>Step 1: l-(4-Fluorophenylsulfonamido)-3-hydroxyadamantane: To a stirred and cooled (0 C) suspension of Intermediate 1 (1.0 g, 5.98 mmol) and triethylamine (0.65 g, 6.58 mmol) in dichloromethane (5 ml) was added a solution of p- fmorobenzenesulfonyl chloride (1.16 g, 6.58 mmol) in dichloromethane (5 ml). Stirring was continued for 2 h. The reaction mixture was further diluted with dichloromethane and washed with IN HCl, water, brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to afford a brown residue. The residue was purified by silica gel column chromatography using 4 % methanol in dichloromethane to afford the pure compound as a white solid (615 mg, 31.6%); IR (KBr) 3469, 2909, 2856, 1592, 1494, 1318, 1128, 1053 cm"1; 1H NMR (300 MHz, DMSO-J6) delta 1.32-1.44 (m, 6H), 1.55 (brs, 6H), 2.03 (brs, 2H), 4.50 (brs, IH), 7.38-7.44 (m, 2H), 7.68 (s, IH), 7.85-7.90 (m, 2H).

Reference： [1]Patent: WO2006/90244,2006,A1 .Location in patent: Page/Page column 37

7
[ 702-82-9 ]
[ 75-36-5 ]
[ 778-10-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide;	11 mmol of acetyl chloride and 12 mmol of triethylamine were dissolved in 2 ml of THF in a nitrogen atmosphere, and to the reactant solution was dropped 10 mmol of DMF (10 ml) solution with said 1-amino-3-adamantanol at a temperature of 40C for 30 minutes. Then, the reactant mixture was stirred at a temperature of 40C for 3 hours. And, as a result, the 1-amino-3-adamantanol was converted into a 1-acetylamino-3-adamantanol (yield: 95%) with a conversion of 99%.

Reference： [1]Patent: EP915077,1999,A1

8
[ 702-82-9 ]
[ 207557-35-5 ]
[ 1036959-23-5 ]
[ 274901-16-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide; In tetrahydrofuran; at 66℃; for 2 - 14h;Heating / reflux;Product distribution / selectivity;	EXAMPLE 5; This example illustrates the synthesis of the compound of formula (I) in accordance with the invention.A 250 mL reactor with thermometer, condenser and magnetic stirring was charged with THF (90 mL), powdered K2CO3 (21.3 g), 3-amino-1-adamantanol (9 g), 1-chloroacetyl-2-cyanopyrrolidine (8.85 g) and KI (0.43 g). The resulting slurry was heated to reflux until complete conversion by TLC (approx. 2 h). The warm suspension was filtered and the solids washed with 30 mL of THF. Solvents were distilled off under vacuum to obtain 16.4 g of a solid. This solid was suspended in 52 mL of MEK and heated to reflux. The resulting clear solution was allowed to cool and the product crystallized as a white solid. The slurry was stirred at 0 C. for 1 hour, filtered, washed with a cold mixture of MEK/MeOBut (1/1) and dried under vacuum to obtain 10.3 g (66% yield). HPLC analysis showed vildagliptin and compound (II) in a 99.7:0.3 ratio. mp 150 C.; 1H-NMR (CDCl3) 1.45-1.73 (m, 12H), 1.81 (brs, 2H), 2.03-2.45 (m, 6H), 3.32-3.76 (m, 4H), 4.70-4.81 (m, 0.8H), 4.83-4.91 (m, 0.2H); 13C-NMR (CDCl3 ) 22.8, 25.0, 29.9, 30.7, 32.3, 35.07, 35.12, 41.07, 41.14, 41.2, 41.3, 43.4, 44.4, 45.5, 46.3, 46.5, 46.6, 49.9, 53.4, 53.7, 69.5, 118.2, 170.6; MS (ESI+) 304 (M++1); [alpha]D25=-85 (c 9.73, MeOH).; EXAMPLES 8-23; These examples illustrate the synthesis of the compound of formula (I) in accordance with embodiments of the invention. In addition, these examples illustrate a method for determining the purity of a compound of formula (I) in accordance with the invention.The following general procedure was used: into a 10 or 25 mL reactor were charged: 0.51 g (2.95 mmol) of 1-chloroacetyl-2-cyanopyrrolidine, 0.57 g (3.40 mmol) of aminoadamantanol, 3.40 mmol of potassium or cesium carbonate and, when indicated, 5 mg (0.03 mmol) of KI. Finally, 5 mL of solvent was also added. The mixture was heated at reflux (or at the temperature indicated in the table) for approximately 14 h, then cooled to room temperature filtered to remove the inorganic salts, which were washed with acetonitrile, the organic phases were collected and evaporated to dryness. A sample was collected for HPLC analysis. After crystallization from a mixture of IPA and MTBE the typical overall yield was about 60-70%.
	With potassium carbonate; In Isopropyl acetate; at 45℃; for 14h;Product distribution / selectivity;	EXAMPLES 8-23; These examples illustrate the synthesis of the compound of formula (I) in accordance with embodiments of the invention. In addition, these examples illustrate a method for determining the purity of a compound of formula (I) in accordance with the invention.The following general procedure was used: into a 10 or 25 mL reactor were charged: 0.51 g (2.95 mmol) of 1-chloroacetyl-2-cyanopyrrolidine, 0.57 g (3.40 mmol) of aminoadamantanol, 3.40 mmol of potassium or cesium carbonate and, when indicated, 5 mg (0.03 mmol) of KI. Finally, 5 mL of solvent was also added. The mixture was heated at reflux (or at the temperature indicated in the table) for approximately 14 h, then cooled to room temperature filtered to remove the inorganic salts, which were washed with acetonitrile, the organic phases were collected and evaporated to dryness. A sample was collected for HPLC analysis. After crystallization from a mixture of IPA and MTBE the typical overall yield was about 60-70%.
	With potassium carbonate; In tetrahydrofuran; for 14h;Heating / reflux;Product distribution / selectivity;	EXAMPLE 5; This example illustrates the synthesis of the compound of formula (I) in accordance with the invention.A 250 mL reactor with thermometer, condenser and magnetic stirring was charged with THF (90 mL), powdered K2CO3 (21.3 g), 3-amino-1-adamantanol (9 g), 1-chloroacetyl-2-cyanopyrrolidine (8.85 g) and KI (0.43 g). The resulting slurry was heated to reflux until complete conversion by TLC (approx. 2 h). The warm suspension was filtered and the solids washed with 30 mL of THF. Solvents were distilled off under vacuum to obtain 16.4 g of a solid. This solid was suspended in 52 mL of MEK and heated to reflux. The resulting clear solution was allowed to cool and the product crystallized as a white solid. The slurry was stirred at 0 C. for 1 hour, filtered, washed with a cold mixture of MEK/MeOBut (1/1) and dried under vacuum to obtain 10.3 g (66% yield). HPLC analysis showed vildagliptin and compound (II) in a 99.7:0.3 ratio. mp 150 C.; 1H-NMR (CDCl3) 1.45-1.73 (m, 12H), 1.81 (brs, 2H), 2.03-2.45 (m, 6H), 3.32-3.76 (m, 4H), 4.70-4.81 (m, 0.8H), 4.83-4.91 (m, 0.2H); 13C-NMR (CDCl3 ) 22.8, 25.0, 29.9, 30.7, 32.3, 35.07, 35.12, 41.07, 41.14, 41.2, 41.3, 43.4, 44.4, 45.5, 46.3, 46.5, 46.6, 49.9, 53.4, 53.7, 69.5, 118.2, 170.6; MS (ESI+) 304 (M++1); [alpha]D25=-85 (c 9.73, MeOH).; EXAMPLES 8-23; These examples illustrate the synthesis of the compound of formula (I) in accordance with embodiments of the invention. In addition, these examples illustrate a method for determining the purity of a compound of formula (I) in accordance with the invention.The following general procedure was used: into a 10 or 25 mL reactor were charged: 0.51 g (2.95 mmol) of 1-chloroacetyl-2-cyanopyrrolidine, 0.57 g (3.40 mmol) of aminoadamantanol, 3.40 mmol of potassium or cesium carbonate and, when indicated, 5 mg (0.03 mmol) of KI. Finally, 5 mL of solvent was also added. The mixture was heated at reflux (or at the temperature indicated in the table) for approximately 14 h, then cooled to room temperature filtered to remove the inorganic salts, which were washed with acetonitrile, the organic phases were collected and evaporated to dryness. A sample was collected for HPLC analysis. After crystallization from a mixture of IPA and MTBE the typical overall yield was about 60-70%.

