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Product Details of [ 830346-50-4 ]

CAS No. :	830346-50-4	MDL No. :	MFCD31811619
Formula :	C₂₈H₂₄F₅N₃O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	545.50	Pubchem ID :	-
Synonyms :

Safety of [ 830346-50-4 ]

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Application In Synthesis of [ 830346-50-4 ]

* 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 [ 830346-50-4 ]

[ 830346-50-4 ] Synthesis Path-Downstream 1~23

1
N-{(R)-2-[5-(2-fluoro-3-methoxy-phenyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-2,2-dimethyl-propionamide [ No CAS ]
[ 239087-08-2 ]
[ 830346-50-4 ]

Yield	Reaction Conditions	Operation in experiment
91%		Uracil 3b (14.5 g, 30.9 mmol), sodium carbonate (50.0 g, 106 mmol), sodium bromide (25.0 g, 102.9 mmol), anhydrous DMF (200 mL), and 2-flouro-6- trifluoromethylbenzyl bromide (12.0 g, 46.7 mmol) in 50 mL toluene were heated at 70- 90 0C for 10 hours (HPLC showed all of the 3b was consumed). The mixture was cooled to room temperature and was slowly charged with 170 mL of cone. HCl solution. (Optionally, the solid carbonate and sodium bromide can be filtered off before the addition of the HCl resulting in the use of less HCL solution). The solution was heated at 60 0C for 10 hours. The pH of the solution was adjusted to 7-8 by slowly adding solid sodium carbonate. 600 mL of DI water was added and the solution was extracted with 2 x 250 mL isopropyl acetate. The phases were separated and the organic layer was washed with 2 x 100 mL of DI water. The organic layer was concentrated to 150 mL and was extracted with 150 mL 10% phosphoric acid. The aqueous layer was agitated with 450 mL of isopropyl acetate and the mixture was neutralized with saturated sodium bicarbonate solution to pH 7. The phases were separated and the organic layer was washed with 2 x 100 mL of water then dried over anhydrous sodium sulfate. The organic layer was filtered and the filtrate was concentrated at 10 mm and 50-60 0C to give 15.8 g of Ie as sticky oil with >98% HPLC peak are at 254 urn (tR = 6.61 min,HPLC method 1). The yield was 91%. The oil can be triturated with hexane to further remove some of the impurities.

Reference： [1]Patent: WO2009/62087,2009,A1 .Location in patent: Page/Page column 15, 16

