[ CAS No. 81846-19-7 ] {[proInfo.proName]}

Name: 81846-19-7|2-(((1R,2R,3aS,9aS)-2-Hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid|98%
Brand: Ambeed
SKU: A465916
Price: 22.0 USD
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Quality Control of [ 81846-19-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 81846-19-7 ]

SDS Specification

Alternatived Products of [ 81846-19-7 ]

Product Details of [ 81846-19-7 ]

CAS No. :	81846-19-7	MDL No. :	MFCD00888847
Formula :	C₂₃H₃₄O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PAJMKGZZBBTTOY-ZFORQUDYSA-N
M.W :	390.51	Pubchem ID :	6918140
Synonyms :	UT-15;BW 15AU;Uniprost;U-62840;Rumodolin;LRX 15

Calculated chemistry of [ 81846-19-7 ]

Physicochemical Properties

Num. heavy atoms :	28
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.7
Num. rotatable bonds :	10
Num. H-bond acceptors :	5.0
Num. H-bond donors :	3.0
Molar Refractivity :	110.03
TPSA :	86.99 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.49 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.42
Log Po/w (XLOGP3) :	4.5
Log Po/w (WLOGP) :	3.58
Log Po/w (MLOGP) :	2.81
Log Po/w (SILICOS-IT) :	4.09
Consensus Log Po/w :	3.68

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-4.59
Solubility :	0.00993 mg/ml ; 0.0000254 mol/l
Class :	Moderately soluble
Log S (Ali) :	-6.05
Solubility :	0.00035 mg/ml ; 0.000000896 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-4.58
Solubility :	0.0103 mg/ml ; 0.0000264 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	4.65

Safety of [ 81846-19-7 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P501-P270-P202-P201-P264-P280-P308+P313-P362+P364-P301+P310+P330-P302+P352+P312-P405	UN#:	2811
Hazard Statements:	H301-H311-H331-H361	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 81846-19-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 81846-19-7 ]

[ 81846-19-7 ] Synthesis Path-Downstream 1~55

1
[ 101692-03-9 ]
[ 81846-19-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium hydroxide; In methanol; water; at 60℃; for 3h;Inert atmosphere;	Compound IIa (3.6 g) was dissolved in methanol (80 ml) under nitrogen and slowly 30% aqueous potassium hydroxide was added. The reaction mixture was heated to 60 C and reacted at 60 C for 3 hours, concentrated under reduced pressure to remove the methanol to give a light brown crude product. Crystallization from ethanol-water gave treprostinil (3.0 g, 86% yield) as a pure white solid.
81%		Examples 36 & 37Preparation of Treprostinil2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-((S)-3-hydroxyoctyl)-1H-cyclopenta[b]naphthalen-5-yloxy)acetic acid[0186]Example 36Preparation of Treprostinil from the product of Example 33[0187]2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-((S)-3-hydroxyoctyl)-1H-cyclopent a[b]naphthalen-5-yloxy)acetonitrile (2 g, 0.005 mmol) in methanol (18 ml) was treated with 20% KOH (6 ml) and refluxed for 3 hr. The reaction was then cooled to 10 C. and 3N HCl was added slowly until pH=?8. The solvent was removed in vacuo. Ethyl acetate and brine were added and then 3N HCl was added slowly until pH=2. The reaction mixture was extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by crystallization from ethanol/H2O. The titled compound was obtained in a crystalline form. Yield: 81%.
81%		2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-((S)-3-hydroxyoctyl)-1H-cyclopent a[b]naphthalen-5-yloxy)acetonitrile (2 g, 0.005mol) in methanol (18ml) was treated with 20% KOH (6 ml) and refluxed for 3 hr. The reaction was then cooled to 10C and 3N HCl was added slowly until pH= - 8. The solvent was removed in vacuo. Ethyl acetate and brine were added and then 3N HCl was added slowly until pH=2. The reaction mixture was extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by crystallization from ethanol/H2O. The titled compound was obtained in a crystalline form. Yield: 81%

A 50-L, cylindrical reactor equipped with a heating/cooling system, a mechanical stirrer, a condenser, and a thermocouple was charged with a solution of benzindene nitrile in methanol (12 L) and a solution of KOH (844 g of KOH dissolved in 4.25 L of water). The reaction mixture was stirred and heated to reflux (temperature 72.2 C.). The progress of the reaction was monitored by TLC (for TLC purpose, 1-2 mL of reaction mixture was acidified with 3M HCl to pH 1-2 and extracted with ethyl acetate. The ethyl acetate extract was used for TLC; Eluent: methanol/CH2Cl2; 1:9, and developed by 10% ethanolic solution of PMA). After completion of the reaction (5 h), the reaction mixture was cooled to -5 to 10 C. and quenched with a solution of hydrochloric acid (3M, 3.1 L) while stirring. The reaction mixture was concentrated in vacuo at 50-55 C. to obtain approximately 12-14 L of condensate. The condensate was discarded.The aqueous layer was diluted with water (7-8 L) and extracted with ethyl acetate (2×6 L) to remove impurities soluble in ethyl acetate. To aqueous layer, ethyl acetate (22 L) was added and the pH of reaction mixture was adjusted to 1-2 by adding 3M HCl (1.7 L) with stirring. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×11 L). The combined organic layers were washed with water (3×10 L) and followed by washing with a solution of NaHCO3 (30 g of NaHCO3 dissolved in 12 L of water). The organic layer was further washed with saturated solution of NaCl (3372 g of NaCl dissolved in water (12 L)) and dried over anhydrous Na2SO4 (950-1000 g), once filtered.The filtrate was transferred into a 72-L reactor equipped with mechanical stirrer, a condenser, and a thermocouple. To the solution of treprostinil in reactor was added activated carbon (110-130 g). The suspension was heated to reflux (temperature 68-70 C.) for at least one hour. For filtration, a pad of Celite 545 (300-600 g) was prepared in sintered glass funnel using ethyl acetate. The hot suspension was filtered through the pad of Celite 545. The Celite 545 was washed with ethyl acetate until no compound was seen on TLC of the washings.The filtrate (pale-yellow) was reduced to volume of 35-40 L by evaporation in vacuo at 50-55 C. for direct use in next step

Reference： [1]Patent: CN106831680,2017,A .Location in patent: Paragraph 0108; 0119; 0120; 0121
[2]Journal of Organic Chemistry,2004,vol. 69,p. 1890 - 1902
[3]Patent: US2013/53581,2013,A1 .Location in patent: Paragraph 0187
[4]Patent: EP2581361,2013,A1 .Location in patent: Paragraph 0183; 0184
[5]Patent: US2009/163738,2009,A1 .Location in patent: Page/Page column 5-6

2
[ 81007-64-9 ]
[ 81846-19-7 ]

Reference： [1]Journal of Organic Chemistry,2004,vol. 69,p. 1890 - 1902
[2]Organic and Biomolecular Chemistry,2019,vol. 17,p. 9489 - 9501

3
[ 223734-62-1 ]
[ 81846-19-7 ]

Reference： [1]Journal of Organic Chemistry,2004,vol. 69,p. 1890 - 1902

4
[ 101692-02-8 ]
[ 81846-19-7 ]

Reference： [1]Journal of Organic Chemistry,2004,vol. 69,p. 1890 - 1902
[2]Patent: WO2012/9816,2012,A1
[3]Patent: WO2012/88607,2012,A1
[4]Patent: US2013/53581,2013,A1
[5]Patent: EP2581361,2013,A1
[6]Patent: US2013/331593,2013,A1
[7]Patent: WO2014/89385,2014,A2
[8]Patent: WO2015/73314,2015,A1
[9]Patent: WO2016/55819,2016,A1
[10]Patent: US2016/152548,2016,A1
[11]Patent: CN106831680,2017,A
[12]Patent: CN107602376,2018,A
[13]Patent: CN107602376,2018,A

5
[ 111-42-2 ]
[ 81846-19-7 ]
[ 830354-48-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	In methanol; at 25 - 35℃; for 0.5h;	70g of <strong>[81846-19-7]treprostinil</strong> (II) is dissolved in 280ml of methanol at 25±5C. To the solution 20.73g of diethanolamine (IV) is added and the reaction mixture is agitated at 35±5C for half an hour, then l050ml of methyl tertiary- butyl ether (TBME) is added. The solution is filtered into an apparatus equipped with stirrer, seeded with approx. 700mg of polymorph form B crystals and agitated at room temperature for 2 hours, then 1400ml of methyl tertiary- butyl ether is added dropwise. Agitation is continued at room temperature for 16-24 hours, then the crystals are filtered off, washed and dried in vacuum at 45±5C. Yield: 87.2g (98%), colorless crystals, corresponding to polymorph form B.
80.42 - 88.00%	In ethanol; ethyl acetate; at 60 - 75℃; for 0.5 - 1h;Product distribution / selectivity;	A 50-L, cylindrical reactor equipped with a heating/cooling system, a mechanical stirrer, a condenser, and a thermocouple was charged with a solution of <strong>[81846-19-7]treprostinil</strong> in ethyl acetate (35-40 L from the previous step), anhydrous ethanol (5.1 L) and diethanolamine (435 g). While stirring, the reaction mixture was heated to 60-75 C., for 0.5-1.0 h to obtain a clear solution. The clear solution was cooled to 55+/-5 C. At this temperature, the seed of polymorph B of <strong>[81846-19-7]treprostinil</strong> diethanolamine salt (12 g) was added to the clear solution. The suspension of polymorph B was stirred at this temperature for 1 h. The suspension was cooled to 20+/-2 C. overnight (over a period of 16-24 h). The <strong>[81846-19-7]treprostinil</strong> diethanolamine salt was collected by filtration using Aurora filter equipped with filter cloth, and the solid was washed with ethyl acetate (2×8 L). The <strong>[81846-19-7]treprostinil</strong> diethanolamine salt was transferred to a HDPE/glass container for air-drying in hood, followed by drying in a vacuum oven at 50+/-5 C. under high vacuum.At this stage, if melting point of the <strong>[81846-19-7]treprostinil</strong> diethanolamine salt is more than 104 C., it was considered polymorph B. There is no need of recrystallization. If it is less than 104 C., it is recrystallized in EtOH-EtOAc to increase the melting point.Data on <strong>[81846-19-7]Treprostinil</strong> Diethanolamine Salt (1:1) Wt. of Wt. of <strong>[81846-19-7]Treprostinil</strong> Batch Benzindene Triol Diethanolamine Salt Yield Melting point No. (g) (1:1) (g) (%) ( C.) 1 1250 1640 88.00 104.3-106.3 2 1250 1528 82.00* 105.5-107.2 3 1250 1499 80.42** 104.7-106.6 4 1236 1572 85.34 105-108 Note: In this batch, approximately 1200 mL of ethyl acetate solution of <strong>[81846-19-7]treprostinil</strong> before carbon treatment was removed for R&D carbon treatment experiments. *Note: This batch was recrystallized, for this reason yield was lower.
7.552 g	In ethanol; ethyl acetate; for 0.25h;Reflux;	Example 29: 2-(((l/f,2/f,3a5,9a5)-2-hydroxy-l-((5)-3-hydroxyoctyl)-2,3,3a,4,9,9a- hexahydro-lH-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid diethanolamine salt (I, dieth Diethanolamine Salt [0436] A solution of <strong>[81846-19-7]treprostinil</strong> I (7.83 g, 20.1 mmol, 1.0 equiv) in ethyl acetate (250 mL) was treated with a solution of diethanolamine (2.1 1 g, 20.1 mmol, 1.0 equiv) in anhydrous ethanol (32 mL) and the resulting slurry heated to reflux for 15 minutes, at which point everything went into solution. This was allowed to slowly cool to room temperature over 18 hours resulting in formation of a white crystalline solid. The solid was filtered, rinsed with ethyl acetate (2 x 100 mL), and dried for 24 hours at 50 C under vacuum to give 7.552 g (76%) of the title compound as a white powder.

	In ethanol; water;Heating;	Synthesis of <strong>[81846-19-7]Treprostinil</strong> diethanolamine (UT-15C)<strong>[81846-19-7]Treprostinil</strong> acid is dissolved in a 1:1 molar ratio mixture of ethanol:water and diethanolamine is added and dissolved. The solution is heated and acetone is added as an antisolvent during cooling.
1.3 g		10080] A mixture of 1.1 g of compound 11 (<strong>[81846-19-7]treprostinil</strong>) and0.35 g of diethanolamine was dissolved in 4 mE of ethanol and 28 mE of ethyl acetate (EtOH/EA). The reaction solution was heated to 70 C. and stirred for 0.5 h. Afier the reaction solution was cooled to 55 C., 0.01 g of polymorph B of <strong>[81846-19-7]treprostinil</strong> diethanolamine as seed was added and the reaction solution was stirred for 1 h. The reaction solution was then cooled to room temperature and stirred for 16 h. Afier the reaction solution was filtered, the resulting solid was washed using 20 mE of ethyl acetate. The solid was then dried under high vacuum to yield 1.3 g of compound 12 (<strong>[81846-19-7]Treprostinil</strong> diethanolamine). ?H NMR (MeOD, 400 MHz) oe 7.01 (t, J=7.8 Hz, 1H), 6.74 (d, J=7.4 Hz, 1H), 6.70 (d, J=8.2 Hz, 1H), 4.34 (s, 2H), 3.78 (t, J=5.3 Hz, 4H), 3.66-3.58 (m, 1H),3.56-3.49 (m, 1H), 3.11 (t, J=5.2 Hz, 4H), 2.83 (dd, J=14.7,6.1 Hz, 1H), 2.73 (dd, J=14.2, 6.1 Hz, 1H), 2.62 (dd, J=14.7,6.1 Hz, 1H), 2.48 (dd, J=14.1, 6.1 Hz, 1H), 2.31-2.22 (m, 1H),2.14-2.05 (m, 1H), 1.94-1.84 (m, 1H), 1.77-1.67 (m, 1H),1.67-1.52 (m, 2H), 1.52-1.39 (m, 4H), 1.39-1.26 (m, 5H),1.26-1.18 (m, 1H), 1.18-1.07 (m, 1H), 0.92 (t, J=6.8 Hz, 3H); ?3C NMR (MeOD, 100 MHz) oe 177.2, 157.2, 141.9, 128.6, 127.0, 121.7, 111.1, 77.7, 72.9, 69.3, 57.9, 52.8, 50.4, 42.4, 42.1,38.3,36.1,34.8,34.2,33.1,29.7,26.8,26.4,23.7, 14.4.