	With caesium carbonate; potassium iodide; In acetonitrile; at 70℃; for 14h;Product distribution / selectivity;	EXAMPLES 8-23; These examples illustrate the synthesis of the compound of formula (I) in accordance with embodiments of the invention. In addition, these examples illustrate a method for determining the purity of a compound of formula (I) in accordance with the invention.The following general procedure was used: into a 10 or 25 mL reactor were charged: 0.51 g (2.95 mmol) of 1-chloroacetyl-2-cyanopyrrolidine, 0.57 g (3.40 mmol) of aminoadamantanol, 3.40 mmol of potassium or cesium carbonate and, when indicated, 5 mg (0.03 mmol) of KI. Finally, 5 mL of solvent was also added. The mixture was heated at reflux (or at the temperature indicated in the table) for approximately 14 h, then cooled to room temperature filtered to remove the inorganic salts, which were washed with acetonitrile, the organic phases were collected and evaporated to dryness. A sample was collected for HPLC analysis. After crystallization from a mixture of IPA and MTBE the typical overall yield was about 60-70%.
	With caesium carbonate; potassium iodide; In tetrahydrofuran; at 66℃; for 14h;Product distribution / selectivity;	EXAMPLES 8-23; These examples illustrate the synthesis of the compound of formula (I) in accordance with embodiments of the invention. In addition, these examples illustrate a method for determining the purity of a compound of formula (I) in accordance with the invention.The following general procedure was used: into a 10 or 25 mL reactor were charged: 0.51 g (2.95 mmol) of 1-chloroacetyl-2-cyanopyrrolidine, 0.57 g (3.40 mmol) of aminoadamantanol, 3.40 mmol of potassium or cesium carbonate and, when indicated, 5 mg (0.03 mmol) of KI. Finally, 5 mL of solvent was also added. The mixture was heated at reflux (or at the temperature indicated in the table) for approximately 14 h, then cooled to room temperature filtered to remove the inorganic salts, which were washed with acetonitrile, the organic phases were collected and evaporated to dryness. A sample was collected for HPLC analysis. After crystallization from a mixture of IPA and MTBE the typical overall yield was about 60-70%.
	With caesium carbonate; In ethyl acetate; at 45 - 70℃; for 14h;Product distribution / selectivity;	EXAMPLES 8-23; These examples illustrate the synthesis of the compound of formula (I) in accordance with embodiments of the invention. In addition, these examples illustrate a method for determining the purity of a compound of formula (I) in accordance with the invention.The following general procedure was used: into a 10 or 25 mL reactor were charged: 0.51 g (2.95 mmol) of 1-chloroacetyl-2-cyanopyrrolidine, 0.57 g (3.40 mmol) of aminoadamantanol, 3.40 mmol of potassium or cesium carbonate and, when indicated, 5 mg (0.03 mmol) of KI. Finally, 5 mL of solvent was also added. The mixture was heated at reflux (or at the temperature indicated in the table) for approximately 14 h, then cooled to room temperature filtered to remove the inorganic salts, which were washed with acetonitrile, the organic phases were collected and evaporated to dryness. A sample was collected for HPLC analysis. After crystallization from a mixture of IPA and MTBE the typical overall yield was about 60-70%.
	With caesium carbonate; In Isopropyl acetate; acetonitrile; at 70℃; for 14h;Product distribution / selectivity;	EXAMPLES 8-23; These examples illustrate the synthesis of the compound of formula (I) in accordance with embodiments of the invention. In addition, these examples illustrate a method for determining the purity of a compound of formula (I) in accordance with the invention.The following general procedure was used: into a 10 or 25 mL reactor were charged: 0.51 g (2.95 mmol) of 1-chloroacetyl-2-cyanopyrrolidine, 0.57 g (3.40 mmol) of aminoadamantanol, 3.40 mmol of potassium or cesium carbonate and, when indicated, 5 mg (0.03 mmol) of KI. Finally, 5 mL of solvent was also added. The mixture was heated at reflux (or at the temperature indicated in the table) for approximately 14 h, then cooled to room temperature filtered to remove the inorganic salts, which were washed with acetonitrile, the organic phases were collected and evaporated to dryness. A sample was collected for HPLC analysis. After crystallization from a mixture of IPA and MTBE the typical overall yield was about 60-70%.
	With caesium carbonate; In acetonitrile; at 70℃; for 14h;Product distribution / selectivity;	EXAMPLES 8-23; These examples illustrate the synthesis of the compound of formula (I) in accordance with embodiments of the invention. In addition, these examples illustrate a method for determining the purity of a compound of formula (I) in accordance with the invention.The following general procedure was used: into a 10 or 25 mL reactor were charged: 0.51 g (2.95 mmol) of 1-chloroacetyl-2-cyanopyrrolidine, 0.57 g (3.40 mmol) of aminoadamantanol, 3.40 mmol of potassium or cesium carbonate and, when indicated, 5 mg (0.03 mmol) of KI. Finally, 5 mL of solvent was also added. The mixture was heated at reflux (or at the temperature indicated in the table) for approximately 14 h, then cooled to room temperature filtered to remove the inorganic salts, which were washed with acetonitrile, the organic phases were collected and evaporated to dryness. A sample was collected for HPLC analysis. After crystallization from a mixture of IPA and MTBE the typical overall yield was about 60-70%.
	With caesium carbonate; In Isopropyl acetate; at 45 - 70℃; for 14h;Product distribution / selectivity;	EXAMPLES 8-23; These examples illustrate the synthesis of the compound of formula (I) in accordance with embodiments of the invention. In addition, these examples illustrate a method for determining the purity of a compound of formula (I) in accordance with the invention.The following general procedure was used: into a 10 or 25 mL reactor were charged: 0.51 g (2.95 mmol) of 1-chloroacetyl-2-cyanopyrrolidine, 0.57 g (3.40 mmol) of aminoadamantanol, 3.40 mmol of potassium or cesium carbonate and, when indicated, 5 mg (0.03 mmol) of KI. Finally, 5 mL of solvent was also added. The mixture was heated at reflux (or at the temperature indicated in the table) for approximately 14 h, then cooled to room temperature filtered to remove the inorganic salts, which were washed with acetonitrile, the organic phases were collected and evaporated to dryness. A sample was collected for HPLC analysis. After crystallization from a mixture of IPA and MTBE the typical overall yield was about 60-70%.
	With caesium carbonate; In tetrahydrofuran; at 45 - 66℃; for 14 - 24h;Product distribution / selectivity;	EXAMPLES 8-23; These examples illustrate the synthesis of the compound of formula (I) in accordance with embodiments of the invention. In addition, these examples illustrate a method for determining the purity of a compound of formula (I) in accordance with the invention.The following general procedure was used: into a 10 or 25 mL reactor were charged: 0.51 g (2.95 mmol) of 1-chloroacetyl-2-cyanopyrrolidine, 0.57 g (3.40 mmol) of aminoadamantanol, 3.40 mmol of potassium or cesium carbonate and, when indicated, 5 mg (0.03 mmol) of KI. Finally, 5 mL of solvent was also added. The mixture was heated at reflux (or at the temperature indicated in the table) for approximately 14 h, then cooled to room temperature filtered to remove the inorganic salts, which were washed with acetonitrile, the organic phases were collected and evaporated to dryness. A sample was collected for HPLC analysis. After crystallization from a mixture of IPA and MTBE the typical overall yield was about 60-70%.
4.25 g		In a 250 ml reaction flask, 6.4 g of potassium carbonate, 4.2 g of 3-hydroxyamantanamine and 70 ml of tetrahydrofuran were added, and 0.5 g of potassium iodide was added thereto, followed by stirring at room temperature. A solution of 4 g of 4-cyano-1- (2-chloroacetyl) pyrrolidine dissolved in tetrahydrofuran (20 ml) was charged into a dropping funnel and allowed to drop into the reaction solution over 30 minutes. After the drop, heat up to 90 C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and the filter cake was washed twice with tetrahydrofuran 1.0 ml. The filtrates were combined and the solvent was distilled off under reduced pressure to give a yellow oil. The isopropanol was recrystallized to give a white solid vildagliptin 4.25 g , Purity 87.41%, compound 8 content 7.32%