2
[ 1150560-59-0 ]
[ 102089-75-8 ]
[ 830346-50-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate In N,N-dimethyl-formamide at 55℃;	1.1E Methanesulfonic acid (S)-3-tert-butoxycarbonylamino-3 -phenyl-propyl ester Id(19.7 kg), 5-(2-fluoro-3-methoxy-phenyl)-l-(2-fluoro-6-trifluoromethyl-benzyl)-6- methyl-lH-pyrimidine-2,4-dione Ic (16.5 kg), potassium carbonate (powder, 325 mesh, 13.4 kg) and DMF (101 L) were charged to a reactor. The mixture was stirred at 55 0C. After reaction completion, the reactor was cooled to 20 0C and isopropyl acetate (132 L) was charged, followed by water (157 L). After agitation and settling, the layers were separated and the organic layer washed with water (87 L). After agitation and settling, the water layer was removed. To the organic layer was charged methanesulfonic acid (11.2 kg) and the reactor contents were heated to 60 0C for 1-2 hours. The reactor contents were cooled to 20 0C and a solution of potassium carbonate/water (26.8 kg/140 L) was added slowly, agitated, and then allowed to settle prior to separation of layers. The organic layer was treated with a solution of 85% phosphoric acid/H2O (22.6 kg/236 kg). The mixture was agitated, allowed to settle, and the layers were separated. The aqueous layer was washed with isopropyl acetate (2 x 167 kg) and the layers were separated. A solution of potassium carbonate/water (36.1 kg/139 kg) was added slowly to the aqueous layer. Isopropyl acetate (206 kg) was charged; the mixture was agitated and then allowed to settle. The aqueous layer was removed and the organic layer was concentrated to provide a solution of 3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3- methoxy-phenyl)- 1 -(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl- 1 H-pyrimidine-2,4- dione Ie in isopropyl acetate (125.4 kg, 30.7 kg contained, 86% yield) for use in the next step. LCMS (ESI) m/z 546.2 (MH+)
84%	With N,N,N',N'-tetramethylguanidine In N,N-dimethyl-formamide at 40℃; for 48h;	1.1E Methanesulfonic acid (S)-3-tert-butoxycarbonylamino-3 -phenyl-propyl ester Id (177.54 g), 5-(2-fluoro-3-methoxy-phenyl)- 1 -(2-fluoro-6-trifluoromethyl-benzyl)-6- methyl- lH-pyrimidine-2,4-dione Ic (160.0 g), 1,1,3,3-tetramethylguanidine (117.72 mL) and DMF (320 mL) were charged to a reactor. The mixture was stirred at 40 0C. After reaction completion (48 hr), 85% H3PO4/water (129.8 g/960 mL) was added followed by isopropyl acetate (960 mL). After agitation and settling, the layers were separated and the organic layer washed with 85% HsPCVwater (43.27 g/48 mL). After agitation and settling, the aqueous layer was removed and the organic layer washed with water (480 mL). After agitation and settling, the aqueous layer was removed. To the organic layer was charged water (76 mL) and methanesulfonic acid (108.2 g) and the reactor contents were heated to 60 0C for 6 hours. The reactor contents were cooled to 40 0C and a solution of potassium carbonate/water (259.34 g/1360 mL) was added slowly, agitated, and then allowed to settle prior to separation of layers. The organic layer was treated with a solution of 85% phosphoric acid/H2O (129.81 g/1360 mL). The mixture was agitated, allowed to settle, and the layers were separated. The aqueous layer was washed with isopropyl acetate (2 x 1120 mL) and the layers were separated. A solution of potassium carbonate/water (259.34 g/480 mL) was added slowly to the aqueous layer. Isopropyl acetate (1360 mL) was charged; the mixture was agitated and then allowed to settle. The aqueous layer was removed and the organic layer was washed with water (480 mL) and the layers were separated. The organic later was filtered through a medium glass frit and the lines/filter were rinsed with 220 mL i-PrOAc. The organic layer was concentrated by distillation to approximately 550-750 mL volume. This solution was heated at 80 0C and heptane (640 mL) was added over one hour. NBI-54048 crystalline seeds (2.0 g) were charged after approximately one third of the heptane charge was complete. After heptane addition the mixture was maintained at 80 0C for 2 hr, then cooled to 10 0C over 180 min. The mixture was filtered to provide a solid that was dried under vacuum at 50-60 0C overnight. 3-((R)-2-amino-2-phenyl-ethyl)-5-(2- fluoro-3 -methoxy-phenyl)- 1 -(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl- 1 H- pyrimidine-2,4-dione Ie (170.9 g, 84% yield) was obtained as a white solid. LCMS (ESI) m/z 546.2 (MH+)
	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 7h;	18 Example 18 (R) -3- (2-amino-2-phenylethyl) -5- (2-fluoro-3-methoxy-phenyl) -1- (2-fluoro-6-trifluoromethyl- Benzyl) -6-methylpyrimidine-2,4 (1H, 3H) -dionePreparation of E9 Into a 100ml reaction flask, add 1g of E8, 1.1g of (R) -2-phenyl 2-tert-butoxycarbonylaminoethyl methanesulfonate, 2g of potassium carbonate, and 25ml of DMF, and react at 100 ° C for 7h.After the reaction, isopropyl acetate and water were added to separate the layers. The organic phase was dried over anhydrous sodium sulfate.Filter, add 0.5 g of methanesulfonic acid to the filtrate, stir at 60 ° C for 2 h, add water,The liquid phase was separated, and the aqueous phase was adjusted to basic pH with an aqueous solution of potassium carbonate, and extracted with isopropyl acetate.The organic phase is dried and concentrated.Get E9 crude 1g(Yield 78.12%).