Reference： [1]Patent: WO2019/171093,2019,A2 .Location in patent: Page/Page column 14; 15; 16; 17
[2]Patent: US2009/163738,2009,A1 .Location in patent: Page/Page column 6-7
[3]Patent: WO2014/89385,2014,A2 .Location in patent: Paragraph 0435-0436
[4]Patent: US2015/259274,2015,A1 .Location in patent: Paragraph 0098
[5]Patent: US2016/152548,2016,A1 .Location in patent: Paragraph 0059; 0079; 0080

6
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[ 81846-19-7 ]

Yield	Reaction Conditions	Operation in experiment
91.0 - 99.0%	With hydrogenchloride; In water; ethyl acetate; for 0.166667h;pH 1;Product distribution / selectivity;	A 250-mL, round-bottom flask equipped with magnetic stirrer was charged with treprostinil diethanolamine salt (4 g) and water (40 mL). The mixture was stirred to obtain a clear solution. To the clear solution, ethyl acetate (100 mL) was added. While stirring, 3M HCl (3.2 mL) was added slowly until pH 1 was attained. The mixture was stirred for 10 minutes and organic layer was separated. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers was washed with water (2×100 mL), brine (1×50 mL) and dried over anhydrous Na2SO4. The ethyl acetate solution of treprostinil was filtered and the filtrate was concentrated under vacuum at 50 C. to give off-white solid. The crude treprostinil was recrystallized from 50% ethanol in water (70 mL). The pure treprostinil was collected in a Buchner funnel by filtration and cake was washed with cold 20% ethanolic solution in water. The cake of treprostinil was air-dried overnight and further dried in a vacuum oven at 50 C. under high vacuum to afford 2.9 g of treprostinil (Yield 91.4%, purity (HPLC, AUC, 99.8%).Analytical Data on Treprostinil from Treprostinil Diethanolamine Salt (1:1) to Treprostinil Batch No. Yield Purity (HPLC) 1 91.0% 99.8% (AUC) 2 92.0% 99.9% (AUC) 3 93.1% 99.7% (AUC) 4 93.3% 99.7% (AUC) 5 99.0% 99.8% (AUC) 6 94.6% 99.8% (AUC)
76%	With hydrogenchloride; In ethanol; water; for 0.25h;Reflux;	Example 30: 2-(((l ,2R,3aS,9aS)-2-hydroxy-l-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a- hexahydro-lH-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid (I). [0438] A solution of the diethanolamine salt of Formula I (5.775 g, 11.65 mmol, 1.0 equiv) in water (60 mL) was treated with aqueous hydrochloric acid (2.11 g, 20.1 mmol, 1.0 equiv) in anhydrous ethanol (32 mL) and the resulting slurry heated to reflux for 15 minutes, at which point everything went into solution. This was allowed to slowly cool to room temperature over 18 hours resulting in formation of a white crystalline solid. The solid was filtered, rinsed with ethyl acetate (2 x 100 mL), and dried for 24 hours at 50 C under vacuum to give 7.552 g (76%) of the title compound as a white powder. Data for I: *H NMR (400 MHz, CHLOROFORM-d) d 7.07 (t, J=7.88 Hz, 1H), 6.82 (d, J=7.69 Hz, 1H), 6.68 (d, J=8.43 Hz, 1H), 4.58-4.72 (m, 2H), 4.40 (br. s., 3H), 3.73 (dt, J=6.23, 9.34 Hz, IH), 3.64 (d, J=3.66 Hz, IH), 2.76 (ddd, J=6.23, 14.20, 19.87 Hz, 2H), 2.61 (dd, J=6.04, 14.84 Hz, IH), 2.48 (dd, J=6.23, 14.29 Hz, IH), 2.20- 2.36 (m, IH), 2.10-2.20 (m, IH), 1.82-1.98 (m, IH), 1.52-1.76 (m, 4H), 1.40-1.52 (m, 3H), 1.21- 1.40 (m, 6H), 1.08-1.21 (m, IH), 0.92 (t, J=6.60 Hz, 3H); MS (ESI+) m/z 413.2 (M+Na+); HPLC, Synergi Hydro RP column (4.6 x 250 mm2), 5 mm; flow rate 2.0 mL/min; 277 nm; mobile phase water (60 ):acetonitrile (40%): trifluoroacetic acid (0.1 %); retention time, 39.12 min (98.0%, I), retention time, 41.05 min (1.2%, 2-(((lR,2R,3aS,9aS)-2-hydroxy-l-((R)-3- hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-lH-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid).
	With hydrogenchloride; water; In ethyl acetate;	The treprostinil monohydrate was prepared according to the following procedure.; A 3.4-kg sample of treprostinil diethanolamine salt was dissolved in 36 L of sterile water, 60 L of ethyl acetate and 3.6 L of 3 M HCl were added and the mixture stirred. The layers were separated and the aqueous layer was extracted thrice with 20-L portions of ethyl acetate. The four organic layers were combined, the organic solution washed twice with 20-L portions of sterile water, once with 20 L of brine and dried over 2.86 kg of anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to yield treprostinil as a gummy solid. This solid was transferred to glass drying trays and let air-dry for 66 hours. This solid was then dissolved in 23.8 kg of ethanol, warmed to 48 C. and treated with 23.8 kg of warm (40-50 C.) sterile water. The solution was stirred and then stirring was stopped to allow the treprostinil to slowly crystallize. The resulting white solid was collected by filtration in an Aurora filter, washed with 45 L of a cold (6 C.) 20% ethanol in sterile water solution, the filter moved to a Hepa-filtered Finishing Room and the solid dried under house vacuum for 23 hours. The solid was transferred to glass drying trays and further air-dried for 115 hours until the total weight of the material was constant (no further solvent loss). A sample of this treprostinil monohydrate was taken as Lot No.D-1007-089 for stability studies. The remaining material was further dried in a vacuum oven at 55 C. and 1.66 Torr for 10 hours to give 2.68 kg (96.4%) of anhydrous treprostinil (Lot No.01G07018).

Reference： [1]Patent: US2009/163738,2009,A1 .Location in patent: Page/Page column 7-8
[2]Patent: WO2014/89385,2014,A2 .Location in patent: Paragraph 0437-0438
[3]Patent: US2009/281189,2009,A1 .Location in patent: Page/Page column 4

7
[ 79950-42-8 ]
[ 81846-19-7 ]

Reference： [1]Patent: WO2011/153363,2011,A1
[2]Patent: WO2012/9816,2012,A1
[3]Patent: US2013/331593,2013,A1

8
[ 1351472-14-4 ]
[ 81846-19-7 ]

Yield	Reaction Conditions	Operation in experiment
		Step 6: Preparation of treprostinil (7); Table 6; HC1 NA (10%) 4-5 ml NAProcedure: A 200-mL round-bottom flask equipped with a magnetic stirrer and stir bar was charged with a solution of tricyclic ketone (6) (0.035 g) in methanol (5.0 mL). It was cooled to -5C and aqueous sodium hydroxide solution (0.030 g, 15 eq, dissolved in 1.0 mL water) was added while stirring. The reaction mixture was stirred for 30 minutes and then sodium borohydride ( 0.004g in 1.0 mL water) was added and stirring was continued at -5C for 2 h. This was slowly allowed to warm to room temperature and stirred overnight (-16 h). The reaction mixture was quenched carefully by dropwise addition of 10% hydrochloric acid (-4-5 mL) until pH 2-3. Then the mixture was concentrated in vacuo and to this water (10 mL) and ethyl acetate (10 mL) were added and stirred for 5-10 minutes. The organic layer was separated and washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo to obtain UT-15 (7) as an off-white solid (0.021 g). The compound was characterized by spectral data and HPLC. The .HNMR and HPLC of the samples were compared with reference UT-15 and were identical; 1H NMR (CDC13, 300 MHz) delta 0.90 (t, 3H, 6 Hz), 1.05 - 1.78 (m, 13 H), 2.85 - 2.85- 2.98 (m, 1H), 2.03 2.12 (m, 1H), 2.21 - 2.32 (m, 1H), 2.45 -2.53 (m, 1H), 2.61 - 2.81 (m, 3H), 3.52 (br s, 1H),3.58 -3.69 (m, 1H), 4.62 (s, 2H), 6.69 (d, 1H, J = 8 Hz), 6.78 (d, 1H, J = 8 Hz), 7.04 (dd, lH, J= 8 Hz).

Reference： [1]Patent: WO2011/153363,2011,A1 .Location in patent: Page/Page column 38-39

9
[ 40359-32-8 ]
[ 81846-19-7 ]

Reference： [1]Patent: WO2012/9816,2012,A1
[2]Patent: US2013/331593,2013,A1
[3]Organic and Biomolecular Chemistry,2019,vol. 17,p. 9489 - 9501

10
[ 81846-19-7 ]
TREPROSTINIL SODIUM [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium carbonate monohydrate; In ethanol; at 20℃;Inert atmosphere;	150 g (0.384 mol) of <strong>[81846-19-7]treprostinil</strong> is dissolved in 2 1 of ethanol. Sodium carbonate monohydrate 26.2 g (0.211 mol) is added to it and under an inert atmosphere the mixture is stirred at room temperature. When the pH of a filtered sample reaches the value of 7-9, the mixture is filtered through a 5 mupiiota pore size filter. The filtrate solution is concentrated on rotadest to approx. 225 g. The concentrate is dissolved in tert-butyl methyl ether which has been saturated with water and allowed to crystallize at room temperature. The crystals are filtered off, washed at room temperature and dried in vacuum at 20-50C. Yield: 158 g (100%) of <strong>[81846-19-7]treprostinil</strong> sodium salt monohydrate (form?A"), white crystals. Mp: 95- 99 C.
88%	With sodium hydroxide; In acetone; at 30℃;pH 8 - 9;	Example 2 : <strong>[81846-19-7]Treprostinil</strong> Sodium salt preparation[0036] A 100ml round bottom flask was charged with <strong>[81846-19-7]Treprostinil</strong> (1.021g, 2.61mmol) followed by 25 ml acetone. This solution was warmed up to 30C and added of 5M Sodium hydroxide (0.61ml, 3.05mmol) dropwise while maintaining an internal temperature below 30C. The pH of the solution was maintained at 8-9. After 15 minutes under agitation, a fiber like solid began to crystallize from the reaction mixture. The mixture was stirred for 1 hour at room temperature then cooled to 0-5C and stirred at this temperature for another hour. The solid was collected by vacuum filtration, rinsed with acetone and dried under vacuum overnight to yield 0.95 g of a white solid, (purity: 99.67% by HPLC; yield : 88%; Sodium content (ICP) : 6.05% w/w). Powder X-ray diffraction spectra of the <strong>[81846-19-7]treprostinil</strong> sodium is shown in Figure 1.
83.8%	With sodium hydroxide; In ethanol; water; at -5 - 5℃;	After cooling the compound of Formula 1 (350 g) dissolved in ethanol (1.6 kg) to -5 to + 5 C, sodium hydroxide (36.2 g) was dissolved in water (0.9 kg) and stirred for 1 to 2 hours .The reaction solvent was filtered and concentrated. Acetonitrile (1.8 kg) and water (800 g) were added to dissolve, cooled to -5 to + 5 C, and stirred for 4 to 6 hours.The resulting solid was filtered and dried for 20-24 hours to give the compound of formula 5 (310 g, 83.8%).

	With sodium hydroxide; In ethanol; at 20℃;	Example 15. Preparation of [(1 R,2R,3aS,9aS)-2-Hvdroxy-1 -((S)-3-hvdroxy-octyl)- 2,3,3a,4,9,9a-hexahydro-1 H-cyclopentafblnaphthalene-5-yloxyl-acetic acid, sodium salt; [0035] [(1 R,2R,3aS,9aS)-2-Hydroxy-1 -((S)-3-hydroxy-octyl)-2,3,3a,4,9,9a- hexahydro-1 H-cyclopenta[b]naphthalene-5-yloxy]-acetic acid, (513mg, 1 .3mmoL) was dissolved in anhydrous ethanol (3ml_). An ethanolic solution of sodium hydroxide (4.6ml_ of 0.28M; 1 .3mmol_) was added and the reaction stirred for 1 -2 hours at room temperature. Toluene (5m L) was added and the solution was concentrated under vacuo to give a solid residue. To this crude material was then added ethyl acetate (5ml_) and the suspension was stirred for 1 - 2 hours at room temperature. After filtration, the cake was washed with ethyl acetate and dried under vacuum.
	With sodium hydroxide; In ethanol; at 15 - 25℃;	Example 31a: 2-(((l/f,2/f,3a5,9a5)-2-hydroxy-l-((5)-3-hydroxyoctyl)-2,3,3a,4,9,9a- hexahydro- -cyclopenta[b]naphthalen-5-yl)oxy)acetic acid sodium salt (I, sodium salt). I I (Na Salt) [0440] A solution of the compound of Formula 1 (1 equiv) will be dissolved in distilled ethanol at 30-50 C and then cooled to 15-25 C. The solution will then be neutralized with a solution of sodium hydroxide (1 molar solution in ethanol) using a glass electrode to detect the point of equivalence (to pH value 9.8-10.2). The solution will be filtered, and the filtrate concentrated to give the crude sodium salt of the compound of Formula I. This may optionally be recrystallized from acetone/water or another appropriate solvent system to furnish a pure form of the title compound.