Reference： [1]Patent: US2008/167479,2008,A1 .Location in patent: Page/Page column 5-6
[2]Patent: US2008/167479,2008,A1 .Location in patent: Page/Page column 5-6
[3]Patent: US2008/167479,2008,A1 .Location in patent: Page/Page column 5-6
[4]Patent: US2008/167479,2008,A1 .Location in patent: Page/Page column 5-6
[5]Patent: US2008/167479,2008,A1 .Location in patent: Page/Page column 5-6
[6]Patent: US2008/167479,2008,A1 .Location in patent: Page/Page column 5-6
[7]Patent: US2008/167479,2008,A1 .Location in patent: Page/Page column 5-6
[8]Patent: US2008/167479,2008,A1 .Location in patent: Page/Page column 5-6
[9]Patent: US2008/167479,2008,A1 .Location in patent: Page/Page column 5-6
[10]Patent: US2008/167479,2008,A1 .Location in patent: Page/Page column 5-6
[11]Patent: CN104817482,2017,B .Location in patent: Paragraph 0007; 0062; 0069; 0070

9
[ 702-82-9 ]
[ 207557-35-5 ]
[ 1036959-23-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate; tri tert-butylphosphoniumtetrafluoroborate; In dichloromethane; at 30℃; for 3h;	Preparation an embodiment of the invention, the compound vildagliptinThey were taken 21.58g Compound I (0.125mol), 8.36g Compound II (0.05mol),8.29g of potassium carbonate (0.06mol), tri-tert-butylphosphine tetrafluoroborate 1.45 g (0.005mol), 500mL methylene chloride, placed 1000mL three-necked flask,Stirring, temperature was raised to 30 , 30 ± 3 reaction incubated 3h, TLC monitoring, completion of the reaction, insolubles were removed by filtration, the filtrate was concentrated under reduced pressure to remove the solvent to give a pale yellow concentrate, to the concentrate was added dropwise acetic acid and 80ml butanone the mixed solution of ethyl (methyl ethyl ketone: ethyl acetate = 1: 2), solid separated was filtered and dried to give 20.00 g vildagliptin compound, yield 91%, purity 99.9%,
72%	With potassium carbonate; potassium iodide; In tetrahydrofuran; for 5h;Heating / reflux;Product distribution / selectivity;	EXAMPLE 4; This example illustrates the synthesis of the compound of formula (II) in accordance with an embodiment of the invention.Synthesis of (2S,2'S)-1,1'-[[(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)imino]bis(1-oxo-2,1-ethanediyl)]di(2-pyrrolidinecarbonitrile). A 50 mL round bottom flask with magnetic stirring was charged with THF (15 mL), powdered K2CO3 (3.3 g, 24 mmol), 3-amino-1-adamantanol (1 g, 6 mmol), 1-chloroacetyl-2-cyanopyrrolidine (2.6 g, 15 mmol) and KI (50 mg, 0.3 mmol). The resulting slurry was heated to reflux for 5 hours. The suspension was cooled down, filtered at room temperature and the solids washed with 5 mL of THF. Solvents were distilled off under vacuum and the resulting crude was recrystallized in 15 mL of isopropanol to obtain 1.9 g of the compound of formula II (72% yield): mp 181-183 C.; IR (KBr) 3420, 2920, 2906, 2880, 2851, 2239, 1650 1450, 1424, 1403, 1311, 1003 cm-1; 1H-NMR (DMSO-d6) 1.30-1.67 (m, 12H), 1.75-2.36 (m, 10H), 3.10-3.29 (m, 1.3H), 3.38-3.84 (m, 6.7H), 4.40-4.51 (m, 1H), 4.57-4.70 (m, 1.5H), 5.95-6.07 (m, 0.4H); 13C-NMR (DMSO-d6, 80 C.) 24.4, 28.9, 29.9, 34.5, 37.8, 43.9, 45.3, 45.9, 46.8, 49.9, 57.5, 67.5, 118.8, 170.0; MS (ESI+) 440 (M++1); [alpha]D25=111 (c 1.0, MeOH).

Reference： [1]Patent: CN105330580,2016,A .Location in patent: Paragraph 0023; 0024; 0025
[2]Asian Journal of Chemistry,2014,vol. 26,p. 3489 - 3492
[3]Patent: US2008/167479,2008,A1 .Location in patent: Page/Page column 5

10
[ 1146970-24-2 ]
[ 702-82-9 ]
[ 1146970-19-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 90℃;	To a solution of 9 (2.0 g, 4.6 mmol) in DMF (20 mL) at room temperature, 3-amino-l- adamantanol (0.76 g, 4.5 mmol) and K2CO3 (1.2 g, 8.7 mmol) were added. The resulting mixture was stirred at 90 0C overnight then was cooled to room temperature and was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 1:1 hexanes:ethyl acetate, 3:7 hexanes:ethyl acetate, ethyl acetate and 9: 1 ethyl acetate: methanol to give 10 (1.8 g, 74% yield) as an off-white solid

Reference： [1]Patent: WO2009/53895,2009,A2 .Location in patent: Page/Page column 33-34

11
[ 1146970-25-3 ]
[ 702-82-9 ]
[ 1146970-20-8 ]

Yield	Reaction Conditions	Operation in experiment
79%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 90℃; for 72h;	To a solution of 12 (2.0 g, 4.7 mmol) in DMF (20 mL) at room temperature, 3-amino-l- adamantanol (0.78 g, 4.7 mmol) and K2CO3 (1.3 g, 9.4 mmol) were added. The resulting mixture was heated to 90 0C for three days then was cooled to room temperature. The mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The solid residue taken up in methanol and filtered, washing with cold methanol. The resulting filter cake was dried under vacuum to give 13 (1.9 g, 79% yield) as a pale yellow solid

Reference： [1]Patent: WO2009/53895,2009,A2 .Location in patent: Page/Page column 34-35

12
[ 768-94-5 ]
[ 702-82-9 ]