With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 7h;

13 Example 13 (R) -3- (2-amino-2-phenylethyl) -5- (2-fluoro-3-methoxy-phenyl) -1- (2-fluoro-6-trifluoro (Methyl-benzyl) -6-methylpyrimidine-2,4 (1H, 3H) -dione E9 Add 1g of E8, 1.1g of (R) -2-phenyl-2-tert-butoxycarbonylaminoethyl methanesulfonate, 2g of potassium carbonate and 25ml of DMF into a 250ml three-necked flask. After reacting at 100 ° C for 7h, add isopropyl acetate After separating with water and separating the organic phase, the organic phase was dried, filtered, 0.5 g of methanesulfonic acid was added to the filtrate, and the mixture was stirred at 60 ° C for 2 h. Water was added and the liquid was separated. The aqueous phase was adjusted to basic pH with an aqueous potassium carbonate solution, and isopropyl acetate was used. After extraction, the organic phase was dried and concentrated to obtain 1 g of crude E9 (yield: 78.12%).

Reference： [1]Current Patent Assignee: NEUROCRINE BIOSCIENCES INC - WO2009/62087, 2009, A1 Location in patent: Page/Page column 8; 11
[2]Current Patent Assignee: NEUROCRINE BIOSCIENCES INC - WO2009/62087, 2009, A1 Location in patent: Page/Page column 8; 12
[3]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN110498771, 2019, A Location in patent: Paragraph 0149-0151
[4]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN110498770, 2019, A Location in patent: Paragraph 0075; 0107-0109

3
[ 830346-50-4 ]
[ 834153-87-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 52 °C 2: sodium hydroxide; lithium hydroxide monohydrate / ethanol / 35 °C
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 2: sodium hydroxide; lithium hydroxide monohydrate / ethanol / 2 h / 50 °C
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 2: sodium hydroxide; lithium hydroxide monohydrate / ethanol / 2 h / 50 °C

Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 24 h / 50 °C 2: lithium hydroxide monohydrate; sodium hydroxide / ethanol / 4 h / 25 °C

Reference： [1]Current Patent Assignee: ANDIKANG WUXI BIOLOGICAL TECH - CN108129400, 2018, A
[2]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN110498771, 2019, A
[3]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN110498770, 2019, A
[4]Current Patent Assignee: SHANGHAI MOAOHAO PHARMACEUTICAL TECH - CN114835650, 2022, A

4
[ 1150560-59-0 ]
[ 110143-62-9 ]
[ 830346-50-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate; In N,N-dimethyl-formamide; at 55℃;	19.7g (S) -Boc- phenylglycinol mesylate,16.5 g 5-(2-Fluoro-3-methoxy-phenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-( 1H,3H)-dione,Potassium carbonate 13.4 g, 100 ml DMF was added to the reaction flask.The temperature was raised to 55 C, and after completion of the reaction, the mixture was cooled to 20 C, and 150 ml of ethyl acetate was added to separate the layers, and the ester layer was left and washed with water.The organic layer was placed in a reaction flask, 11.2 g of methanesulfonic acid was added, and the reaction mixture was warmed to 60 C and stirred for 2 hr.The reaction solution was cooled to room temperature, and an aqueous potassium carbonate solution was added thereto to adjust the pH, and the layers were stood still. The ester layer was spun to near dryness, cyclohexane was added over 1 hr, and the slurry was refluxed.Filtered to a white solid with a yield of 88%.