Reference： [1]Patent: WO2016/55819,2016,A1 .Location in patent: Page/Page column 57
[2]Patent: WO2012/88607,2012,A1 .Location in patent: Page/Page column 10-11
[3]Patent: KR2017/123132,2017,A .Location in patent: Paragraph 0027-0028; 0067-0068
[4]Patent: WO2012/9816,2012,A1 .Location in patent: Page/Page column 17-18
[5]Patent: WO2014/89385,2014,A2 .Location in patent: Paragraph 0439-0440

11
[ 1355990-07-6 ]
[ 81846-19-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium hydroxide; In tetrahydrofuran; water; at 20℃;Inert atmosphere;	180 g (0.43 mol) of TREP-16 (ethyl ester) is dissolved in 650 ml of tetrahydrofuran. Under nitrogen atmosphere, at room temperature 2.7 1 of 0.5 M sodium hydroxide solution is added and the reaction mixture is stirred at room temperature. At the end of the reaction the mixture is washed with distilled tert-butyl methyl ether. To the aqueous alkaline phase tert-butyl methyl ether is added and the pH of the mixture is set to pH <3 with 1M sodium hydrogen sulfate solution. The aqueous acidic phase is then extracted with tert-butyl methyl ether, the united organic phase is washed with water and evaporated. Yield: 165g (98%) of crystallizing oil. NMR data (d6-DMSO), 1H NMR (400 MHz): 12.915 (COOH-1, 1), broad; 7.03 ppm (H-22, 1), t, J=7.8 Hz; 6.76 ppm (H-23, 1), d, J=7.4 Hz; 6.68 ppm (H-21, 1), d, J=8.2 Hz; 4.62 ppm (H-2, 2), s; 4.47 ppm (OH-11, 1), broad; 4.21 ppm (OH-15, 1), broad; 3.47 ppm (H-11, 1), m (q), J-8.0 Hz; 3.35 ppm (H-15, 1), m, 2.80-2.60 ppm (H-4a and H-7a, 2), m (in: 2.725 ppm (H-4a, 1), dd, J=14.7 Hz and 6.2 Hz; 2.67 ppm (H-7a, 1), dd, J=14.2 Hz and 6.2 Hz); 2.48-2.34 ppm (H-4b and H-7b, 2), m (in: 2.49 ppm (H-4b, 1), dd, J=14.6 Hz and 6.6 Hz; 2.39 ppm (H-7b, 1), dd, J=14.2 Hz and 6.5 Hz); 2.11 ppm (H-9, 1), m (tq), J-10.1 Hz and -6.7 Hz; 1.955 ppm (H-10a, 1), m (ddd/dt), J=12.1 Hz and 6.7 Hz; 1.76 ppm (H-8, 1), m (tt), J=10.0 Hz and 6.2 Hz; 1.61 ppm (H- 13a, 1) m; 1.53-1.33 ppm (H-14, H-16a and H-17a, 4), m (in:1.46 ppm (H-14a, 1), m; 1.43 ppm (H-14b, 1), m; 1.38 ppm (H- 17a, 1), m; 1.35 ppm (H- 16a, l), m); 1.33-1.15 ppm (H-13b, H-16b, H-17b, H-18 and H-19, 7), m (in: 1.32 ppm (H-13b, 1), m; 1.30 ppm (H-16b, 1), m; 1.275 ppm (H-19, 2), m; 1.26 ppm (H-17b, 1), m; 1.25 ppm (H-18, 2), m); 1.15-0.93 ppm (H-lOb and H-13, 2), m (in: H-1.09 ppm (H-12, 1), m (tt), J=9.0 Hz and 6.1 Hz; 1.00 ppm (H-lOb, 1), m (ddd/dt), J=11.7 Hz and 10.2 Hz); 0.87 ppm (H-20, 3), m (t), J=6.9 Hz; 13C NMR (100 MHz): 170.36 ppm (C-l), 154.63 ppm (C-3), 140.56 ppm (C-6), 126.75 ppm (C- 5), 125.85 (C-22), 120.65 ppm (C-23), 109.37 ppm (C-21), 75.44 ppm (C-11), 70.13 ppm (C-15), 64,96 ppm (C-2), 51.49 ppm (C-12), 41.15 ppm (C-10), 40.48 ppm (C-8), 37.06 ppm (C-16), 35.03 ppm (C-14), 33.37 ppm (C-7), 32.42 ppm (C-9), 31.53 ppm (C-l 8), 28.36 ppm (C-l 3), 25.62 ppm (C-4), 24.96 ppm (C-17), 22.18 ppm (C-19), 13.96 ppm (C-20).
		Example 14. Preparation of [(1 R,2R,3aS.9aS)-2-Hvdroxy-1 -((S)-3-hvdroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1 H-cyclopenta[b1naphthalene-5-yloxy1-acetic acid; [0034] [(1 R,2R,3aS,9aS)-2-Hydroxy-1 -((S)-3-hydroxy-octyl)-2,3,3a,4,9,9a- hexahydro-1 H-cyclopenta[b]naphthalene-5-yloxy]-acetic acid, ethyl ester (142mg; 0.34mmol_) was dissolved in anhydrous ethanol (1 ml_). Aqueous 20% sodium hydroxide (0.1 mL; ~20mg; ~0.5mmol_) was added and mixture stirred for 1 -2 hours. 1 M aqueous hydrochloric acid (1 ml_) was added followed by water and methyl t-butylether. The layers were separated and the aqueous layer further extracted with methyl t-butylether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum, to give treprostinil as a solid.
	With water; potassium hydroxide; In ethanol; at 20℃; for 1.5h;Inert atmosphere;	Example 28: 2-(((l/f,2/f,3a5,9a5)-2-hydroxy-l-((5)-3-hydroxyoctyl)-2,3,3a,4,9,9a- hexahydro-lH-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid (I). [0434] Potassium hydroxide (5.623 g in 19 mL water, 30% solution in water, 100.2 mmol, 5.0 equiv) was added to a solution of ethyl ester 25a (8.390g, 20.04 mmol, 1.0 equiv) in ethanol (100 mL) and stirred at room temperature, under nitrogen for 90 minutes. The reaction was then concentrated under reduced pressure to remove the ethanol, diluted with water (50 mL) and extracted with ethyl acetate (50 mL) to remove organic impurities. The aqueous layer was acidified to pH 2-3 by addition of 3 N aqueous hydrochloric acid and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were treated with activated charcoal (800 mg) and heated to reflux for 1 hour, cooled to room temperature, filtered through celite and concentrated to give 8.2 g of the title compound as an off-white solid. This material was moved forward to the next step crude and was not characterized further. Data for I: Rf = 0.27 (90: 10: 1 methylene chloride / methanol / acetic acid).

With potassium hydroxide; In ethanol; water; at 20℃; for 1.5h;Inert atmosphere;

[0413] Potassium hydroxide (5.623 g in 19 mL water, 30% solution in water, 100.2 mmol, 5.0 equiv) was added to a solution of ethyl ester 25a (8.390g, 20.04 mmol, 1.0 equiv) in ethanol (100 mL) and stirred at room temperature, under nitrogen for 90 minutes. The reaction was then concentrated under reduced pressure to remove the ethanol, diluted with water (50 mL) and extracted with ethyl acetate (50 mL) to remove organic impurities. The aqueous layer was acidified to pH 2-3 by addition of 3 N aqueous hydrochloric acid and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were treated with activated charcoal (800 mg) and heated to reflux for 1 hour, cooled to room temperature, filtered through celite and concentrated to give 8.2 g of the title compound as an off-white solid. This material was moved forward to the next step crude and was not characterized further. Data for I: Rf = 0.27 (90: 10: 1 methylene chloride / methanol / acetic acid).

Reference： [1]Patent: WO2016/55819,2016,A1 .Location in patent: Page/Page column 55; 56
[2]Patent: WO2012/9816,2012,A1 .Location in patent: Page/Page column 17
[3]Patent: WO2014/89385,2014,A2 .Location in patent: Paragraph 0433-0434
[4]Patent: WO2015/73314,2015,A1 .Location in patent: Paragraph 0412; 0413

12
[ 81845-98-9 ]
[ 81846-19-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; In ethanol; water;	Compound (4) (380 g) dissolved in ethanol (2.0 kg)Was added sodium hydroxide (75 g) dissolved in water (2.0 kg)And the mixture was stirred for 3-5 hours. The reaction was terminated by HPLC.After the reaction solvent was concentrated, water (2.0 kg) was added and stirred, and hydrochloric acid (210 g) dissolved in water (1820 g) was added and acidified to pH 3-4.Ethyl acetate (4.5 kg) was added and stirred for 20-30 minutes, then the organic layer was separated.Water (5.0 kg) was added to the separated organic layer, stirred for 20-30 minutes, and the organic layer was separated.Brine (5.0 kg) was added to the separated organic layer, stirred for 20-30 minutes, and the organic layer was separated.Sodium sulfate was added, followed by drying, filtration and concentration to obtain the compound of Formula 1 (367 g, 100%).
100%		To the compound of formula 11a (0.38 g) dissolved in ethanol (2.0 mL) was added water (2.0 mL) Dissolve the dissolved sodium hydroxide (75 mg)The mixture was stirred for 3-5 hours, and the reaction was terminated by HPLC. The reaction solvent was concentrated, and then water (2.0 mL) was added to the reaction mixture, which was stirred and acidified to pH 3-4 by adding hydrochloric acid (0.21 g) dissolved in water (1.82 mL). Ethyl acetate (4.5 mL) was added, stirred for 20-30 minutes, and the organic layer was separated.Water (5.0 mL) was added to the separated organic layer, stirred for 20-30 minutes, and the organic layer was separated.Brine (5.0 mL) was added to the separated organic layer, stirred for 20-30 minutes, and the organic layer was separated. Sodium sulfate was added thereto, followed by drying,Filtered and concentrated to give the compound of formula (Ia) (367 mg, 100%).
		Example 1 : Treprostinil preparation[0034] A mixture of Intermediate 1 (3.8g; 11.3mmol_), methyl bromoacetate (2.2g; 14.1mmol_) and potassium carbonate (3.1g; 22.4mmol_) in acetone (30ml_) was refluxed for 6.5 hours and then cooled to room temperature. The reaction mixture was filtered and the cake was washed forward with acetone. The filtrate was concentrated and dried under high vacuum to give 4.5 g of intermediate 2 (having a methyl ester acetate) that was carried forward without purification.Methanol/water mixture (16mLyi6mL) was added to intermediate 2 and potassium hydroxide (0.63g; 15.8mmol_). The reaction mixture was refluxed for 2 hours then cooled to room temperature. Aqueous 2M hydrochloric acid (lOmL) was added to adjust the pH to 1-2. The slurry was stirred overnight, filtered and washed with a mixture of methanol/water (40ml_, 1 : 1) and 2xl0ml_ water. The solid was dried under vacuum to give Treprostinil as a white solid (4.0g; 90%).

With water; sodium hydroxide; In ethanol;

[(1R,2R,3aS,9aS)-2-Hydroxy-1-((S)-3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-5-yloxy]-acetic acid, ethyl ester (142 mg; 0.34 mmoL) was dissolved in anhydrous ethanol (1 mL). Aqueous 20% sodium hydroxide (0.1 mL; 20 mg; 0.5 mmoL) was added and mixture stirred for 1-2 hours. 1M aqueous hydrochloric acid (1 mL) was added followed by water and methyl t-butylether. The layers were separated and the aqueous layer further extracted with methyl t-butylether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum, to give treprostinil as a solid.

Reference： [1]Patent: KR2017/123132,2017,A .Location in patent: Paragraph 0027-0028; 0063-0064
[2]Patent: KR2017/123126,2017,A .Location in patent: Paragraph 0197-0199
[3]Patent: WO2012/88607,2012,A1 .Location in patent: Page/Page column 10
[4]Patent: US2013/331593,2013,A1 .Location in patent: Paragraph 0058; 0059

13
[ 81845-88-7 ]
[ 81846-19-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With 5%-palladium/activated carbon; hydrogen; potassium hydroxide; In methanol; at 20℃;	Example 37Preparation of Treprostinil from the Product of Examples 34 & 35[0188]2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-((S,E)-3-hydroxyoct-1-enyl)-1H-cyclopenta[b]naphthalen-5-yloxy)acetic acid (2.5 g, 0.008 mol) in dry methanol (25 ml) was treated with potassium hydroxide (0.5 g, 0.008 mol), then with 5% Pd/C (0.5 g, 20% wt) under hydrogen overnight at room temperature. Then, the reaction mixture was filtered with celite pad. The solvent was evaporated off under vacuum. The residues was diluted with 50 m ethyl acetate and 50 ml saturated sodium bicarbonate aqueous. The mixture was phase separated and the organic layers was extracted with 50 ml saturated sodium bicarbonate aqueous. The aqueous layers were combined and then 3N HCl was added slowly until pH=?2. The aqueous layer was extracted with 100 ml ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by crystallization. The titled compound was obtained in a crystalline form. Yield: 88%[0189]1H-NMR (CDCl3): 7.08 (t, 1H), 6.83 (d, 1H), 6.69 (d, 1H), 4.65 (s, 2H), 3.75 (q, 1H), 3.67?3.58 (m, 1H), 2.82?2.73 (m, 2H), 2.62?2.58 (m, 1H), 2.51?2.47 (m, 1H), 2.29?2.27 (m, 1H), 2.20?2.15 (m, 1H), 1.91?1.84 (m, 1H), 1.66?1.65 (m, 1H), 1.49?1.33 (m, 4H), 1.32?1.21 (m, 8H), 1.17 (q, 1H), 0.91 (t, 3H)[0190]13C-NMR (CDCl3): delta 170.86, 154.80, 141.12, 127.92, 126.32, 122.18, 110.25, 76.75, 72.75, 65.96, 52.28, 41.51, 41.39, 37.47, 35.02, 33.60, 32.98, 31.94, 28.69, 26.06, 25.35, 22.61, 13.94
88%	With 5%-palladium/activated carbon; hydrogen; potassium hydroxide; In methanol; at 20℃;	2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-((S,E)-3-hydroxyoct-1-enyl)-1H-cy clopenta[b]naphthalen-5-yloxy)acetic acid (2.5 g, 0.008 mol) in dry methanol (25 ml) was treated with potassium hydroxide (0.5 g, 0.008 mol), then with 5% Pd/C (0.5 g, 20%wt) under hydrogen overnight at room temperature. Then, the reaction mixture was filtered with celite pad. The solvent was evaporated off under vacuum. The residues was diluted with 50ml ethyl acetate and 50ml saturated sodium bicarbonate aqueous. The mixture was phase separated and the organic layers was extracted with 50 ml saturated sodium bicarbonate aqueous. The aqueous layers were combined and then 3N HCl was added slowly until pH=2. The aqueous layer was extracted with 100 ml ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by crystallization. The titled compound was obtained in a crystalline form. Yield: 88% 1H-NMR (CDCl3): delta 7.08 (t, 1H), 6.83 (d, 1H), 6.69 (d, 1H), 4.65 (s, 2H), 3.75 (q, 1H), 3.67?3.58 (m, 1H),2.82?2.73 (m, 2H), 2.62?2.58 (m, 1H), 2.51?2.47 (m, 1H), 2.29?2.27 (m, 1H), 2.20?2.15 (m, 1H), 1.91?1.84 (m, 1H),1.66?1.65 (m,1H), 1.49?1.33 (m, 4H), 1.32?1.21 (m, 8H), 1.17 (q, 1H), 0.91 (t, 3H)13C-NMR (CDCl3): delta 170.86, 154.80, 141.12, 127.92, 126.32, 122.18, 110.25, 76.75, 72.75, 65.96, 52.28,41.51, 41.39, 37.47, 35.02, 33.60, 32.98, 31.94, 28.69, 26.06, 25.35, 22.61, 13.94

Reference： [1]Patent: US2013/53581,2013,A1 .Location in patent: Paragraph 0188; 0189; 0190
[2]Patent: EP2581361,2013,A1 .Location in patent: Paragraph 0183; 0185; 0186; 0187

14
[ 10416-59-8 ]
[ 81846-19-7 ]
[ 84414-22-2 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 20℃; for 12h;	<strong>[81846-19-7]Treprostinil</strong> (61 mg, 0.156 mmol) was dissolved in toluene (dry, molecular sieve, 2.5 ml) and silylation reagent BSA (0.6 mL, 0.245 mmol) was added. The reaction mixture was stirred for 12 h at RT. Volatile solvents were removed in vacuo and the TMS protected <strong>[81846-19-7]treprostinil</strong> was used without further purification
	In toluene; at 20℃; for 12h;Molecular sieve;	<strong>[81846-19-7]Treprostinil</strong> (61 mg, 0.156 mmol) was dissolved in toluene (dry, molecular sieve, 2.5 ml) and silylation reagentBSA (0.6 mE, 0.245 mmol) was added. The reaction mixture was stirred for 12 h at RT. Volatile solvents were removed in vacuo and the TMS protected <strong>[81846-19-7]treprostinil</strong> was usedwithout thrther purification.