Yield	Reaction Conditions	Operation in experiment
90%		Example 1: Preparation of 3-amino-adamantan-l-ol (0099) In a clean and dry 5.0 L 4 necks RBF equipped with liquid addition funnel, TP. Charged cone, sulphuric acid (300 mL, 2 V) and cooled the reaction mass to 5-10 C. To the cooled mass 1-adamantyl amine (150 g, 1 eq.) was added lot wise at 5-10 C. After complete addition, stirred the reaction mass to get clear (slightly hazy) solution and maintained the reaction mass at 5-15 C. Meanwhile a nitrating mixture was prepared by adding 150 mL of 65-70 % nitric acid to 450 mL cone, sulphuric acid maintaining temperature at 0-10 C). The nitrating mixture was added to the reaction mass maintaining reaction temperature at 20 ± 5 C. After the addition was over, stirred the reaction mass at 20 ± 5C for 3 to 5 h. Completion of the reaction was confirmed by GC. The reaction mass was cooled to 0 - 5 C and added water (150 mL, I V) to the reaction mass maintaining 0-20 C and again cooled reaction mass to 5-10 C. Second lot of water (300 mL, 2 V) was added to the reaction mass maintaining 5-20 C. The reaction mass was cooled again to 5-10 C and added third lot of water (1050 mL, 7 V) to the reaction mass maintaining 5-20 C. After complete addition of water the reaction mass was cooled to 0-5 C and added 50 % NaOH solution maintaining 0- 40 C and stirred for 1 h at 35-40 C. Filtered the solid obtained and washed the cake with water (150 mL, IV). Wet weight: 1 185 g. The wet cake was dried under reduced pressure at 60-70 C. Mixed the above dried solid with IPA (750 mL, 5 V w.r.t. adamantly amine) and heated at 50 - 60C and maintained for 1 h. Then cooled reaction mass to 20-25C and maintained at 20-25C for 1 h. Filtered the solid obtained and wash with IPA (150 mL, 1 V). Distilled around 600 mL, 4 - 4.5 V of IPA from reaction mass under reduced pressure and cooled the residual reaction mass to 40-45C. Added cyclohexane (1200 mL, 8 V) to reaction mass and heated to 50-55C. Applied 200-250 Torr vacuum slowly to the reaction mass and distilled cyclohexane (900 mL, 6 V) from reaction mass under reduced pressure. Filtered the solid and wash with cyclohexane (150 mL, IV) Unload solid and dry it for 10-12 h under reduced pressure at 60C. Yield range: 90%; GC purity > 98%; melting point: 265C; 1H NMR (CDC13, 400 MHz) delta: 1.35-1.48 (m, 14H, 6xCH2, l NH2); 2.08 (brs, 2H, 2*CH); 4.36 (s, IotaEta, OmicronEta).
81%	With sulfuric acid; nitric acid; at 0 - 10℃; for 2h;	To a round bottom flask containing compound 13 (100mg, 0.53mmol) a mixture of concentrated sulfuric acid (2mL, 37.1mmol) and concentrated nitric acid (0.2mL, 4.46mmol) was added at 0C. The mixture was left to stir for two hours at 10C. Ice-cold water was then carefully added to the reaction mixture, following this addition the reaction mixture was made basic using solid sodium hydroxide until precipitation could be seen. The solution was thereafter filtered, and the wet solid collected and dissolved in DCM and left to stir for 30min. Next, the solid was removed from the solution by filtration and washed with DCM. The DCM-solution containing 14 was concentrated in vacuo to afford compound 14 (70mg, yield 81%). 1H NMR (CDCl3 300MHz) delta: 2.24-2.16 (m, 2H), 1.62-1.58 (m, 4H), 1.54-1.50 (m, 2H), 1.49-1.43(m, 6H). 13C NMR (CDCl3, 75.4MHz) delta: 69.6 (HOC), 53.9, 50.5, 44.9, 44.2, 34.9, 31.1 (aliphatic C).
	With sulfuric acid; nitric acid; at 90℃;	Adding concentrated sulfuric acid and amantadine in the storage tank 1 at a mass ratio of 1:8 to prepare an amantadine sulfuric acid solution, and injecting into the preheating module 3 by using a metering pump 3 at a rate of 100 ml/min; Using a metering pump 4 to inject 50% nitric acid in the storage tank 2 into another preheating module 3 of the microchannel reactor at a rate of 15 ml/min; The liquid in the two preheating modules 3 simultaneously enters the mixing module 4 for reaction, and the temperature in the mixing module 4 is controlled to be 90 C, and the reaction retention time is 80 s. Then, it enters the cooling module 5, and finally enters the reaction liquid collector 6 in a continuous flow state. After quenching with ice water, the pH was adjusted to 13 with sodium hydroxide solution, and the solid was precipitated at 60 C. After centrifugation, the solid was recrystallized to obtain a white solid powder. The molar yield was found to be 82%, the purity was 99%, and the dinitro by-product was 0.02%.