Reference： [1]Patent: CN108129400,2018,A .Location in patent: Paragraph 0037; 0043; 0044

5
[ 1150560-54-5 ]
[ 830346-50-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium hydroxide; tri tert-butylphosphoniumtetrafluoroborate / acetone; water / 0.83 h / 15 - 45 °C 2: potassium carbonate / N,N-dimethyl-formamide / 55 °C
	Multi-step reaction with 4 steps 1: zinc; methanesulfonic acid / N,N-dimethyl-formamide / 1 h / 10 - 70 °C / Inert atmosphere 2: tris-(o-tolyl)phosphine; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / N,N-dimethyl-formamide / 1 h / 50 - 60 °C / Inert atmosphere 3: potassium carbonate / acetonitrile / 6 h / 60 - 70 °C / Inert atmosphere 4: palladium 10% on activated carbon; ammonium formate / methanol / 6 h / 20 °C
	Multi-step reaction with 4 steps 1: zinc; methanesulfonic acid / N,N-dimethyl-formamide / 1 h / 10 - 70 °C / Inert atmosphere 2: tris-(o-tolyl)phosphine; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / N,N-dimethyl acetamide / 3 h / 60 - 70 °C / Inert atmosphere 3: potassium carbonate / acetonitrile / 6 h / 60 - 70 °C / Inert atmosphere 4: palladium 10% on activated carbon; ammonium formate / methanol / 6 h / 20 °C

	Multi-step reaction with 2 steps 1.1: potassium hydroxide; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / acetone; water / 2.5 h / 40 - 45 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 55 °C 2.2: 1 h / 20 °C
	Multi-step reaction with 2 steps 1.1: potassium hydroxide; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / acetone; water / 2.5 h / 40 - 45 °C 2.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 2 h / 20 °C 2.2: 1 h / 20 °C
	Multi-step reaction with 2 steps 1.1: potassium hydroxide; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / acetone; water / 2.5 h / 40 - 45 °C 2.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 2 h / 20 °C 2.2: 1 h / 60 °C

Reference： [1]Current Patent Assignee: ANDIKANG WUXI BIOLOGICAL TECH - CN108129400, 2018, A
[2]Current Patent Assignee: LIVZON PHARMACEUTICAL GROUP INC. - CN110437159, 2019, A
[3]Current Patent Assignee: LIVZON PHARMACEUTICAL GROUP INC. - CN110437159, 2019, A
[4]Current Patent Assignee: SCINOPHARM TAIWAN, LTD. - US2021/78956, 2021, A1
[5]Current Patent Assignee: SCINOPHARM TAIWAN, LTD. - US2021/78956, 2021, A1
[6]Current Patent Assignee: SCINOPHARM TAIWAN, LTD. - US2021/78956, 2021, A1

6
[ 352303-67-4 ]
[ 830346-50-4 ]

Reference： [1]Patent: CN108129400,2018,A
[2]Patent: CN110498771,2019,A
[3]Patent: CN110498771,2019,A
[4]Patent: CN110498771,2019,A
[5]Patent: CN110498771,2019,A

7
[ 1150560-59-0 ]
[ 830346-50-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 20 °C 2: palladium 10% on activated carbon; hydrogen / water; methanol / 5 h
	Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 6 h / 60 - 70 °C / Inert atmosphere 2: palladium 10% on activated carbon; ammonium formate / methanol / 6 h / 20 °C
	Multi-step reaction with 2 steps 1: N,N,N',N'-tetramethylguanidine / N,N-dimethyl-formamide / 36.25 h / 25 - 45 °C 2: methanesulfonic acid / water / 4 h / 25 - 45 °C

Reference： [1]Current Patent Assignee: LUPIN LIMITED - WO2018/198086, 2018, A1
[2]Current Patent Assignee: LIVZON PHARMACEUTICAL GROUP INC. - CN110437159, 2019, A
[3]Current Patent Assignee: NEULAND LABORATORIES LTD - WO2021/64561, 2021, A1

8
[ 830346-47-9 ]
[ 830346-50-4 ]

Reference： [1]Patent: WO2018/198086,2018,A1
[2]Patent: WO2019/115019,2019,A1

9
[ 830346-48-0 ]
[ 830346-50-4 ]