Reference： [1]Patent: WO2013/24051,2013,A1 .Location in patent: Page/Page column 94
[2]Patent: US9561287,2017,B2 .Location in patent: Page/Page column 105; 106

15
[ 1135-39-3 ]
[ 81846-19-7 ]
[ 1422974-92-2 ]

Yield	Reaction Conditions	Operation in experiment
50%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 12h;	Example 2: Coupling reaction of benzylated 3-hydroxybutanoic acid 2 with <strong>[81846-19-7]treprostinil</strong>: <strong>[81846-19-7]Treprostinil</strong> acid (10.5 mg, 0.0268 mmol) was dissolved in DCM (4.5 mL) and DCC (9.4 mg, 0.0455 mmol), HOBT (7.5 mg, 0.0489 mmol) and DMAP (7.5 mg, 0.0613 mmol) were added to the solution. Then benzylated 3-hydroxybutanoic acid 2 (15 mg, 0.0772 mmol) was dissolved in DCM (0.5 mL) and added to the reaction mixture. The mixture was stirred at RT until the consumption was complete (analytical RP-HPLC). Volatile solvents were removed in vacuo and the residue was purified over a small silica column (3 ml silica, DCM / MeOH (100 : 0) - DCM / MeOH (95 : 5) to obtain the desired linker <strong>[81846-19-7]treprostinil</strong> 3 as yellow oil. Yield: 8 mg (50 %) MS: m/z 589.3 = [M+Na]+ (MW+Na calculated = 589.7)
50%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;	Example 2: Coupling reaction of benzylated 3-hydroxybutanoic acid 2 with <strong>[81846-19-7]treprostinil</strong>: <strong>[81846-19-7]Treprostinil</strong> acid (10.5 mg, 0.0268 mmol) was dissolved in DCM (4.5 mL) and DCC (9.4 mg, 0.0455 mmol), HOBT (7.5 mg, 0.0489 mmol) and DMAP (7.5 mg, 0.0613 mmol) were added to the solution. Then benzylated 3-hydroxybutanoic acid 2 (15 mg, 0.0772 mmol) was dissolved in DCM (0.5 mL) and added to the reaction mixture. The mixture was stirred at RT until the consumption was complete (analytical RP-HPLC). Volatile solvents were removed in vacuo and the residue was purified over a small silica column (3 ml silica, DCM / MeOH (100 : 0) - DCM / MeOH (95 : 5) to obtain the desired linker <strong>[81846-19-7]treprostinil</strong> 3 as yellow oil. Yield: 8 mg (50 %) MS: m/z 589.3 = [M+Na]+ (MW+Na calculated = 589.7)
50%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;	Example 2:Coupling reaction of benzylated 3-hydroxybutanoic acid 2 with <strong>[81846-19-7]treprostinil</strong>: <strong>[81846-19-7]Treprostinil</strong> acid (10.5 mg, 0.0268 mmol) was dissolved in CH2C12 (4.5 mL) and DCC (9.4 mg, 0.0455 mmol), HOBT (7.5 mg, 0.0489 mmol) and DMAP (7.5 mg, 0.0613 mmol) wereadded to the solution. Then benzylated 3-hydroxybutanoic acid 2 (15 mg, 0.0772 mmol) was dissolved in CH2C12 (0.5 mL) and added to the reaction mixture. The mixture was stirred at RT until the consumption was complete (analytical RP-HPLC). Volatile solvents were removed in vacuo and the residue was purified over a small silica column (3 ml silica, DCM / MeOH (100 : 0) - DCM / MeOH (95 : 5) to obtain the desired linker <strong>[81846-19-7]treprostinil</strong> 3 as yellowoil.Yield: 8 mg (50 %)MS: m/z 589.3 = [M+Na] (MW+Na calculated = 589.7)

50%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;	<strong>[81846-19-7]Treprostinil</strong> acid (10.5 mg, 0.0268 mmol) was dissolved in DCM (4.5 mE) and DCC (9.4 mg, 0.0455 mmol), HOST (7.5 mg, 0.0489 mmol) and DMAP (7.5 mg, 0.06 13 mmol) were added to the solution. Then benzylated 3-hydroxybu- tanoic acid 2 (15 mg, 0.0772 mmol) was dissolved in DCM (0.5 mE) and added to the reaction mixture. The mixture wasstirred at RT until the consumption was complete (analytical RP-HPEC). Volatile solvents were removed in vacuo and the residue was purified over a small silica colunm (3 ml silica, DCMJMeOH (100:0)-DCM/MeOH (95:5) to obtain the desired linker <strong>[81846-19-7]treprostinil</strong> 3 as yellow oil.Yield: 8 mg (50%)MS: mlz 589.3=[M+Na] (MW+Na calculated=589.7)
50%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 12h;	<strong>[81846-19-7]Treprostinil</strong> acid (10.5 mg, 0.0268 mmol) was dissolved in DCM (4.5 mL) and DCC (9.4 mg, 0.0455 mmol), HOBT (7.5 mg, 0.0489 mmol) and DMAP (7.5 mg, 0.0613 mmol) were added to the solution. Then benzylated 3-hydroxybutanoic acid 2 (15 mg, 0.0772 mmol) was dissolved in DCM (0.5 mL) and added to the reaction mixture. The mixture was stirred at RT until the consumption was complete (analytical RP-HPLC). Volatile solvents were removed in vacuo and the residue was purified over a small silica column (3 ml silica, DCM/MeOH (100:0)-DCM/MeOH (95:5) to obtain the desired linker <strong>[81846-19-7]treprostinil</strong> 3 as yellow oil. Yield: 8 mg (50%) MS: m/z 589.3=[M+Na]+ (MW+Na calculated=589.7)
50%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 12h;	<strong>[81846-19-7]Treprostinil</strong> acid (10.5 mg, 0.0268 mmol) was dissolved in CH2Cl2 (4.5 mL) and DCC (9.4 mg, 0.0455 mmol), HOBT (7.5 mg, 0.0489 mmol) and DMAP (7.5 mg, 0.0613 mmol) were added to the solution. Then benzylated 3-hydroxybutanoic acid 2 (15 mg, 0.0772 mmol) was dissolved in CH2Cl2 (0.5 mL) and added to the reaction mixture. The mixture was stirred at RT until the consumption was complete (analytical RP-HPLC). Volatile solvents were removed in vacuo and the residue was purified over a small silica column (3 ml silica, DCM / MeOH (100 : 0) - DCM / MeOH (95 : 5) to obtain the desired linker <strong>[81846-19-7]treprostinil</strong> 3 as yellow oil. Yield: 8 mg (50 %) MS: m/z 589.3 = [M+Na]+ (MW+Na calculated = 589.7)

Reference： [1]Patent: WO2013/24051,2013,A1 .Location in patent: Page/Page column 87; 88
[2]Patent: WO2013/24052,2013,A1 .Location in patent: Page/Page column 120; 121
[3]Patent: WO2013/24053,2013,A1 .Location in patent: Page/Page column 84; 85
[4]Patent: US9561287,2017,B2 .Location in patent: Page/Page column 96; 97; 98
[5]Patent: US9872864,2018,B2 .Location in patent: Page/Page column 64
[6]Patent: EP3643306,2020,A2 .Location in patent: Paragraph 0269-0270

16
2-chlorotrityl chloride polystyrene resin [ No CAS ]
[ 81846-19-7 ]
C₄₂H₄₆ClO₅Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;	A 10 mL single use syringe reactor equipped with a PE frit was loaded with 2-chlorotrityl chloride (TCP) resin (153 mg, loading 1.22 mmol/g, 0.186 mmol). A solution of <strong>[81846-19-7]treprostinil</strong> (54 mg, 0.138 mmol) and DIPEA (60 mu, 0.346 mmol) in DCM (anhydrous, mol. sieve) was drawn into the reactor. Reactor was agitated for 2 h at RT. 200 mu methanol were added and reactor was agitated for further 10 min. Solution was dispelled and resin was washed with DCM (5x), DMF (5x) and DCM (lOx). Resin was dried under vacuum (1 mbar). Based on weight, a <strong>[81846-19-7]treprostinil</strong> loading of 0.72 mmol/g TCP resin was obtained

Reference： [1]Patent: WO2013/24051,2013,A1 .Location in patent: Page/Page column 108; 109

17
[ 10416-59-8 ]
[ 81846-19-7 ]
C₂₆H₄₂O₅Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 20℃; for 12h;Molecular sieve;	Example 8: Synthesis of Dmob protected <strong>[81846-19-7]treprostinil</strong> 8: , RT , EDC-HC1, DMAP, - alcohol, RT 5h ater O H <strong>[81846-19-7]Treprostinil</strong> (61 mg, 0.156 mmol) was dissolved in toluene (dry, molecular sieve, 2.5 ml) and silylation reagent BSA (0.6 mL, 0.245 mmol) was added. The reaction mixture was stirred for 12 h at RT. Volatile solvents were removed in vacuo and the TMS protected <strong>[81846-19-7]treprostinil</strong> was used without further purification.
	In toluene; at 20℃; for 12h;Molecular sieve;	<strong>[81846-19-7]Treprostinil</strong> (61 mg, 0.156 mmol) was dissolved in toluene (dry, molecular sieve, 2.5 ml) and silylation reagent BSA (0.6 mE, 0.245 mmol) was added. The reaction mixture was stirred for 12 h at RT. Volatile solvents were removed in vacuo and the TMS protected <strong>[81846-19-7]treprostinil</strong> was used without thrther purification.

Reference： [1]Patent: WO2013/24052,2013,A1 .Location in patent: Page/Page column 126
[2]Patent: US9872864,2018,B2 .Location in patent: Page/Page column 70

18
C₂₉H₄₈O₅Si [ No CAS ]
[ 81846-19-7 ]

Yield	Reaction Conditions	Operation in experiment
91%	With hydrogen fluoride; In water; acetonitrile; at -20 - 0℃;	EXAMPLE 16: Preparation of Treprostinil (18) Treprostinil A portion of 17 (15.1 g; 29.9 mmol) was dissolved in 300 mL of acetonitrile. The solution was cooled to 0C. 73 mL of 48% HF was carefully added in portions. After 5 min, TLC (100% ethyl acetate) indicated no starting material remained. The reaction was stored at -20C overnight. The reaction was warmed to RT and with vigorous stirring was diluted with 1 .5 L of distilled water. A precipitate was formed and stirring was continued for 5 min. The solid was allowed to settle and filtered through a Buchner funnel. The solid was rinsed with 250 mL of distilled water. The solid was dried under vacuum for 30 min. The solid was placed under high vacuum for 5 h at RT. 17.6 g of solid was recovered. The material was stirred in 300 mL of hexane for 5 h. The solid was filtered through a Buchner funnel and dried under vacuum for 15 min. Finally the material was placed on the lyophilizer for 48 h to remove any trace solvents. 10.5 g (91 %) of treprostinil (18) were recovered as desired product.
91%	With hydrogen fluoride; In water; acetonitrile; at -20 - 20℃;	A portion of 17 (15.1 g; 29.9 mmol) was dissolved in 300 mL of acetonitrile. The solution was cooled to 0C. 73 mL of 48% HF was carefully added in portions. After 5 min, TLC (100% ethyl acetate) indicated no starting material remained. The reaction was stored at -20C overnight. The reaction was warmed to RT and with vigorous stirring was diluted with 1.5 L of distilled water. A precipitate was formed and stirring was continued for 5 min. The solid was allowed to settle and filtered through a Buchner funnel. The solid was rinsed with 250 mL of distilled water. The solid was dried under vacuum for 30 min. The solid was placed under high vacuum for 5 h at RT. 17.6 g of solid was recovered. The material was stirred in 300 mL of hexane for 5 h. The solid was filtered through a Buchner funnel and dried under vacuum for 15 min. Finally the material was placed on the lyophilizer for 48 h to remove any trace solvents. 10.5 g (91 %) of treprostinil (18) were recovered as desired product.