Reference： [1]Patent: WO2015/128718,2015,A1 .Location in patent: Page/Page column 15
[2]Tetrahedron,2018,vol. 74,p. 2905 - 2913
[3]Russian Journal of Organic Chemistry,2009,vol. 45,p. 1137 - 1142
[4]Patent: CN109824524,2019,A .Location in patent: Paragraph 0018-0022

13
[ 1311403-44-7 ]
[ 702-82-9 ]
[ 1338996-19-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	In acetonitrile; at 23℃; for 5h;	A mixture of 4.89 parts of Salt (I-9), 1.67 parts of a compound represented by the formula (IV-2) and 50 parts of acetonitrile was stirred at 23 C. for 5 hours. The mixture was concentrated and then, 30 parts of chloroform and 15 parts of ion-exchanged water were added to the residue obtained. The mixture obtained was separated to obtain an organic layer. The organic layer was washed with 15 parts of ion-exchanged water and then, concentrated. The residue obtained was dissolved in 20 parts of acetonitrile, and the solution obtained was concentrated. To the residue, 20 parts of ethyl acetate was added. The mixture obtained was concentrated.The residue obtained was mixed with 20 parts of tert-butyl methyl ether. The mixture obtained was stirred and then, the supernatant solution was removed. The residual layer was concentrated, and the residue obtained was mixed with 20 parts of ethyl acetate. The mixture obtained was stirred and the supernatant solution was removed. The residual layer was concentrated to obtain 4.75 parts of the salt represented by the formula (B1-22).Yield: 81% based on Salt (I-9)Yield: 81% based on the salt represented by the formula (II-1).
	In acetonitrile; at 23℃; for 1h;	59.52 parts of a solution containing the salt represented by the formula (IV-1) and 3.81 parts of the compound represented by the formula (V-8)After stirring at 23 C. for 1 hour,It was filtered.The collected filtrate was concentrated,To the obtained concentrate,100 parts of chloroform and 30 parts of ion exchanged water were charged,After stirring for 30 minutes,And separated.This washing operation was repeated three times.By concentrating the recovered organic layer,9.44 parts of a salt represented by the formula (I-8) was obtained.

Reference： [1]Patent: US2011/201823,2011,A1 .Location in patent: Page/Page column 41-42
[2]Patent: JP5879696,2016,B2 .Location in patent: Paragraph 0289-0290

14
[ 702-82-9 ]
[ 298-12-4 ]
[ 1334337-69-7 ]

Yield	Reaction Conditions	Operation in experiment
96.1%	With acetic anhydride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 2h;Reflux;	27.6 g (0.30 mol, 1.5 eq) of glyoxylic acid monohydrate,3-amino-1-adamantanol 33.5 g (0.20 mol, 1.0 eq),38.8 g (0.30 mol, 1.5 eq) of diisopropylethylamine and 250 g of tetrahydrofuran were placed in the reaction flask.51.1 g (0.50 mol, 2.5 eq) of acetic anhydride was added dropwise.Heat and reflux for 2 hours.The remaining amount of controlled raw materials in HPLC is less than 1%.Add 50g of water and stir for 30 minutes.Layered,The aqueous layer was extracted once with 50 g of dichloromethane.The organic layer was concentrated under reduced pressure to give a white solid.Compound II 42.8g,The yield is 96.1%.Purity 96.6%
	In tetrahydrofuran; for 3h;Reflux;	Example-17: Preparation of 2-(3-hydroxyadamantan-l-yl-imino) acetic acid compound of formula 11:To the solution of l-aminoadamantane-3-ol (5 grams) in 50 ml of tetrahydrofuran 2-oxo acetic acid (2.25 grams) was added and stirred. The reaction mixture was heated to reflux for 3 hrs. The reaction mixture was cooled to room temperature and quenched with water. The reaction mixture was extracted with dichloromethane. The dichloromethane solvent was dried and distilled off to get the title compound.Yield: 6 grams.