Reference： [1]Patent: WO2018/198086,2018,A1
[2]Patent: CN110437159,2019,A
[3]Patent: WO2020/194115,2020,A1
[4]Patent: WO2020/194115,2020,A1
[5]Patent: WO2021/64561,2021,A1
[6]Patent: WO2021/130776,2021,A1

10
[ 830346-50-4 ]
[ 692-29-5 ]
[ 834153-87-6 ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 25℃; for 18h;	1; 2; 3; 4; 5; 6 Example 1 In the reactor, 1.0 g, 1.0 equiv. as shown in Formula II(R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione is dissolved in 10 mL of dichloromethane.To this was added 1.2 equiv. of 4-oxobutyric acid, 1.0 equiv. acetic acid and 3.0 equiv. of sodium triacetoxyborohydride as shown in Formula V, and the reaction was stirred at 25 ° C for 18 h;After completion of the reaction, the reaction solution was washed successively with a 1M aqueous solution of hydrochloric acid and brine, and then dried over sodium sulfate, and the solvent was evaporated to dryness, and finally, to the residue of 0.65 equiv. Elagolix as shown in Formula I, in a yield of 65% .High-resolution mass spectrometry (ESI-) was used to detect the value of 630.2039; the high resolution mass spectrum of M-H+ was calculated to be 630.2033, and the product structure was confirmed by comparison.

Reference： [1]Current Patent Assignee: ANHUI NATURE PHARMACEUTICAL - CN109651265, 2019, A Location in patent: Paragraph 0023-0035

11
[ 134364-69-5 ]
[ 830346-50-4 ]

Reference： [1]Patent: CN109956906,2019,A

12
[ 830346-50-4 ]
[ 14273-85-9 ]
sodium 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-[(2R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-2,4(1H,3H)-pyrimidinedione trifluoroacetate; methyl 4-iodobutanoate With N-ethyl-N,N-diisopropylamine In acetone at 50 - 60℃; for 10h; Inert atmosphere; Stage #2: With ethanol; sodium hydroxide at 30 - 40℃; for 4h; Inert atmosphere;	1.1.6-1.1.7; 2.6-2.7; 3.6-3.7 Preparation of compound 9 from compound 7 6) In a 250mL three-neck flask, add 45mL of acetone, compound 7 (9.0g, 16.50mmoL), methyl 4-iodobutyrate (4.5g, 19.80mmoL), N, N-diisopropylethylamine (4.3g, 33.0 mmoL), replaced with nitrogen three times, heated to 50-60 ° C. under nitrogen protection, and maintained for 10 h. The progress of the reaction was monitored by HPLC. After the reaction was completed, the temperature was lowered to 30-40 ° C, and 180 mL of water was added dropwise to precipitate a solid; the temperature was maintained at 20-30 ° C for 1 hour, and the mixture was filtered and washed to obtain a wet compound 8.; 7) Add 250 mL of ethanol, 45 mL of compound 8 to a 250 mL three-necked flask, 10 mL of 4N sodium hydroxide solution, heat up to 30-40 ° C under nitrogen protection, and hold for 4 h. Monitor the progress of the reaction by HPLC. After the reaction is completed, the solution is concentrated to a small volume, water is added, and a hydrochloric acid solution is added dropwise to adjust the pH to 5.5-6.0. A solid is precipitated, stirred, and filtered to obtain an off-white wet product. The wet product was dissolved by stirring in 2N sodium hydroxide solution, extracted once with dichloromethane, ethanol was added dropwise to the aqueous phase, the temperature was lowered to 0 ± 5 ° C, the temperature was maintained for 10 hours, and the filter was dried to obtain 9.5 g of a white powder with a target product purity of 99.4% (Figure 1) The yield is 88%.