Reference： [1]Patent: WO2013/174848,2013,A2 .Location in patent: Page/Page column 27-28
[2]Patent: EP2674413,2013,A1 .Location in patent: Paragraph 0050; 0051

19
[ 77-86-1 ]
[ 81846-19-7 ]
treprostinil tromethamine salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.4 g	In tert-butyl methyl ether; water; isopropyl alcohol; at 50 - 60℃;	A 3000-mL, three-necked, round-bottom flask equipped with a mechanical stirrer, thermometer and condenser was charged with UT-iS (54.55 g), isopropanol (330 mL), and water (15 mL) and was heated at 50-55 C. until clear solution was obtained, then tromethamine (17.06 g) was added. The reaction mixture was heated to 60 C. while stirring to obtain a clear solution. To his clear solution methyl t-butyl ether (MTBE) was added slowly keeping the temperature between 50-55C. Afier complete addition of MTBE, the solution was allowed to cool to ambient temperature overnight while stirring. The product was filtered, washed with water and dried under vacuo for 1 h. The product was transferred from the Buchner funnel to a glass tray and dried over night in a thme hood. Finally the product was dried under high vacuum at 45-48C. for4 hours (55.4 g, mp. 68-71 C.). Table 8 provides data for tromethamine salt.

Reference： [1]Patent: US2014/275616,2014,A1 .Location in patent: Paragraph 0079

20
[ 81846-19-7 ]
treprostinil potassium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83.6%	With potassium hydroxide; In ethanol; acetone; at 20℃; for 0.166667h;	To a clear solution of potassium hydroxide (1 eq.) in ethanol (5 mE) in a round bottom flask, was added UT-iS (1 eq.). The mixture was stirred at room temperature for about 10 minutes until a clear solution was obtained. Then acetone was added to the ethanol solution while stirring. The stirring was stopped when white solid started coming out from the solution. The mixture was lefi at room temperature overnight. The solid was collected by filtration. It was washed with acetone and then dried at 70 C. under vacuum for 4 hours. See the detail results in Table 1 and in FIG. 2.

Reference： [1]Patent: US2014/275616,2014,A1 .Location in patent: Paragraph 0061; 0062; 0065; 0066

21
[ 81846-19-7 ]
treprostinil magnesium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With magnesium hydroxide; In ethanol; hexane; tert-butyl methyl ether; water; at 55 - 80℃;	A 500-mL, two-necked, round-bottom flask equipped with a magnetic stirrer, and a thermometer was charged withUT-1 5 (5.75 g), ethanol (86 mE), water (55 mE), and magnesium hydroxide (439 mg). The reaction mixture was stirred and heated to 70-80 C. to obtain a clear solution. The solution was filtered to remove any insoluble foreign particles. The filtrate was evaporated under vacuum to give a gummy material. The gummy material was dissolved in ethanol (86 mE) by heating to 70-80 C. At this temperature, MTBE (86 mE) was added slowly keeping the temperature of solution higher than 55 C., followed by hexanes (30 mE). After complete addition of MTBE and hexanes, the solution was allowed to cool to 45 C. during 1-2 hours, then to ambient temperature overnight. At ambient temperature, the product was isolated by filtration and washed with MTBE. The product was transferred from Buchner funnel to a glass container for air-drying over night in thme hood. The product was dried thrther under vacuum at 50-55 C. for 4 hours. Table 16 provides data for the magnesium salt.

Reference： [1]Patent: US2014/275616,2014,A1 .Location in patent: Paragraph 0090

22
[ 81846-19-7 ]
treprostinil ammonium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; In hexane; tert-butyl methyl ether; isopropyl alcohol; at 30 - 45℃; for 0.75h;	A 500-mE, two-necked, round-bottom flask equipped with a magnetic stirrer, and a thermometer was charged with UT-iS (4.00 g), 2-propanol (40 mE). The mix- tare was stirred and heated to 40-45 C. to obtain a clear solution. Allow the temperature of the solution to cool to 30-35 C., and then bubble the ammonia gas through the solution for 45 minutes. Ammonia gas inlet was removed, and hexane (75 mE) was added and allowed the mixture to stir overnight at ambient temperature. At ambient temperature, the product was isolated by filtration; product was washed with MTI3E/hexanes (1:1). The product was transferred from l3uchner thnnel to a glass dish for air-drying over night in fume hood. The product (lot D-1029-043) was dried further under vacuum at 50-55C. for 4 hours. Table 20 provides data for the ammonium salt.

Reference： [1]Patent: US2014/275616,2014,A1 .Location in patent: Paragraph 0094

23
[ 81846-19-7 ]
treprostinil calcium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50.2 g	With calcium hydroxide; In ethanol; at 70 - 80℃; for 1h;	A 3000-mE, three-necked, round-bottom flask equipped with a mechanical stirrer, thermometer and condenser was charged with UT-iS (60 g), and ethanol (600 mE). Mixture was heated at 75-80 C. until cleat To the clear solution calcium hydroxide (5.40 g) was added in two portions. The reaction mixture was stirred and heated to 70-80 C. to obtain a clear solution (.-i h). Water (1800 mE) was added slowly keeping the temperature of solution at 75-80 C. Afier complete addition of water, the solution was allowed to cool to ambient temperature overnight while stirring. The product was filtered, washed with water and dried under vacuo for 1 h. The product was transferred from the Buchner fimnel to a glass and dried over night in a thme hood. Finally

Reference： [1]Patent: US2014/275616,2014,A1 .Location in patent: Paragraph 0077

24
[ 74-79-3 ]
[ 81846-19-7 ]
treprostinil-L-arginine salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water; ethyl acetate; isopropyl alcohol; at 70 - 80℃;	A 500-mE, two-necked, round-bottom flask equipped with a magnetic stirrer, and a thermometer was charged with UT-i5-L-Arginine salt (i7.Oi g), ethanol (200 mE). The mixture was heated to 70-80 C. while stirring. At this temperature, water (3 mE) was added slowly to obtain a clear solution. After complete addition of water, the solution was allowed to cool slowly to ambient temperature. The product was isolated by filtration and washed with ethanol. The product was transferred from the Buchner flannel to a glass container for air-drying over night in a thme hood. The product (lot D-i 04i -Oi i) was dried under high vacuum at 70-75 C. for i6 hours. Table iO provides data for the arginine salt.

Reference： [1]Patent: US2014/275616,2014,A1 .Location in patent: Paragraph 0084

25
[ 56-87-1 ]
[ 81846-19-7 ]
treprostinil-L-lysine salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water; ethyl acetate; isopropyl alcohol; at 55 - 80℃;	A 500-mE, two-necked, round-bottom flask equipped with a magnetic stirrer, and a thermometer was charged with UT- 15 (4.5 g), 2-propanol (108 mE), water (9 mE), and E-lysine (1.685 g). The reaction mixture was stirred and heated to 70-80 C. to obtain a clear solution. At this temperature, ethyl acetate was added slowly keeping the temperature of solution higher than 55 C. After complete addition of ethyl acetate, the solution was allowed to cool to 45 C. during 1-2 hours, then to 35 C. for one hour, and then to 25 C. for an addition one hour. At ambient temperature, the product was isolated by filtration; product was washed with ethyl acetate. The product was transferred from l3uchner thnnd to a glass container for air-drying over night in a fume hood. The product was dried further under high vacuum at 50-55 C. for 4-5 hours. Table 12 provides data for L-lysine salt.

Reference： [1]Patent: US2014/275616,2014,A1 .Location in patent: Paragraph 0086

26
[ 6284-40-8 ]
[ 81846-19-7 ]
treprostinil-N-methylglucamine salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In hexane; tert-butyl methyl ether; water; isopropyl alcohol; at 55 - 80℃;	A 500-mL, two-necked, round-bottom flask equipped with a magnetic stirrer, and a thermometer was charged with UT-iS (4.0 g), 2-propanol (108 mE), water (0.8 mE), and N-methylglucamine (2.00 g). The reaction mixture was stirred and heated to 70-80 C. to obtain a clear solution. At this temperature, MTI3E (120 mE) was added slowly keeping the temperature of solution higher than 55 C., followed by hexanes (40 mE). Afier complete addition of MTI3E and hexanes, the solution was allowed to cool to 45C. during 1-2 hours, then to 35 C. for one hour, and then to 25 C. for an additional 30 minutes. At ambient temperature, the product was isolated by filtration and washed with MTI3E/hexanes (1:1). The product was transferred from l3uchner funnel to a glass container for air-drying over night in thme hood. The product was dried thrther under vacuum at 50-55 C. for 4 hours. Table 14 provides results for N-methylglucamine salt.

Reference： [1]Patent: US2014/275616,2014,A1 .Location in patent: Paragraph 0088

27
[ 123-41-1 ]
[ 81846-19-7 ]
treprostinil choline salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tert-butyl methyl ether; isopropyl alcohol; at 20 - 80℃;	A 500-ml, two-necked, round-bottom flask equipped with a magnetic stirrer, and a thermometer was charged with UT-iS (4.50 g), 2-propanol (60 mE). The mix- tare was stirred and heated to 70-80 C. to obtain a clear solution. To the solution was added choline hydroxide (3.1 g) and stirred the mixture for short period. The solvent was evaporated under vacuum to give a gummy material. The gummy material was dissolved in 2-propanol (90 mE) by heating to 70-80 C. At this temperature, MTBE (115 mE) was added slowly keeping the temperature of solution more than 55 C. After complete addition of MTBE, the solution was allowed to cool to 50 C., then to 40 C. and to ambient temperature overnight. At ambient temperature, the product was isolated by filtration; product was washed with MTBE/ hexanes (1:1). The product was transferred from Buchner funnel to a glass container for air-drying over night in fume hood. The product was dried further under vacuum at 50-55 C. for 4 hours. Table 22 provides data for the choline salt.

Reference： [1]Patent: US2014/275616,2014,A1 .Location in patent: Paragraph 0096

28
[ 143-27-1 ]
[ 81846-19-7 ]
C₃₉H₆₇NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In 1,4-dioxane; acetonitrile; at 40℃;	To a solution of (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1- [(3S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]acetic acid (i.e., <strong>[81846-19-7]treprostinil</strong>) (78.1 mg, 200 mumoles) dissolved in 1,4-Dioxane (2.0 mL) was added triethylamine (TEA) (98 muL, 700 mumoles, 3.5 equivalents), alkylamine R1-NH2 (240 mumoles, 1.2 equivalents), and a solution of PyBOP (364 mg, 700 mumoles, 3.5 equivalents) dissolved in 2.0 mL MeCN (acetonitrile). [00346] The reaction mixture was heated to 40 C and allowed to shake at approximately 100 rpm overnight. Solvent was removed under reduced pressure to yield the crude product as a thick yellow oil. The product was extracted (l-l extraction) from the oil by repeated washings with 20% nPrOH/Hexanes (3 x 3 mL). Solvent was removed from the organic extract using a gentle stream of warmed N2 gas and gentle heat to yield a thick, slightly yellow oil. The crude material was dissolved in 20% nPrOH/Hexanes, passed through a 0.45 mum syringe filter, and submitted to preparatory HPLC purification. Solvent was removed from the purified material using a gentle stream of warmed N2 gas and gentle heat to yield a thick, colorless oil. The pure material was suspended in ethyl lactate for storage and was submitted to analytical HPLC for concentration determination. [00347] The following <strong>[81846-19-7]treprostinil</strong> amide derivatives of Formula B were made by the synthesis scheme provided above. (Table 17) Percentage yield is also provided in parentheses.
88%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In 1,4-dioxane; acetonitrile; at 40℃;	General procedure: To a solution of (1R,2R,3 aS,9a5)-[[2,3,3 a,4,9,9a-hexahydro-2-hydroxy- 1- [(3 S)-3 -hydroxyoctyl] -1 H-benz[f] inden-5-yl]oxy] acetic acid (i.e., <strong>[81846-19-7]treprostinil</strong>) (78.1 mg, 200iimoles) dissolved in 1,4-Dioxane (2.0 mL) was added triethylamine (TEA) (98 1iL, 700 jimoles, 3.5 equivalents), alkylamine R1-NH2 (240 jimoles, 1.2 equivalents), and a solution of PyBOP (364 mg, 700 iimoles, 3.5 equivalents) dissolved in 2.0 mL MeCN (acetonitrile).jOOll6j The reaction mixture was heated to 40 C and allowed to shake at approximately 100 rpm overnight. Solvent was removed under reduced pressure to yield the crude product as a thick yellow oil. The product was extracted (1-1 extraction) from the oil by repeated washings with 20% WrOH/Hexanes (3 x 3 mL). Solvent was removed from the organic extract using a gentle stream of warmed N2 gas and gentle heat to yield a thick, slightly yellow oil. The crude material was dissolved in 20% PrOH/Hexanes, passed through a 0.45 lim syringe filter, and submitted to preparatory HPLC purification. Solvent was removed from the purified material using a gentle stream of warmed N2 gas and gentle heat to yield a thick, colorless oil. The pure material was suspended in ethyl lactate for storage and was submitted to analytical HPLC for concentration determination.jOOll7j The following <strong>[81846-19-7]treprostinil</strong> amide derivatives of Formula B were made by the synthesis scheme provided above. (Table 6) Percentage yield is also provided in parentheses
88%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In 1,4-dioxane; acetonitrile; at 40℃;	General procedure: To a solution of (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3- hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]acetic acid (i.e., <strong>[81846-19-7]treprostinil</strong>) (78.1 mg, 200 mumoles) dissolved in 1,4-Dioxane (2.0 mL) was added triethylamine (TEA) (98 muL, 700 mumoles, 3.5 equivalents), alkylamine R1-NH2 (240 mumoles, 1.2 equivalents), and a solution of PyBOP (364 mg, 700 mumoles, 3.5 equivalents) dissolved in 2.0 mL MeCN (acetonitrile). The reaction mixture was heated to 40 C and allowed to shake at approximately 100 rpm overnight. Solvent was removed under reduced pressure to yield the crude product as a thick yellow oil. The product was extracted (l-l extraction) from the oil by repeated washings with 20% nPrOH/Hexanes (3 x 3 mL). Solvent was removed from the organic extract using a gentle stream of warmed N2 gas and gentle heat to yield a thick, slightly yellow oil. The crude material was dissolved in 20% nPrOH/Hexanes, passed through a 0.45 mum syringe filter, and submitted to preparatory HPLC purification. Solvent was removed from the purified material using a gentle stream of warmed N2 gas and gentle heat to yield a thick, colorless oil. The pure material was suspended in ethyl lactate for storage and was submitted to analytical HPLC for concentration determination.