Reference： [1]Patent: CN108503571,2018,A .Location in patent: Paragraph 0016; 0035-0037; 0038; 0040
[2]Patent: WO2011/101861,2011,A1 .Location in patent: Page/Page column 23

15
[ 702-82-9 ]
[ 274901-16-5 ]

Yield	Reaction Conditions	Operation in experiment
56.5 g	With potassium carbonate; potassium iodide; In acetone; at 25 - 30℃;	Example 23: Preparation of Vildagliptin To a mechanically stirred solution of 3-amino- 1-adamantanol (50 gm), K2CO3 (41.3 gm) and Kl (2.5 gm) in acetone (375 ml), solution of 1- chloroacetyl (S)-2-cyanopyrrolidine (51.6 g) in acetone (125 ml) was added drop wise. The reaction mass was stirred for 6-8 h at 25C to 30C. Upon completion of reaction, acetone was distilled out under reduced pressure to obtain crude vildagliptin. DM water (500 ml) was added to the crude vildagliptin and pH of aqueous solution was adjusted to 5-6 using acetic acid. Aqueous acidic solution was washed with dichloromethane (3 X 250 ml). Aqueous layer was separated and basified using aqueous ammonia till pH 9- 10. Product was extracted from aqueous layer using dichloromethane (400 ml and 2 X 100 ml). DM water (200 ml) was charged into organic layer and pH was adjusted to 5-6 using tartaric acid solution. Reaction mass was stirred and organic layer was separated. Aqueous layer was washed with MDC (3X250 ml), separated and aqueous layer was basified with aq.NH3 to pH 9- 0.Product was extracted with MDC (400 ml and 2 X 100 ml), organic layer was distilled off atmospherically to obtain vildagliptin. Methyl ethyl ketone (300 ml) was charged to vildagliptin and heated the reaction mass at 78±2C to get clear solution. Obtained clear solution was distilled approx. 5 to 10 % under reduced pressure then gradually cooled at 25C to 30C and further cooled at 0C to 5C for 30 minutes. Solid was filtered and washed with methyl ethyl ketone (12.5 ml). [Yield: 56.5 gm, Purity: 99.98%]

Reference： [1]Patent: WO2011/101861,2011,A1
[2]Patent: WO2011/101861,2011,A1
[3]Patent: WO2012/4210,2012,A1
[4]Patent: WO2013/179300,2013,A2 .Location in patent: Page/Page column 39; 40
[5]Patent: WO2015/128718,2015,A1
[6]Patent: WO2015/128718,2015,A1
[7]Patent: WO2015/128718,2015,A1
[8]Patent: WO2015/128718,2015,A1
[9]Patent: WO2015/128718,2015,A1
[10]Patent: WO2015/128718,2015,A1
[11]Patent: CN103980175,2016,B
[12]Patent: CN107033054,2017,A
[13]Patent: CN108503571,2018,A
[14]Patent: CN108658826,2018,A

16
[ 94-82-6 ]
[ 702-82-9 ]
4-(2,4-dichloro-phenoxy)-N-((1R,3S,5R,7S)-3-hydroxy-adamantan-1-yl)-butyramide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		EXAMPLESExample 1-1 (General procedure (A))4-(2,4-Dichloro-phenoxy)-N-((1 R,3S,5R,7S)-3-hvdroxy-adamantan-1-yl)-butyramideTo a stirred solution of 4-(2,4-dichloro-phenoxy)-butyric acid (0.8 g, 3.21 mmol) in dry THF (25 mL) was added HOBt (0.48 mg, 3.533 mmol) and EDAC (0.68 g, 3.533 mmol). After stirring for 10 min. at room temperature, DIPEA (0.62 mL) and 3-amino-adamantan-1- ol (0.59 g, 3.533 mmol) were added and the resulting mixture was stirred for 16 hrs. at room temperature. The volatiles were removed in vacuo and to the residue was added water (25 mL) followed by extraction with EtOAc (3x35 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The oily residue was crystallised from diethyl ether (5 mL) affording after drying at 50 0C in vacuo 800 mg (62 %) of the title compound as a solid. 1H NMR (400 MHz, DMSO-c/6) delta 1.35 - 1.58 (m, 6H), 1.70 - 1.85 (m, 6H), 1.91 (q, 2H) 2.09 (br.s., 2H), 2.21 (t, 2H), 4.04 (t, 2H), 4.48 (br.s., 1 H), 7.15 (d, 1 H), 7.36 (dd, 1 H), 7.40 (br.s., 1 H), 7.57 (d, 1 H).

Reference： [1]Patent: WO2008/134221,2008,A1 .Location in patent: Page/Page column 48

17
[ 1436430-30-6 ]
[ 702-82-9 ]
[ 1436430-33-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; HATU; In N,N-dimethyl-formamide; for 2h;	To a solution of (2S)-2-[(4S,5S)-3-(tert-butoxycarbonyl)-4-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]methyl}-2,2-dimethyl-1,3-oxazolidin-5-yl]methyl}-3-methylbutanoic acid (150 mg, 0.256 mmol) and <strong>[702-82-9]1-amino-3-hydroxyadamantane</strong> (128 mg, 0.768 mmol) in DMF (3 mL) were added Et3N (214 muL, 1.54 mmol) and HATU (389 mg, 1.02 mmol) at room temperature, and the mixture was stirred at 40 C for 2 h. Water was added, and the water layer was extracted with AcOEt. The combined organics were washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (eluent, CH2Cl2/MeOH = 99:1-91:9) to obtain 19a (160 mg, 87%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): a mixture of rotamers delta 8.02 (s, 1H), 7.47-7.24 (m, 4H), 5.44 (br s, 1H), 4.04-2.60 (m, 8H), 2.24-1.50 (m, 33H), 1.25-1.21 (m, 6H), 0.95-0.94 (m, 6H).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 3175 - 3196

18
[ 702-82-9 ]
[ 214398-99-9 ]
[ 274901-16-5 ]

Reference： [1]Asian Journal of Chemistry,2013,vol. 25,p. 7557 - 7560

19
[ 702-82-9 ]
[ 25947-11-9 ]
[ 1458056-29-5 ]