Reference： [1]Current Patent Assignee: LIVZON PHARMACEUTICAL GROUP INC. - CN110437159, 2019, A Location in patent: Paragraph 0097; 0110-0114; 0125; 0135-0139; 0149-0152; 0188

13
[ 830346-50-4 ]
[ 7425-53-8 ]
[ 832720-84-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 50 - 60℃; for 12h;Inert atmosphere;	In a 250 mL three-necked flask, add 30 mL of acetonitrile, compound 5 (6.0 g, 11.00 mmoL),Ethyl 4-iodobutyrate (3.2g, 13.20mmoL), anhydrous potassium carbonate (2.3g, 16.5mmoL), replaced with nitrogen three times, heated to 50-60 C under nitrogen protection, and maintained for 12h.The progress of the reaction was monitored by HPLC. After the reaction was completed, the temperature was lowered to 30-40 C.120 mL of water was added dropwise to precipitate a solid, which was maintained at 20-30 C for 1 hour, filtered and washed with water.Compound 6 was obtained as a wet product;

Reference： [1]Patent: CN110372608,2019,A .Location in patent: Paragraph 0071; 0080-0082

14
[ 295376-21-5 ]
[ 830346-50-4 ]

Reference： [1]Patent: CN110372608,2019,A

15
[ 239087-06-0 ]
[ 830346-50-4 ]

Reference： [1]Patent: CN110498771,2019,A
[2]Patent: CN110498771,2019,A
[3]Patent: CN110498771,2019,A
[4]Patent: CN110498771,2019,A
[5]Patent: CN110498770,2019,A
[6]Patent: CN110498770,2019,A
[7]Patent: CN110498770,2019,A
[8]Patent: CN110498770,2019,A

16
[ 60611-24-7 ]
[ 830346-50-4 ]

17
[ 830346-46-8 ]
[ 830346-50-4 ]

18
[ 1150560-59-0 ]
[ 33125-05-2 ]
[ 830346-50-4 ]

Yield	Reaction Conditions	Operation in experiment
39%	Stage #1: 5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-6-methylpyrimidine-2,4(1H,3H)-dione; Boc-D-Phg-OH With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20 - 30℃; Stage #2: With hydrogenchloride In tetrahydrofuran at 50 - 60℃;	11 Example 11 In a three-necked flask, compound X (1.0 g, 2.4 mmol) was added.N- (tert-butoxycarbonyl) -D-2-phenylethanolamine (0.67 g, 2.8 mmol), triphenylphosphine (0.74 g, 2.8 mmol) and tetrahydrofuran (50 ml).Control temperature 20 30 ,Diisopropyl azodicarboxylate (0.71 g, 3.5 mmol) was added dropwise. After the reaction is complete,Further concentrated hydrochloric acid (1 mL) was added.After stirring the reaction at 50-60 ° C to complete,Concentrate to remove tetrahydrofuran.To the residue were added isopropyl acetate and an aqueous sodium hydroxide solution, and the mixture was separated after stirring. The organic phase was concentrated and separated by column chromatography (ethyl acetate: n-hexane = 20% to 100%) to obtain Compound I (0.5 g, 39%).

Reference： [1]Current Patent Assignee: SHANGHAI VASTPRO TECH DEVELOPMENT - CN110759870, 2020, A Location in patent: Paragraph 0078; 0084; 0119; 0140-0141

19
[ 1150560-59-0 ]
(R)-N-benzylidene-2-hydroxy-1-phenylethylamine [ No CAS ]
[ 830346-50-4 ]