Reference： [1]Patent: WO2015/61720,2015,A2 .Location in patent: Paragraph 00345; 00346; 00347
[2]Patent: WO2016/81658,2016,A1 .Location in patent: Paragraph 00115; 00116; 00117
[3]Patent: WO2016/176555,2016,A1 .Location in patent: Paragraph 00396-00398

29
[ 36653-82-4 ]
[ 81846-19-7 ]
hexadecyl treprostinil [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Amberlyst 15 resin; In 1,4-dioxane; at 40℃;	To a solution of (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1- [(3S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]acetic acid (<strong>[81846-19-7]treprostinil</strong>) (78.1 mg, 200 mumoles) dissolved in 1,4-dioxane (2.0 mL) was added Amberlyst 15 resin (2.0 g) and alcohol R2-OH (2.0 mmoles, 10 equivalents). The reaction mixture was heated to 40 C and allowed to shake at approximately 100 rpm for 18-196 hours. Solvent was removed and the resin was washed with acetonitrile (MeCN) (3 x 3 mL). The 1,4-dioxane and MeCN extracts were combined and dried using a gentle stream of warmed N2 gas and gentle heat to yield a thick waxy solid. The crude material was dissolved in 20% nPrOH/Hexanes and submitted to preparatory HPLC purification. Solvent was removed from the purified material using a gentle stream of warmed N2 gas and gentle heat to yield an off-white waxy solid. The pure material was suspended in ethyl lactate for storage and was submitted to analytical HPLC for concentration determination. [00224] By way of example, the following compounds of Formula (A) were synthesized by the method of scheme 2.
	With Amberlyst-15; In 1,4-dioxane; for 18h;	General procedure: A general diagram for synthesis of the alkyl ester of <strong>[81846-19-7]treprostinil</strong> is shown in Scheme 1, below as well as Figure 1. The alcohol can be modified based on the desired alkyl ester chain length (e.g., C5-C18 alkyl esters of even or odd chain length, straight chain or branched). Other reaction conditions used to synthesize <strong>[81846-19-7]treprostinil</strong> ester prodrugs are provided in Table 6, below
	With Amberlyst 15 resin; In 1,4-dioxane; at 40℃;	General procedure: To a solution of (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3- hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]acetic acid (<strong>[81846-19-7]treprostinil</strong>) (78.1 mg, 200 mumoles) dissolved in 1,4-dioxane (2.0 mL) was added Amberlyst 15 resin (2.0 g) and alcohol R2-OH (2.0 mmoles, 10 equivalents). The reaction mixture was heated to 40 C and allowed to shake at approximately 100 rpm for 18-196 hours. Solvent was removed and the resin was washed with acetonitrile (MeCN) (3 x 3 mL). The 1,4-dioxane and MeCN extracts were combined and dried using a gentle stream of warmed N2 gas and gentle heat to yield a thick waxy solid. The crude material was dissolved in 20% nPrOH/Hexanes and submitted to preparatory HPLC purification. Solvent was removed from the purified material using a gentle stream of warmed N2 gas and gentle heat to yield an off-white waxy solid. The pure material was suspended in ethyl lactate for storage and was submitted to analytical HPLC for concentration determination.

Reference： [1]Patent: WO2015/61720,2015,A2 .Location in patent: Paragraph 00223; 00224
[2]Patent: WO2016/81658,2016,A1 .Location in patent: Paragraph 00105
[3]Patent: WO2016/176555,2016,A1 .Location in patent: Paragraph 00274; 00275; 00276
[4]Drug Research,2018,vol. 68,p. 605 - 614

30
[ 105-59-9 ]
[ 81846-19-7 ]
2-hydroxy-N-(2-hydroxyethyl)-N-methylethanaminium 2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl)oxy)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
339 mg	In ethanol; ethyl acetate; at 20℃;Reflux;	[0415] A solution of 2-(((lR,2R,3aS,9aS)-2-hydroxy-l-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a- hexahydro-lH-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid (I) (50 mg, 0.13 mmol, 1.0 equiv) in ethanol (88 mu,) and ethyl acetate (1.6 mL) was warmed to reflux until homogenous and then N-methyldiethanolamine (14.7 mu, 0.128 mmol, 1.0 equiv) was added. This clear solution was then allowed to slowly cool to room temperature overnight resulting in formation of fine white needles as a precipitate. The precipitate was filtered and dried under vacuum to give 60 mg of the title compound as fine white needles. HPLC analysis showed minor enrichment as the free acid had an HPLC purity of 96.47 % and the salt had an HPLC purity of 96.98 %. These crystals were used as seed crystals for subsequent recrystallizations. [0416] A solution of 2-(((lR,2R,3aS,9aS)-2-hydroxy-l-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a- hexahydro-lH-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid (I) (500 mg, 1.28 mmol, 1.0 equiv) and N-methyldiethanolamine (429 mu of a 33.3% v/v solution in ethanol, 1.25 mmol, 1.0 equiv) in ethanol (0.45 mL) and ethyl acetate (16 mL) was warmed to reflux until homogenous. An oil formed upon cooling to room temperature, so the mixture was warmed back to reflux until homogenous and the resulting clear mixture cooled to about 50 C and seeded with 2-hydroxy- N-(2-hydroxyethyl)-N-methylethanaminium 2-((( 1 R,2R,3aS,9aS)-2-hydroxy- 1 -((S)-3- hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-lH-cyclopenta[b]naphthalen-5-yl)oxy)acetate obtained as previously described. This was then allowed to cool to room temperature over 5 hours. A precipitate of fine white needles was filtered and dried under vacuum to give 551 mg of the title compound as fine white needles. HPLC analysis showed considerable enrichment as the free acid had an HPLC purity of 87.12% and the salt had an HPLC purity of 93.36%. [0417] The 443 mg 2-hyo^oxy-N-(2-hydroxyemyl)-N-memylemanaminium 2- (((lR,2R,3aS,9aS)-2-hy(koxy-l-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahychO-lH- cyclopenta[b]naphthalen-5-yl)oxy)acetate obtained above was warmed to reflux as a solution in 0.58 mL ethanol and 10.4 mL ethyl acetate until homogenous and then allowed to cool to room temperature overnight. A precipitate of fine white needles was filtered and dried under vacuum to give 339 mg of the title compound as fine white needles. HPLC purity of this batch was enriched to 98.20%. Data for N-methyldiethanolamine salt of I: mp = 83.5-85.5 "C; [ct]25D = +30.4 (c = 0.514, EtOH); NMR (400 MHz, DMSO-d6) delta 6.99 (t, J=7.69 Hz, 1H), 6.64 (dd, J=7.87, 14.83 Hz, 2H), 4.34 (s, 2H), 3.86 (t, J=5.31 Hz, 4H), 3.39-3.60 (m, 2H), 3.29 (br. s., 4H), 2.83-2.95 (m, 3H), 2.75 (dd, J=4.94, 14.46 Hz, 1H), 2.54 (dd, J=5.86, 13.92 Hz, 1H), 2.21- 2.42 (m, 2H), 2.03 (d, J=4.03 Hz, 2H), 0.95-1.76 (m, 15H), 0.88 (t, J=6.77 Hz, 3H); ,3C NMR (101 MHz, DMSO-di) 6 171.25, 155.07, 140.30, 126.58, 125.70, 120.11, 109.39, 75.47, 70.12, 66.14, 58.86, 57.43, 51.50, 41.73, 41.16, 40.52, 37.02, 35.01, 33.42, 32.45, 31.50, 28.33, 25.66, 24.92, 22.14, 13.92; IR (KBr pellet) 3392.1 (s), 3248.9 (m), 3081.7 (m), 2926.6 (s), 2903.8 (s), 2854.7 (m), 1609.9 (vs), 1473.1 (m), 1397.2 (ra), 1318.9 (m), 1278.0 (ra), 1243.7 (m), 1210.5 (w), 1113.9 (m), 1080.8 (m), 1051.2 (w), 1032.6 (w), 1006.0 (w), 915.2 (w), 902.6 (w), 774.0 (w) cm"1; MS (ESI+) m/z 413.2 (M+Na+); HPLC, Synergi Hydro RP column (4.6 x 250 mm2), 5 muiotaeta; flow rate 1.0 mL/min; 277 nm; mobile phase A: 0.1% formic acid in water; mobile phase B: 0.1% formic acid in acetonitrile; 0-45 min (40% B), 45-55 min (40-95% B gradient), 55-65 min (90% B), 65.1 min (40% B); retention time, 37.43 min (98.2%, 27a), retention time, 39.44 min (0.53%, 2-hydroxy-N-(2-hydroxyethyl)-N-methylethan- 1 -aminium 2-((( l_,2 ?,3a5',9a1S)-2- hydroxy-l-((-5')-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-lH-cyclopenta[b]naphthalen-5- yl)oxy)acetate).

Reference： [1]Patent: WO2015/73314,2015,A1 .Location in patent: Paragraph 0414-0417

31
[ 141-43-5 ]
[ 81846-19-7 ]
C₂₃H₃₄O₅*C₂H₇NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; ethyl acetate; at 20℃;Reflux;	General procedure: [0421] A solution of 2-(((lR,2R,3aS,9aS)-2-hydroxy-l-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a- hexahydro-lH-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid (I) (50 mg, 0.13 mmol, 1.0 equiv) in ethanol (88 mu.) and ethyl acetate (1.6 mL) was warmed to reflux until homogenous and then an amine selected from amines A-l to A-12 ( 0.128 mmol, 1.0 equiv.) in Table 2 was added. This clear solution was then allowed to slowly cool to room temperature overnight. In the event that a precipitate formed, it was filtered and dried under vacuum and the yield and HPLC purity reported in the table below. [0422] Table 2: Amine salts of 2-(((lR,2R,3aS,9aS)-2-hydroxy-l-((S)-3-hydroxyoctyl)- 2,3 ,3a,4,9,9a-hexahydro- 1 H-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid (I). [0423] As demonstrated in Table 1, efforts to generate solid form salts of 2-(((lR,2R,3aS,9aS)- 2-hydroxy- 1 -((S)-3-hydroxyoctyl)-2,3 ,3a,4,9,9a-hexahydro- 1 H-cyclopenta[b]naphthalen-5- yl)oxy)acetic acid resulted in the generation of only three salts out of the eleven attempted. Thus, the formation of amine salts of 2-(((lR,2R S,9aS)-2-hydroxy-l-((S)-3-hydroxyocty-)- 2,3,3a,4,9,9a-he ahyclro-lH-cyclopenta[b]naphalen-5-yl)o y)ac^^ acid is unpredictable.

Reference： [1]Patent: WO2015/73314,2015,A1 .Location in patent: Paragraph 0420-0423

32
2-hydroxy-N-(2-hydroxyethyl)-N-methylethanaminium 2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl)oxy)acetate [ No CAS ]
[ 81846-19-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogenchloride; In Isopropyl acetate; water; at 20℃;	[0419] A solution of the N-methyldiethanolamine salt of Formula I (100 mg, 0.196 mmol, 1.0 equiv) in water (1 mL) and isopropyl acetate (2.5 mL) was treated with aqueous hydrochloric acid (0.080 mL, 0.23 mmol, 1.2 equiv, 3.0 M solution in water) and the resulting biphasic slurry was stirred at room temperature until the layers cleared. The layers were separated, and the aqueous phase was extracted with isopropyl acetate (2 2.5 mL). The combined organic phases were washed with water (2 chi 2.5 mL), dried (Na2S04) and concentrated to give 75 mg (97%) of the title compound as a white powder. The free acid may be recrystallized by methods known in the art to further improve the purity. Data for I: NMR (400 MHz, CHLOROFORM-d) delta 7.07 (t, J=7.88 Hz, 1H), 6.82 (d, J=7.69 Hz, 1H), 6.68 (d, J=8.43 Hz, 1H), 4.58-4.72 (m, 2H), 4.40 (br. s., 3H), 3.73 (dt, J=6.23, 9.34 Hz, 1H), 3.64 (d, J=3.66 Hz, 1H), 2.76 (ddd, J=6.23, 14.20, 19.87 Hz, 2H), 2.61 (dd, J=6.04, 14.84 Hz, 1H), 2.48 (dd, J=6.23, 14.29 Hz, 1H), 2.20- 2.36 (m, 1H), 2.10-2.20 (m, 1H), 1.82-1.98 (m, 1H), 1.52-1.76 (m, 4H), 1.40-1.52 (m, 3H), 1.21- 1.40 (m, 6H), 1.08-1.21 (m, 1H), 0.92 (t, J=6.60 Hz, 3H); MS (ESI+) m/z 413.2 (M+Na*).

Reference： [1]Patent: WO2015/73314,2015,A1 .Location in patent: Paragraph 0418; 0419

33
[ 100-39-0 ]
[ 81846-19-7 ]
treprostinil benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In acetonitrile; for 1h;Reflux;	Synthesis of the benzyl ester of <strong>[81846-19-7]Treprostinil</strong> 13The benzyl ester 11 was synthesized by adapting the method described by J. C. Lee et al. in Organic Prep. and Proc. Intl., 1996, 28(4), 480-483. To a solution of 1 (620 mg, 1.6 mmoles) and cesium carbonate (782.4 mg, 2.4 mmoles) in acetonitrile (30 ml) was added benzyl bromide (0.48 ml, 4 mmoles) and the mixture was stirred at reflux for 1 hour. After cooling at room temperature, the precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in chloroform (150 ml) and washed with a 2% aqueous solution of NaHCO3 (3×30 ml). The organic layer was washed with brine, dried on Na2SO4, filtered and the solvent was removed in vacuo to afford 750 mg of the crude benzyl ester 13 (yield 98%) as a yellow viscous oil. The crude benzyl ester 13 can be purified by column chromatography (100-0% dichioromethane(methanol) but it can also be used crude in subsequent reactions.