Yield	Reaction Conditions	Operation in experiment
33%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 49h;Cooling with ice;	General procedure: To a 100 ml RBF, compound 6a (10 mmol), heterocyclic amine (2.18 g, 10 mmol) and TBTU (3.21 g, 10 mmol) and dry CH2Cl2 (15 ml) were taken and the contents of the flask were cooled in an ice-bath. DIPEA (8.9 ml, 50 mmol) was added drop wise to the flask over a 1-hr period. The reaction mixture became clear after complete addition. The ice-bath was removed and the reaction mixture was stirred at room temperature for 48 hrs. The white solid (precipitated out of the reaction mixture) was filtered and washed with water (20 ml). The crude products were directly recrystallised from boiling 1,4-dioxane.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5740 - 5743

20
3-(4-fluoro-3-oxobenzo[d]isothiazol-2(3H)-yl)propanoic acid [ No CAS ]
[ 702-82-9 ]
N-(3-hydroxyadamantan-1-yl)-3-(4-fluoro-3-oxobenzo[d]isothiazol-2(3H)-yl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 70h;Inert atmosphere;	General procedure: N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (0.15 g, 0.78 m Mol, 1.2 equiv) and 3-amino-5,7-dimethyladamantan-1-ol (9b) (0.15 g, 0.76 m Mol, 1.06 equiv) were successively added to a solution of 2-(3-oxobenzo[d]isothiazol-2(3H)-yl)acetic acid (8) (0.15 g, 0.72 m Mol, 1.0 equiv) in anhydrous DMF (5 mL) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 70 h. The solvent was evaporated under reduced pressure and the residue was partitioned between water (20 mL) and ethyl acetate (10 mL). The aqueous phase was additionally extracted with ethyl acetate (3 * 7 mL). The combined organic layer was successively washed with 5% aqueous solution of citric acid (7 mL), 5% aqueous solution of NaHCO3 (8 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. Crystallization of the crude product from a mixture consisting from ethyl acetate and hexanes provided 1c (47 mg, 17%).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 5988 - 6003

21
[ 702-82-9 ]
[ 89139-48-0 ]
N-(3-hydroxyadamantan-1-yl)-3-(3-oxobenzo[d]isothiazol-2(3H)-yl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 70h;Inert atmosphere;	General procedure: N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (0.15 g, 0.78 m Mol, 1.2 equiv) and 3-amino-5,7-dimethyladamantan-1-ol (9b) (0.15 g, 0.76 m Mol, 1.06 equiv) were successively added to a solution of 2-(3-oxobenzo[d]isothiazol-2(3H)-yl)acetic acid (8) (0.15 g, 0.72 m Mol, 1.0 equiv) in anhydrous DMF (5 mL) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 70 h. The solvent was evaporated under reduced pressure and the residue was partitioned between water (20 mL) and ethyl acetate (10 mL). The aqueous phase was additionally extracted with ethyl acetate (3 * 7 mL). The combined organic layer was successively washed with 5% aqueous solution of citric acid (7 mL), 5% aqueous solution of NaHCO3 (8 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. Crystallization of the crude product from a mixture consisting from ethyl acetate and hexanes provided 1c (47 mg, 17%).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 5988 - 6003

22
[ 702-82-9 ]
ethyl 1-(2-ethoxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate [ No CAS ]
1-(2-ethoxyethyl)-N-(3-hydroxyadamantan-1-yl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%		General procedure: To a suspension of 3a (206 mg, 0.748 mmol) in DMF (10 mL) was added DIPEA (0.392 mL, 2.245 mmol) and the solution was stirred at rt for 30 min. HBTU (568 mg, 1.497 mmol) was added portion wise, followed by the addition of 1-aminoadamantane (0.136 g, 0.898 mmol). The mixture was stirred at rt for 4 h and diluted with EtOAc (60 mL), washed with water (3 x 10 mL), HCl (0.5 M, 10 mL), water (10 mL) and brine (15 mL). Solvents were removed under reduced pressure and the residue was purified with flash chromatography using hexane:EtOAc (10:1 to 2:1) to give RS-005 (263 mg, 0.644 mmol, 86% yield).

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 92,p. 554 - 564

23
[ 702-82-9 ]
(2S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile [ No CAS ]
[ 274901-16-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example II: Preparation of crude Vildagliptin (formula-l) To the 750 cc acetone charged 0.72 mole of formula-II with 1.45 mole of potassium carbonate and 0.003 mole potassium iodide. The reaction mass stirred for 15min at ambient temperature.Then charged 0.58 mole formula-IIIin 200cc acetone and stirred for 4-5 hrs at 40-65C. After completion of reaction, filtered the solid potassium chloride and potassium carbonate.Concentrated the filtrate up to minimum volume and stirred for 60 min at 15-40C to get 82% yield of crude Vildagliptin. HPLC PURITY: 97-99%, Dimer IMP: 2.0-3.0%

Reference： [1]Patent: WO2015/92806,2015,A1 .Location in patent: Sheet 11

24
[ 1376771-60-6 ]
[ 702-82-9 ]
3-(1,5,3-dithiazepan-3-yl)adamantan-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With samarium(III) chloride hexahydrate; In ethanol; chloroform; at 20℃; for 3.5h;Inert atmosphere;	General procedure: A mixture of 0.136 or 0.272 g (1 or 2 mmol) of 1-oxa-3,6-dithiacycloheptane (1) [3] in 5 mL of chloroform and 0.018 g (0.05 mmol) of SmCl3 · 6 H2O was stirred for 30 min at room temperature under argon, and a solution of 1 mmol of the corresponding amine in 5 mL of ethanol was added dropwise. The mixture was stirred for 3 h at room temperature, treated with 2 mL of water, stirred for 30 min more, and extracted with chloroform (20 mL). The extract was evaporated, and the product (compound 2-17) was isolated from the residue by column chromatography on silica gel.