Yield	Reaction Conditions	Operation in experiment
92.2%	Stage #1: 5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-6-methylpyrimidine-2,4(1H,3H)-dione; (R)-N-benzylidene-2-hydroxy-1-phenylethylamine With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2h; Stage #2: With hydrogenchloride; water In toluene at 20℃; for 1h;	3 Example 3: Preparation of the Compound of Formula VII To a suitable reactor, the compound of formula V (5.00 g), N-benzylidene-D-phenylglycinol (4.63 g), PPh3 (6.15 g) and THF (75 mL) were added, followed by addition of DIAD (4.74 g). The reaction was stirred at room temperature for 2 hours. Upon completion, the reaction was quenched with water (10 mL) and then stirred for 10 min. The resulting mixture concentrated via solvent-swap with toluene (30 mL) to 6 vol. 3N HCl (11.7 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. Upon completion, MeOH (30 mL) was added. The solution was washed with n-heptane (30 mL) for three times, followed by concentration via solvent-swap with toluene to 6 vol. The solution was neutralized with K2CO3 (8.12 g) in water (42.5 mL). The aqueous layer was extracted with toluene (25 mL). The combined organic layers were extracted with 10% H3PO4 (50 mL) twice. The aqueous layer was washed with IPAc (50 mL) twice. The aqueous layer was neutralized with K2CO3 (16.28 g) in water (25 mL). The resulting solution was extracted with IPAc (42.5 mL). The organic layer was washed with water (15 mL) and then recrystallized with IPAc/n-heptane to give the compound of formula VII (5.89 g, 92.2% yield).

Reference： [1]Current Patent Assignee: SCINOPHARM TAIWAN, LTD. - US2021/78956, 2021, A1 Location in patent: Paragraph 0121; 0122

20
[ 1150560-59-0 ]
[ 245443-16-7 ]
[ 830346-50-4 ]

Yield	Reaction Conditions	Operation in experiment
89.9%	Stage #1: 5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-6-methylpyrimidine-2,4(1H,3H)-dione; N-isopropylidene-D-phenylglycinol With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2h; Stage #2: With methanesulfonic acid; water In toluene at 60℃; for 1h;	4 Example 4: Preparation of the Compound of Formula VII To a suitable reactor, the compound of formula V (3.00 g), N-isopropylidene-D-phenylglycinol (2.54 g), PPh3 (3.69 g) and THF (45 mL) were added, followed by addition of DIAD (2.90 g). The reaction was stirred at room temperature for 2 hours. Upon completion, the reaction was quenched with water (6 mL) and then stirred for 10 min. The resulting mixture concentrated via solvent-swap with toluene (18 mL) to 6 vol. MsOH (0.91 mL) was added. The resulting mixture was stirred at 60° C. for 1 hour. Upon completion, K2CO3 (3.89 g) in water (25.5 mL) was added at NMT 30° C. Toluene (15 mL) was added to the mixture for phase separation. The aqueous layer was extracted with toluene (15 mL). The combined organic layers were extracted with 10% H3PO4 (30 mL) twice. The combined aqueous layer was washed with IPAc (30 mL) twice. The aqueous layer was neutralized with K2CO3 (9.76 g) in water (15 mL). The resulting solution was extracted with IPAc (25.5 mL). The organic layer was washed with water (9 mL) and then recrystallized with IPAc/n-heptane to give the compound of formula VII (3.45 g, 89.9% yield).

Reference： [1]Current Patent Assignee: SCINOPHARM TAIWAN, LTD. - US2021/78956, 2021, A1 Location in patent: Paragraph 0123; 0124

21
[ 1150560-59-0 ]
[(2R)-2-[(E)-benzylideneamino]-2-phenyl-ethyl] methanesulfonate [ No CAS ]
[ 830346-50-4 ]

Yield	Reaction Conditions	Operation in experiment
84.1%	Stage #1: 5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-6-methylpyrimidine-2,4(1H,3H)-dione; [(2R)-2-[(E)-benzylideneamino]-2-phenyl-ethyl] methanesulfonate With potassium carbonate In N,N-dimethyl-formamide at 55℃; Stage #2: With hydrogenchloride; water In Isopropyl acetate at 20℃; for 1h;	5 Example 5: Preparation of the Compound of Formula VII To a suitable reactor, the compound of formula V (3.00 g), [(2R)-2-[(E)-benzylideneamino]-2-phenyl-ethyl] methanesulfonate (3.44 g), K2CO3 (2.43 g) and DMF (20 mL) were added. The reaction was stirred at 55° C. Upon completion, IPAc (24 mL) and water (28.5 mL) were charged to the reactor. The organic layer was washed with water (16 mL). 3N HCl (0.78 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. Upon completion, MeOH (18 mL) was added. The solution was washed with n-heptane (18 mL) for three times, followed by concentration via solvent-swap with toluene to 6 vol. The solution was neutralized with K2CO3 (4.87 g) in water (25.5 mL). The aqueous layer was extracted with toluene (15 mL). The combined organic layers were extracted with 10% H3PO4 (30 mL) twice. The aqueous layer was washed with IPAc (30 mL) twice. The aqueous layer was neutralized with K2CO3 (9.77 g) in water (15 mL). The resulting solution was extracted with IPAc (25.5 mL). The organic layer was washed with water (9 mL) and then recrystallized with IPAc/n-heptane to give the compound of formula VII (3.23 g, 84.1% yield).