Reference： [1]Patent: US2015/259274,2015,A1 .Location in patent: Paragraph 0123; 0124

34
[ 67-56-1 ]
[ 81846-19-7 ]
[ 81845-98-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; at 20℃; for 24h;	Synthesis of methyl ester of <strong>[81846-19-7]Treprostinil</strong> (2)Methyl ester of <strong>[81846-19-7]treprostinil</strong> (2) was prepared by treating 1.087 g (2.8 mmoles) of <strong>[81846-19-7]treprostinil</strong> (1) with 50 ml of a saturated solution of dry hydrochloric acid in methanol. After 24 hours at room temperature, the methanol was evaporated to dryness and the residue was taken in 200 ml dichloromethane. The dichloromethane solution was washed with a 10% aqueous potassium carbonate solution, and then with water to a neutral pH, it was dried over sodium sulfate, filtered and the solvent was removed in vacuo affording <strong>[81846-19-7]treprostinil</strong> methyl ester (2) in 98% yield as a yellow oil. The crude methyl ester was used as such in subsequent reactions.

Reference： [1]Patent: US2015/259274,2015,A1 .Location in patent: Paragraph 0090; 0091; 0096

35
C₂₄H₃₆O₄ [ No CAS ]
[ 81846-19-7 ]

Yield	Reaction Conditions	Operation in experiment
1.2 g	With water; potassium hydroxide; In methanol; for 2h;Reflux;	10078] A mixture of 1.4 g of compound 10 and 0.34 gpotassium hydroxide (KOH) was dissolved in 10 mEmethanol and 10 mE of water. The reaction solution was next heated and refluxed for 2 h. Afier cooled to room temperature, 5.5 mE of aqueous 2N HC1 was added, and the reaction solution was stirred for 2 hours. The reaction solutionthen filtered and the resulting crude solid was washed using methanol and water (5 mE/lO mE). The solid was next dried under high vacuum to yield 1.2 g of compound 11 (Treprostinil). ?H NMR (MeOD, 400 MHz) oe 7.04 (t, J=7.9 Hz, 1H), 6.79 (d, J=7.3 Hz, 1H), 6.70 (d, J=8.2 Hz, 1H), 4.62 (s, 2H),3.66-3.58 (m, 1H), 3.56-3.49 (m, 1H), 2.77 (dd, J=14.7,Hz, 1H), 2.73 (dd, J=14.2, 6.2 Hz, 1H), 2.64 (dd, J=14.7,Hz, 1H), 2.50 (dd, J=14.3, 6.0 Hz, 1H), 2.33-2.21 (m, 1H), 2.12-2.04 (m, 1H), 1.96-1.87 (m, 1H), 1.76-1.66 (m, 1H),1.66-1.53 (m, 2H), 1.53-1.26 (m, 9H), 1.25-1.16 (m, 1H),1.15-1.06 (m, 1H), 0.92 (t, J=6.8 Hz, 3H); ?3C NMR (MeOD, 100MHz) oe 173.1, 156.7, 142.3, 128.9, 127.3, 122.6, 111.0,77.8,73.1, 66.7, 52.6,42.5,42.2,38.4,36.2,34.7,34.2,33.3,29.8, 26.8, 26.6, 23.9, 14.6.

Reference： [1]Patent: US2016/152548,2016,A1 .Location in patent: Paragraph 0059; 0077; 0078

36
[ 112-53-8 ]
[ 81846-19-7 ]
dodecyl treprostinil [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide; In 1,4-dioxane; for 84h;	General procedure: A general diagram for synthesis of the alkyl ester of <strong>[81846-19-7]treprostinil</strong> is shown in Scheme 1, below as well as Figure 1. The alcohol can be modified based on the desired alkyl ester chain length (e.g., C5-C18 alkyl esters of even or odd chain length, straight chain or branched). Other reaction conditions used to synthesize <strong>[81846-19-7]treprostinil</strong> ester prodrugs are provided in Table 6, below

Reference： [1]Patent: WO2016/81658,2016,A1 .Location in patent: Paragraph 00105
[2]Drug Research,2018,vol. 68,p. 605 - 614

37
[ 112-72-1 ]
[ 81846-19-7 ]
tetradecyl treprostinil [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Amberlyst-15; In 1,4-dioxane; for 18h;	General procedure: A general diagram for synthesis of the alkyl ester of <strong>[81846-19-7]treprostinil</strong> is shown in Scheme 1, below as well as Figure 1. The alcohol can be modified based on the desired alkyl ester chain length (e.g., C5-C18 alkyl esters of even or odd chain length, straight chain or branched). Other reaction conditions used to synthesize <strong>[81846-19-7]treprostinil</strong> ester prodrugs are provided in Table 6, below

Reference： [1]Patent: WO2016/81658,2016,A1 .Location in patent: Paragraph 00105
[2]Drug Research,2018,vol. 68,p. 605 - 614

38
[ 623-93-8 ]
[ 81846-19-7 ]
C₃₂H₅₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Amberlyst-15; In 1,4-dioxane; for 72h;	General procedure: A general diagram for synthesis of the alkyl ester of <strong>[81846-19-7]treprostinil</strong> is shown in Scheme 1, below as well as Figure 1. The alcohol can be modified based on the desired alkyl ester chain length (e.g., C5-C18 alkyl esters of even or odd chain length, straight chain or branched). Other reaction conditions used to synthesize <strong>[81846-19-7]treprostinil</strong> ester prodrugs are provided in Table 6, below

Reference： [1]Patent: WO2016/81658,2016,A1 .Location in patent: Paragraph 00105

39
trityl chloride polystyrene resin [ No CAS ]
[ 81846-19-7 ]
C₄₂H₄₇O₅Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;Molecular sieve;	A 10 mE single use syringe reactor equipped with aPE frit was loaded with 2-chlorotrityl chloride (TCP) resin (153 mg, loading 1.22 mmol/g, 0.186 mmol). A solution of <strong>[81846-19-7]treprostinil</strong> (54 mg, 0.138 mmol) and DIPEA (60 jtl, 0.346 mmol) in DCM (anhydrous, mol. sieve) was drawn into the reactot Reactor was agitated for 2 h at RT. 200 jtl methanol were added and reactor was agitated for further 10 mm. Solution was dispelled and resin was washed with DCM (5x), DMF (5x) and DCM (lOx). Resin was dried under vacuum (1 mbar). Based on weight, a <strong>[81846-19-7]treprostinil</strong> loading of 0.72 mmol/g TCP resin was obtained.

Reference： [1]Patent: US9561287,2017,B2 .Location in patent: Page/Page column 119; 120

40
TREPROSTINIL SODIUM [ No CAS ]
[ 81846-19-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrogenchloride; In water;pH 3 - 4;	2 N hydrochloric acid was slowly added to the compound of formula 5 (310 g) dissolved in water (1.2 kg) and acidified to pH 3-4.Ethyl acetate (3.7 kg) was added and stirred, and the organic layer was separated and concentrated. Acetonitrile (3.1 kg) and water (3.1 kg) were added to dissolve, cooled to -5 to + 5 C, and stirred for 4 to 6 hours.The resulting solid was filtered and vacuum dried at 55 C for 20-24 hours to give the compound of formula 1 (250 g, 85%).

Reference： [1]Patent: KR2017/123132,2017,A .Location in patent: Paragraph 0027-0028; 0071-0072

41
[ 1738-76-7 ]
[ 81846-19-7 ]
C₃₂H₄₃NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.396 g	With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine; In dichloromethane; at 20℃;Inert atmosphere;	A 50 ml round bottom flask equipped with magnetic stir bar was charged with a solution of UT-iS (0.5 g, 1.28 mmol) in anhydrous DCM (20 ml) under argon. To this solution wasadded Bop-Cl (0.49 g, 1.92 mmol) followed by glycine benzyl esterp-toluenesulfonate (0.43 g, 1.28 mmol) at room temperature under argon. The reaction mixture was stirred for 20 minutes, then the triethylamine (0.39 g, 3.84 mmol) was added. The reaction mixture was stirred overnight until the reaction was complete. The progress of reaction was checked by tlc. The reaction was quenched with 0. iN HC1 (10 ml), the DCM layer was separatedand washed with 10% NaHCO3 (10 ml), water (10 ml) and brine (10 ml), dried overanhydrous Na2 SO4, filtered and concentrated in vacuo to obtain crude product (0.9 g, RDUT-1161-i0i). The crude product was purified on silica gel using a gradient solvent of 30- 60% EtOAc in hexanes to obtain pure product (Amide II) (0.3 96 g, RD-UT-i 161-biB). The compound was characterized by 1H NMR.

Reference： [1]Patent: WO2018/58124,2018,A1 .Location in patent: Page/Page column 51; 52

42
[ 81846-19-7 ]
[ 74-88-4 ]
C₂₅H₃₈O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
230 mg	With sodium hydride; In tetrahydrofuran; hexane; mineral oil; at 20℃; for 5h;Inert atmosphere;	A 50-ml round bottom flask was charged with sodium hydride (0.61g, 15.36 mmol, 60% in mineral oil) and this was washed with hexane (2 x 20 ml) to remove the mineral oil. To thissolid NaH, anhydrous THF (10 ml) was added and stirred at ambient temperature under argon. To this suspension, <strong>[81846-19-7]treprostinil</strong> (1) (0.5 g, 1.26 mmol) in THF (5.0 ml) was added dropwise, followed by methyl iodide (3.0 ml). The reaction mixture was stirred for 5 h and the progress of the reaction was monitored by TLC (DCM/methanol, 9:1). The reaction was quenched with aq. saturated NH4C1 solution (1.0 ml), diluted with water (10.0 ml). The pHwas adjusted to 1-2 with 2N HC1. The organic layer was separated and aqueous layer was extracted with EtOAc (3 x 20 ml). The extracts were combined and dried over Na2504. The solvent was removed in vacuo to obtain crude product. The crude product was purified by silica gel chromatography using a gradient solvent (0-10% methanol in DCM) to give product dimethyl ether of <strong>[81846-19-7]treprostinil</strong> (Prodrug IX) (230 mg).

Reference： [1]Patent: WO2018/58124,2018,A1 .Location in patent: Page/Page column 95; 96

43
[ 42854-62-6 ]
[ 81846-19-7 ]
C₃₃H₄₅NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97.8%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; water; at 20℃; for 2.5h;Inert atmosphere;	To a suspension of treprostinil (1) (1.0 g, 2.561 mmol) and L-alanine benzyl esterptoluenesulfonate salt (0.9 g, 2.561 mmol) in dichloromethane (30 mL) was added triethylamine (0.89 mL, 6.401 mmol). To this mixture 1-ethyl-3-(3?- dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (0.59 g, 3.073 mmol) and 1- hydroxybenzotriazole hydrate (0.42 g, 3.073 mmol) were added. The reaction mixture wasstirred at ambient temperature under argon for 2.5 h. Based on TLC (eluent: ethyl acetate) the reaction was found to be complete. The reaction mixture was quenched with water (30 mL) and the organic layer was separated, dried over sodium sulfate and evaporated in vacuo to obtain crude product. The crude product was purified using silica gel column chromatography using 0-70% ethyl acetate in hexane to obtain pure treprostinil alanineamide benzyl ester (2) (1.34 g, 97.8% yield).

Reference： [1]Patent: WO2018/58124,2018,A1 .Location in patent: Page/Page column 100

44
[ 16652-76-9 ]
[ 81846-19-7 ]
C₃₅H₄₉NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.3%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; water; at 20℃; for 2h;	To a suspension of treprostinil (1) (1.0 g, 2.561 mmol) and L-valine benzyl esterptoluenesulfonate salt (0.97 g, 2.561 mmol) in dichloromethane (30 mL) was added triethylamine (0.89 mL, 6.401 mmol). To this mixture 1-ethyl-3-(3?- dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (0.59 g, 3.073 mmol) and 1- hydroxybenzotriazole hydrate (0.42 g, 3.073 mmol) were added. The reaction mixture wasstirred at ambient temperature under argon for 2 h. Based on TLC (eluent: ethyl acetate) the reaction was found to be complete. The reaction mixture was quenched with water (30 mL) and stirred for 15 mm. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo to obtain crude product. The crude product was purified using silica gel column chromatography using 0-50% ethyl acetate in hexane to obtain pure treprostinilvaline amide benzyl ester (2) (1.3 g, 90.3% yield).

Reference： [1]Patent: WO2018/58124,2018,A1 .Location in patent: Page/Page column 101

45
[ 16652-76-9 ]
[ 81846-19-7 ]
C₂₈H₄₃NO₆ [ No CAS ]

Reference： [1]Patent: WO2018/58124,2018,A1

46
[ 2886-33-1 ]
[ 81846-19-7 ]
C₄₁H₅₁NO₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97.6%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; water; at 20℃; for 2h;	To a suspension of treprostinil (1) (1.0 g, 2.561 mmol) and L-aspartic acid dibenzyl esterptoluenesulfonate salt (1.24 g, 2.56 1 mmol) in dichloromethane (30 mL) was added triethylamine (0.89 mL, 6.401 mmol). To this mixture 1-ethyl-3-(3?- dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (0.59 g, 3.073 mmol) and 1- hydroxybenzotriazole hydrate (0.42 g, 3.073 mmol) were added. The reaction mixture wasstirred at ambient temperature under argon for 2 h. Based on TLC (eluent: ethyl acetate) the reaction was found to be complete. The reaction mixture was quenched with water (30 mL) and stirred for 15 mm. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo to obtain crude product. The crude product was purified using silica gel column chromatography using 0-50% ethyl acetate and hexane as a mobile to obtainpure treprostinil aspartic acid amide benzyl ester (2) (1.63 g, 97.6% yield).

Reference： [1]Patent: WO2018/58124,2018,A1 .Location in patent: Page/Page column 102

47
[ 3695-68-9 ]
[ 81846-19-7 ]
C₃₃H₄₅NO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49.3%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; water; at 20℃; for 2h;	To a suspension of <strong>[81846-19-7]treprostinil</strong> (1)(1.0 g, 2.561 mmol) and L-serine benzyl ester benzenesulfonate salt (0.9 g, 2.561 mmol) in dichloromethane (30 mL) was added triethylamine (0.89 mL, 6.401 mmol). To this mixture 1-ethyl-3-(3?- dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (0.59 g, 3.073 mmol) and 1- hydroxybenzotriazole hydrate (0.42 g, 3.073 mmol) were added. The reaction mixture wasstirred at ambient temperature under argon for 2 h. Based on TLC (eluent: ethyl acetate) the reaction was found to be complete. The reaction mixture was quenched with water (30 mL) and stirred for 15 mm. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo to obtain crude product. This was purified using silica gel column chromatography using 0-100% ethyl acetate and hexane as a mobile to obtain pure<strong>[81846-19-7]treprostinil</strong> serine amide benzyl ester (2) (0.62 g, 49.3% yield).