Reference： [1]Russian Journal of Organic Chemistry,2015,vol. 51,p. 951 - 956
Zh. Org. Khim.,2015,vol. 51,p. 971 - 976,6

25
[ 702-82-9 ]
[ 107-14-2 ]
(3-hydroxyadamantan-1-ylamino)acetonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; potassium iodide; In ethyl acetate; at 75℃;	Example 5: (3-Hydroxy-adamantan-l-ylamino)-acetonitrile (0107) In a 500 mL RBF 3-amino-adamantan-l -ol (30 g, leq.) was dissolved in ethyl acetate (300 mL, 10V). To this solution potassium carbonate (54.5 g, 2.2 eq.) and potassium iodide (3 g, 0.1 eq) was added under stirring. After 10 min. chloroacetonitrile (16.2 g, 1.2 eq.) was added and the mixture was heated at 75C under stirring for 5-6 h. Completion of reaction was confirmed by TLC. After complete conversion the reaction mixture was cooled to 20-25C. The reaction mass was filtered and washed the wet cake with ethyl acetate (30 mL, IV). The concentration of EtOAc layer gave 36 g (yield: 97%) of the title compound; 1H NMR Assay: 97.9%; NMR (CDC13, 400 MHz) delta: 1.49-1.78 (m, 12H, 6 CH2), 2.30 (s, 2H, 2x CH), 3.57 (s, 2H, l x CH2)

Reference： [1]Patent: WO2015/128718,2015,A1 .Location in patent: Page/Page column 16-17

26
[ 702-82-9 ]
[ 207557-35-5 ]
vildagliptin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4 g	With potassium carbonate; potassium iodide; In tetrahydrofuran; at 40℃; for 4.5h;Reflux;	A mixture of 3 g of 3-aminoadamantane, 0.25 g of potassium iodide and 10 g of potassium carbonate was added to 30 ml of tetrahydrofuran.To a temperature of 40 C, 3 g of (S) -1-chloroacetyl-2-cyanopyrrolidine was slowly added dropwise to a solution of 30 g of tetrahydrofuranOf the solution, about 1.5 hours dripping. After completion of the reaction, the temperature was raised to 40 C for 1 hour, and the temperature was raised to reflux for 2 hours. Back to the endThe filter cake was washed with a small amount of tetrahydrofuran and the filtrate was combined and concentrated to an oil. The oil is added to the appropriate amount of butanone dissolved, putCrystallization, filtration, drying of amino-monosubstituted adamantanyl alcohol 4 grams,

Reference： [1]Patent: CN106432026,2017,A .Location in patent: Paragraph 0033; 0034; 0036

27
[ 702-82-9 ]
[ 207557-35-5 ]
[ 1036959-27-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; potassium iodide; In butanone; at 70℃; for 1h;	1) A mixed solution of 3-amino-1-adamantanol and 1-chloroacetyl-2-cyanopyrrolidine in a solvent was mixed with a suspension of a base and a catalyst and then preheated by a preheater;2) The preheated mixture enters the tubular reactor, the residence time of the material in the tubular reactor is 60min, and then the reaction liquid withdrawn from the tubular reactor is collected and filtered, washed and purified to obtain the product.The process parameters are as follows:The preheater temperature is 70 C, the tube reactor temperature is 70 C, and the flow rate of the material in the line is 0.5 m / s.The molar ratio of 3-amino-1-adamantanol to 1-chloroacetyl-2-cyanopyrrolidine was 2: 1,3-amino-1-adamantanol was 0.13 g / ml, 1-chloro The concentration of acetyl-2-cyanopyrrolidine was 0.068 g / ml, the molar ratio of potassium carbonate to 1-chloroacetyl-2-cyanopyrrolidine was 1: 1, the amount of potassium iodide was the same as that of 1-chloroacetyl The molar ratio of 2-cyanopyrrolidine was 0.5: 1, and the reaction solvent was 2-butanone.Under this operating condition, the yield of the Viglitin reaction was 85% and the amount of the disubstituted compound was 4.5%.

Reference： [1]Patent: CN104311467,2017,B .Location in patent: Paragraph 0032-0041

28
[ 702-82-9 ]
C₇H₈Cl₂N₂O [ No CAS ]
[ 274901-16-5 ]

Yield	Reaction Conditions	Operation in experiment
10.5 g		10.35 g of the compound of the formula I, 15.0 g of sodium trihydrate, 8.36 g of 3-hydroxyadamentamine and 80 ml of water were added, stirred and heated under reflux for four hours and cooled to 5 to 10 C to obtain a reaction solution. Sodium hydroxide was added to the reaction solution, and the mixture was allowed to stand at 5 to 10 C and reacted for 1 hour. The resulting reaction solution was adjusted to pH 3.0 with hydrochloric acid and extracted twice with methylene chloride, 50 ml each. The organic phase was discarded and the aqueous phase was adjusted to pH 9.0 with sodium hydroxide and extracted three times with methylene chloride. The combined extracts were dried over anhydrous sodium sulfate. Filtration, filtering sodium sulfate, the filtrate was concentrated to dryness, add isopropyl alcohol 80ml, dissolved by heating, cooling and crystallization. (400 MHz, CDC13),?: 1.51-1.64 (m, 12H), 2.16 to 2.20 (m, 12H), and the residue was filtered to dryness and dried to dryness to give a product , 3H), 2.24 to 2.27 (m, 4H), 2.27 to 3.43 (m, 1 H), 3.45 (s, 2H), 3.43 to 3.60 (m, 2H) , LH) ^ ESI-HRMSC calculated), m / z: 303.1945 (303-1947)

Reference： [1]Patent: CN104817482,2017,B .Location in patent: Paragraph 0044; 0059; 0060

29
[ 702-82-9 ]
[ 18791-79-2 ]
3-[(5-bromothiophen-3-yl)methyl]amino}adamantan-1-ol [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 1111 - 1116

30
[ 702-82-9 ]
[ 167366-05-4 ]
3-[(4-bromo-1,3-thiazol-2-yl)methyl]amino}adamantan-1-ol [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 1111 - 1116

31
[ 464192-28-7 ]
[ 702-82-9 ]
3-[(2-bromo-1,3-thiazol-5-yl)methyl]amino}adamantan-1-ol [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 1111 - 1116

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
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. 702-82-9 ]

Quality Control of [ 702-82-9 ]

Related Doc. of [ 702-82-9 ]

Product Details of [ 702-82-9 ]

Calculated chemistry of of [ 702-82-9 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 702-82-9 ]

Application In Synthesis of [ 702-82-9 ]

[ 702-82-9 ] Synthesis Path-Upstream 1~8

[ 702-82-9 ] Synthesis Path-Downstream 1~31

Related Functional Groups of [ 702-82-9 ]

Amines

Aliphatic Cyclic Hydrocarbons

Alcohols

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 702-82-9 ]