Reference： [1]Current Patent Assignee: SCINOPHARM TAIWAN, LTD. - US2021/78956, 2021, A1 Location in patent: Paragraph 0125; 0126

22
[ 830346-50-4 ]
[ 147-71-7 ]
C₂₈H₂₄F₅N₃O₃*C₄H₆O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In ethanol at 40℃;	2-8 Example 2 Take an appropriate amount of the crude compound of formula II prepared in Example 1, add 8 times the volume to mass ratio of ethanol, stir to dissolve at 25°C, and add the acids shown in Table 1 (1 times equivalent to the crude formula II), 40°C Stir and crystallize at ; the results show that only in the presence of L-tartaric acid, it can precipitate as a salt solid, the molar yield is 85%

Reference： [1]Current Patent Assignee: CHENGDU BRILLIANT PHARMACEUTICAL CO LTD - CN112694445, 2021, A Location in patent: Paragraph 0024-0058

23
[ 830346-50-4 ]
[ 2969-81-5 ]
[ 834153-87-6 ]

Yield	Reaction Conditions	Operation in experiment
98.6%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 16h;	17 he present embodiment provides a preparation method of Elagoli The purified intermediate 2 (50 g, 92 mmol) obtained in Example 12 was dissolved in 200 mL of DMF, and ethyl 4-bromobutyrate (28.6 g, 147 mmol) and N,N-diisopropylethylamine (35.6 g) were added. g, 276 mmol), warmed to 60 °C, heated overnight for approximately 16 h until HPLC showed intermediate 2≤4%.stop the reaction;400 mL of isopropyl acetate and 400 mL of water were added to the reaction solution, stirred, separated into layers, and washed twice with water; the organic phase was washed twice with a 10% aqueous phosphoric acid solution (200 ml × 2); washed once with a 10% aqueous potassium carbonate solution, and saturated chlorine Washed with sodium chloride, dried over anhydrous sodium sulfate, the organic phase obtained 52.4 g of yellow oil, with a yield of 86.3%.The above oil was dissolved in 250 mL of ethanol, then 40% NaOH aqueous solution (3.8 g, 96 mmol) was added, and the reaction was completed at room temperature (about 1.5 h); the ethanol was removed by concentration, and 200 mL of water and 200 mL of butanone were added to the concentrated solution to warm up to 55°C, continue to stir for 0.5h, and discard the organic phase; add 200 mL of ethyl acetate and 10 mL of saturated 48% NaOH aqueous solution to the aqueous phase, stir and react for 0.5 h, and discard the aqueous phase; the organic phase is washed with brine, without It was dried over sodium sulfate and concentrated to obtain 51.2 g of white solid, namely Elagoli, with a yield of 98.6%, a purity of 99.78%, and a maximum unknown impurity content of 0.06%.

Reference： [1]Current Patent Assignee: HEBEI INTELLIGENT CONSTANT MEDICINE SCIENCE AND TECH STOCK - CN114685379, 2022, A Location in patent: Paragraph 0107-0113

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P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
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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. 830346-50-4 ] {[proInfo.proName]}

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[ 830346-50-4 ] Synthesis Path-Downstream 1~23

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