Reference： [1]Patent: WO2018/58124,2018,A1 .Location in patent: Page/Page column 103

48
C₂₃H₃₄O₄ [ No CAS ]
[ 81846-19-7 ]

Yield	Reaction Conditions	Operation in experiment
68%	With dihydrogen peroxide; potassium carbonate; In methanol;	Compound 2 in a weight ratio of 7:1 and potassium carbonate were dissolved in a 3:1 volume ratio of methanol and hydrogen peroxide solution, stirred, pressurized and evaporated to give treprostinil.

Reference： [1]Patent: CN107602376,2018,A .Location in patent: Paragraph 0043; 0047; 0056; 0060; 0061; 0062-0077

49
[ 64-17-5 ]
[ 81846-19-7 ]
[ 1355990-07-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sulfuric acid; at 0 - 86℃; for 16h;Inert atmosphere;	Ethanol (~15 mL) was dried by stirring in the presence of heat-activated 4 A molecular sieves in an argon purged sealed 50 mL round bottom flask (RBF) for 20 minutes before allowing to settle. Ethanol was transferred via syringe fitted with a 0.22 mm syringe filter. <strong>[81846-19-7]Treprostinil</strong> 2 (495.8 mg, 1.270 mmol) was dissolved in dry absolute ethanol (9.0 mL) in a 50 mL round bottom flask and cooled to 0 C with ice bath. Sulfuric acid (6.8 muL, 0.127 mmol) was then added and the solution was refluxed at 86 C for 16 hours. The reaction was monitored by TLC (silica, 20% methanol/ethyl acetate, visualised by UV and PMA). Towards the end of reaction sodium sulfate was added to complex water. Once complete, the filtrate was neutralised by addition of saturated potassium carbonate solution (3 mL) and removed in vacuo. Crude product was dissolved in ethyl acetate (10 mL × 3) and extracted 3 times from 20% aqueous potassium carbonate solution (15 mL). Combined organic layers washed with brine and dried over sodium sulfate before solvent removal in vacuo to afford dry white solid 7 (472.4 mg, 88% yield). 1H NMR (500 MHz, CDCl3) dH: 7.03 (t, J = 7.8 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 4.58 (s, 2H), 4.22 (d, J = 7.1 Hz, 2H), 3.65 (dd, J = 14.5, 11.0 Hz, 1H), 3.53 (s, 1H), 2.88 (dd, J = 14.7, 6.0 Hz, 1H), 2.72 (dd, J = 14.3, 6.2 Hz, 1H), 2.46 (ddd, J = 21.1, 20.1, 12.4 Hz, 2H), 2.27 - 2.07 (m, 2H), 1.82 (t, J = 16.5 Hz, 1H), 1.72 - 1.57 (m, 2H), 1.56 - 1.36 (m, 5H), 1.34 - 1.19 (m, 9H), 1.14 (dd, J = 21.7, 10.4 Hz, 1H), 0.88 (t, J = 6.9 Hz, 3H). 13C NMR (CDCl3, 500 Hz) dC: 165.87, 154.94, 141.02, 127.79, 126.56, 109.71, 72.60, 66.09, 61.25, 52.31, 41.46, 41.28, 37.45, 35.01, 33.76, 32.79, 31.92, 28.88, 25.98, 25.40, 22.67, 14.20, 14.08. FTIR (ATR) nu /cm-1: 3352 (OH), 2931 (CH), 1751 (C=O ester), 1601 (Ar-H), 1179 (C-O ester). [M-H]- found: 417.2639 m/z.

Reference： [1]Tetrahedron Letters,2019
[2]Drug Research,2018,vol. 68,p. 605 - 614

50
[ 544-77-4 ]
[ 81846-19-7 ]
[ 1706528-83-7 ]

Yield	Reaction Conditions	Operation in experiment
58.6 g	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 1h;	1 Preparation of Crude Hexadecyl Treprostinil Example 1 Preparation of Crude Hexadecyl Treprostinil 2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid (40.0 g, 102.4 mmol) was dissolved in 600 ml dimethylformamide and followed by addition of 42.0 g potassium carbonate with 72.0 g I-iodohexadecane, and stirred at 60° C. for 1 hour. Afterwards, the reaction mixture was slowly cooled to 10° C., and 650 ml water and 650 ml ethyl so acetate with 50.0 g magnesium sulfate were added to the reaction mixture for extraction. The extraction solution was evaporated off under vacuum at room temperature to get crude product. The crude product was then purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent to obtain 58.6 g off-white waxy solid (crude Hexadecyl Treprostinil).

Reference： [1]Current Patent Assignee: CHIROGATE INTERNATIONAL, INC. - US10781160, 2020, B1 Location in patent: Page/Page column 8

51
[ 81846-19-7 ]
[ 74-88-4 ]
[ 2644751-03-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide In dimethyl sulfoxide at 20℃;	7 Procedure for the Synthesis of Treprostinil Methyl Ester Cyclopentyl Methyl Ether (101) To a stirring solution of treprostinil (100) (1.0 eq) in anhydrous DMSO (20 v/wt) at room temperature were added potassium hydroxide (9.0 eq), and methyl iodide (20 eq). The resulting mixture was stirred at room temperature overnight. It was filtered and the filtrate was concentrated in vacuo to give crude product. Water and DCM were added, the layers separated. Aqueous layer was extracted with DCM. Combined organic layers washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give crude product. It was purified on silica gel column chromatography to give the treprostinil methyl ester cyclopentyl methyl ether (101). The compound 101 was characterized by 1H NMR and LCMS. The purity was determined by HPLC.

Reference： [1]Current Patent Assignee: UNITED THERAPEUTICS CORP - US2021/54009, 2021, A1 Location in patent: Paragraph 0776

52
[ CAS Unavailable ]
[ 81846-19-7 ]

Yield	Reaction Conditions	Operation in experiment
93.7%	With potassium hydroxide In isopropanol at 80℃; for 2h;	1-2; 4-5 Preparation of Treprostinil Monohydrate Form I Crystal 2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-H-cyclopenta[b]naphthalen-6-yl)oxy)acetonitrile (1.00 g, 2.7 mmol) was dissolved in 10 ml 2-propanol and followed by an addition of 4 ml potassium hydroxide solution (16% w/v), and stirred at 80° C. for 2 hours. Afterwards, the reaction mixture was slowly cooled to room temperature and quenched by hydrochloric acid solution, and concentrated to remove the 2-propanol, and 25 ml saturation sodium hydrogen carbonate aqueous solution with 25 ml ethyl acetate was added for extraction. The resulting Treprostinil was then extracted to the sodium hydrogen carbonate solution (pH value about 8.3) to form a homogenous solution at 30° C. Afterwards, the basic Treprostinil aqueous solution was acidified by slowly adding 7N phosphoric acid aqueous solution to adjust the pH value to about 2.5 in a decreasing rate of about 0.17 per minute, and then was stirred at 30° C. for 1 h until most of the crystal was precipitated. Thereafter, the resulting precipitate crystal was filtered and rinsed by 200 ml water, and then dried under high vacuum (about 0.01 Torr) at 30° C. for 2 hours to give 1.03 g Treprostinil monohydrate Form I crystal (yield: 93.7%). The XRPD and DSC results are the same as those shown in FIG. 5 and FIG. 6. UPLC analysis of the product shows that the purity is 100.0%. The Treprostinil ethyl ester and the Treprostinil dimers are non-detectable, and the other impurities are not found.
	With potassium hydroxide	1 Preparation of Treprostinil Monohydrate Form I Crystal Example 1 Preparation of Treprostinil Monohydrate Form I Crystal 2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-6-yl)oxy)acetonitrile (1.00 g, 2.7 mmol) was dissolved in 10 ml 2-propanol and followed by an addition of 4 ml potassium hydroxide solution (16% w/v), and stirred at 80° C. for 2 hours. Afterwards, the reaction mixture was slowly cooled to room temperature and quenched by hydrochloric acid solution, and concentrated to remove the 2-propanol, and 30 ml saturation sodium hydrogen carbonate aqueous solution with 30 ml ethyl acetate was added for extraction. The resulting Treprostinil was then extracted to the sodium hydrogen carbonate solution (pH value about 8.3) to form a homogenous solution at 20° C.
	With potassium hydroxide	4 Preparation of Treprostinil Monohydrate Form II Crystal Example 4 Preparation of Treprostinil Monohydrate Form II Crystal 2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-6-yl)oxy)acetonitrile (1.00 g, 2.7 mmol) was dissolved in 10 ml 2-propanol and followed by addition of 4 ml potassium hydroxide solution (16% w/v), and stirred at 80° C. for 2 hours. Afterwards, the reaction mixture was slowly cooled to room temperature and quenched by hydrochloric acid solution, and concentrated to remove the 2-propanol, and 30 ml potassium hydroxide solution with 30 ml ethyl acetate was added for extraction. The resulting Treprostinil was then extracted to the potassium hydroxide aqueous solution (pH value about 14) to form a homogenous solution at 20° C.

With potassium hydroxide; sodium hydroxide

5 Preparation of Treprostinil Monohydrate Form II Crystal Example 5 Preparation of Treprostinil Monohydrate Form II Crystal 2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-6-yl)oxy)acetonitrile (1.00 g, 2.7 mmol) was dissolved in 10 ml 2-propanol and followed by addition of 4 ml potassium hydroxide solution (16% w/v), and stirred at 80° C. for 2 hours. Afterwards, the reaction mixture was slowly cooled to room temperature and quenched by hydrochloric acid solution, and concentrated to remove the 2-propanol, and 20 ml sodium hydroxide solution with 20 ml ethyl acetate was added for extraction. The resulting Treprostinil was then extracted to the sodium hydroxide aqueous solution (pH value about 12) to form a homogenous solution at 10° C.

Reference： [1]Current Patent Assignee: JIHE GUI SCIENCE AND TECH; CHIROGATE INTERNATIONAL, INC. - US2022/135511, 2022, A1 Location in patent: Paragraph 0080-0081; 0083-0084
[2]Current Patent Assignee: JIHE GUI SCIENCE AND TECH; CHIROGATE INTERNATIONAL, INC. - US2022/135511, 2022, A1
[3]Current Patent Assignee: JIHE GUI SCIENCE AND TECH; CHIROGATE INTERNATIONAL, INC. - US2022/135511, 2022, A1
[4]Current Patent Assignee: JIHE GUI SCIENCE AND TECH; CHIROGATE INTERNATIONAL, INC. - US2022/135511, 2022, A1

53
[ 75-64-9 ]
[ 81846-19-7 ]
[ 2413467-26-0 ]

Yield	Reaction Conditions	Operation in experiment
83%	In acetone at 20 - 50℃; Cooling;	Preparation of 2-[[(lR,2R,3aS,9aS)-2-hydroxy-l-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a- hexah dro- lH-cyclopenta [g] naphthalen-5-yl] oxy] acetic acid t-butylamine Treprostinil free acid (100 mg) is added to acetone (2 mL) while stirring at room temperature. The suspension is heated to 50°C. In a separate vessel, t-butylamine (26 mg, 1.4 equiv) is mixed with acetone (1 mL). The base solution is added dropwise and the suspension becomes a solution for a few minutes, after which time a suspension forms. Acetone (1 mL) is added and mixing continues for 2 hours. The mixture is stirred and cooled overnight. The white solid is isolated by vacuum filtration on Whatman paper.The resulting cake of white solid is air dried in place to give 99 mg (83% yield) of the title compound.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2020/60823, 2020, A1 Location in patent: Page/Page column 5

54
[ 81846-19-7 ]
[ 5437-45-6 ]
[ 2831291-17-7 ]

Yield	Reaction Conditions	Operation in experiment
86.9%	With potassium carbonate In propan-2-one at 20℃; for 64h; Inert atmosphere;	1 Synthesis of Treprostinil Acetoxy Acetate Benzyl Ester (6) To a solution of treprostinil (5) (100.2 g, 256.58 mmol) in acetone (1.5 L) was added benzyl bromoacetate (44.3 mL, 282.23 mmol) potassium carbonate (106.4 g, 769.74 mmol). To this, acetone (800 mL) was added, and the mixture was stirred vigorously at room temperature under argon environment. After 64 h the reaction was found to be complete based on TLC. The reaction was filtered through celite and evaporated in vacuo to obtain crude treprostinil acetoxy acetate benzyl ester (6). This was purified by column chromatography using ethyl acetate:hexanes (0-60%) as mobile phase to obtain three fractions of treprostinil acetoxy acetate benzyl ester (6) (A: 6.4 g, B: 65.3 g, C: 50.2 g). The fraction C (50.2 g) was crystallized using ethyl acetate (400 mL) and hexane (100 mL) at 65° C. to obtain 28.1 g of product (6). The mother liquor (21.8 g) from this and fraction A (6.4 g) were combined and crystallized with ethyl acetate (170 mL) and hexane (60 mL) at 65 to 70° C. to obtain pure product (6) (26.7 g) (total, 120.1 g, 86.9% yield). The pure product was characterized by 1H NMR.

Reference： [1]Current Patent Assignee: UNITED THERAPEUTICS CORP - US2022/280430, 2022, A1 Location in patent: Paragraph 0161; 0165-0166

55
[ 2807-30-9 ]
[ 81846-19-7 ]
[ 2883626-18-2 ]

Yield	Reaction Conditions	Operation in experiment
	With NKC-9 strong acid resin In 1,4-dioxane at 40℃;	1 Synthesis method General procedure: Dissolve treprostinil (10mg/mL) and the corresponding alkoxide (50mg/mL) in 1,4-dioxane, use NKC-9 strong acid resin to catalyze the reaction, stir overnight at 40°C, and monitor the reaction by TLC Complete, the product was obtained by HPLC purification.

Reference： [1]Current Patent Assignee: GUANGZHOU KAISHI BIOTECHNOLOGY CO LTD; GUANGZHOU KAISHI MEDICINE CO LTD - CN115448839, 2022, A Location in patent: Paragraph 0052-0056

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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. 81846-19-7 ] {[proInfo.proName]}

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[ 81846-19-7 ] Synthesis Path-Downstream 1~55

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Aryls

Ethers

Alcohols

Carboxylic Acids

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[ 81846-19-7 ]