105-45-3|Methyl 3-oxobutanoate| Ambeed

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

Methyl acetylacetate is an endogenous metabolite.

Synonyms: Acetoacetate methyl ester; Methyl 3-oxobutanoate; Methyl 3-oxobutyrate

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of Methyl acetylacetate Purity: 95% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of Methyl acetylacetate

CAS No. :	105-45-3
Formula :	C₅H₈O₃
M.W :	116.12
SMILES Code :	CC(CC(OC)=O)=O
Synonyms :	Acetoacetate methyl ester; Methyl 3-oxobutanoate; Methyl 3-oxobutyrate
MDL No. :	MFCD00008784
InChI Key :	WRQNANDWMGAFTP-UHFFFAOYSA-N
Pubchem ID :	7757

Safety of Methyl acetylacetate

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H319
Precautionary Statements:	P305+P351+P338

Application In Synthesis of Methyl acetylacetate

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

Upstream synthesis route of [ 105-45-3 ]
Downstream synthetic route of [ 105-45-3 ]

[ 105-45-3 ] Synthesis Path-Upstream 1~12

1
[ 105-45-3 ]
[ 81569-44-0 ]

References: [1] Journal of Medicinal and Pharmaceutical Chemistry, 1959, vol. 1, p. 577,594.
[2] Journal of the American Chemical Society, 1939, vol. 61, p. 891.

2
[ 67-56-1 ]
[ 105-45-3 ]
[ 81114-96-7 ]

References: [1] Tetrahedron, 1988, vol. 44, # 6, p. 1603 - 1608.

3
[ 35929-79-4 ]
[ 105-45-3 ]
[ 73257-49-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With ammonium hydroxide In ethanol at 110℃; Flow reactor	General procedure: Diethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (4a). EtOH solution (3 mL) ofbenzaldehyde (0.67 M) mixed with ethyl acetoacetate (1.34 M) and the 25percent aqueous NH3 (3 mL) wererespectively transferred into gas-tight syringe 1 and syringe 2. The syringes were placed in a LongerLSP02-1B syringe pump which was set to deliver the reactants into the mixer at identical flow rate of 6.7μL/min. The reaction mixture was then allowed to flow through a stainless steel tube reactor which wasdipped in a 110 C oil bath. The output mixture was collected in a cooled sample vial. After reactioncompletion, rinsed the reactor with ethanol to collect all of the reactant solution and then concentratedunder vacuum. The residue was subjected to silica gel column chromatography with Pet-EA (5:1) aseluent to give 4a (612mg, 93percent yield).

References: [1] Heterocycles, 2016, vol. 93, # 2, p. 755 - 761.

4
[ 105-45-3 ]
[ 873-76-7 ]
[ 73257-49-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	With ammonium hydroxide; hydrogen bromide; dimethyl sulfoxide In water at 75℃; for 2.53333 h;	General procedure: A mixture of HBr (48percent aq., 1 mmol) in DMSO (1 mL) was stirred for 2 min at 75 °C. Then, benzylic alcohol (1 mmol), alkyl acetoacetate (2 mmol), and ammonium hydroxide (1.5 mmol) were added to the reaction mixture and stirring was continued at 75 °C for 2.5 h. The completion of reaction was followed by TLC. After the reaction was complete, the reaction mixture was cooled to ambient temperature, quenched by addition of water (2 mL), and stirring was continued for 10 min at ambient temperature. The resulting precipitate was filtered, washed with water, dried, and recrystallized from ethanol to afford the pure product 4.

References: [1] Tetrahedron Letters, 2018, vol. 59, # 46, p. 4102 - 4106.

5
[ 631-61-8 ]
[ 104-88-1 ]
[ 105-45-3 ]
[ 73257-49-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	With iron supported on copper/Zeolite Socony Mobil-5 nanocatalyst In water at 20℃; Sonication	General procedure: In a typical experiment, aromatic aldehyde (1 mmol), bketoester(2 mmol), ammonium acetate (1 mmol), and Fe-Cu/ZSM-5 (3 wtpercent) in 2 ml water were introduced in a 20-mL heavy-walled pear-shaped two-necked flask with nonstandard-tapered outer joint. The flask was attached to a12-mm tip diameter probe, and the reaction mixture was sonicated at ambient temperature at 20 percent power of the processor. After completion of the reaction (monitored byTLC, within 5–8 min), the solid product was filtered,washed with water and ethanol, dried, and recrystallized from ethanol. The supported reagent was washed thrice with water and ethanol and dried under vacuum before reuse.

References: [1] Journal of the Iranian Chemical Society, 2016, vol. 13, # 2, p. 267 - 277.

6
[ 104-88-1 ]
[ 105-45-3 ]
[ 73257-49-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	at 80℃; for 0.3 h;	General procedure: A mixture of the alkyl or aryl aldehyde (1 mmol), -dicarbonyl(2 mmol) and ammonium acetate (1.5 mmol) in the presence ofFe3O4NPs (0.024 g, equal to 10 molpercent) was heated at 80C, withstirring. The progress of the reaction was monitored by TLC (elu-ent: EtOAc:n-hexane). After completion of the reaction, the mixturewas cooled to room temperature and then ethanol was added tothe resulting mixture and separated Fe3O4NPs by a normal mag-net. After evaporation of solvent, the solid product was filtered andrecrystallized from ethanol to give the pure products in 72–95percentyields based on the starting aldehyde.
95%	With C₂₃H₃BF₁₆N₂O; ammonium acetate In toluene at 100℃; for 10 h;	In a 100 mL single-necked flask, 0.01 molpercent of Lewis acid-base bifunctional catalyst I was added (where Rf = CF3R1,R2, R3, R4, R5, R6 = F), 0.1 mol of p-chlorobenzaldehyde (R7 = 4-Cl-Ph), 0.1 mol of methyl acetoacetate (R8 = Me;Me), 0.1 mol of ammonium acetate, 10 mL of toluene, and the reaction was stirred at 100 ° C for 10 hours. TLC followed the reaction to complete the reaction. anti-The yield of the product II (R7 = 4-Cl-Ph; R8 = Me; R9 = Me) was 95percent; the catalyst system was reused 10 timesAfter its catalytic performance did not decline
94%	for 2.25 h; Heating; Green chemistry	General procedure: A mixture of aldehyde 1 (1 mmol), 1,3-dicarbonyl compound 2 (2 mmol), and nitrogen source 3 (3 mmol) were mixed and heated in the presence of a low-melting sugar mixture.The progress of the reaction was monitored by thin-layer chromatography (TLC) using n-hexane–ethyl acetate (7:3) as the solvent system. The Rf values of the product spots ranged from 0.5 to 0.6. After completion of the reaction, water was added to the reaction mixture to obtain the solid product as a precipitate. In cases where the product was obtained as a melt, several washings with water followed by bicarbonate solution gave crystalline products. The solids were filtered and washed with cold water. In most of the cases, the product obtained was pure, and when impure, the product was recrystallized from hot ethanol. Further two products were obtained as oils (Table 5, entries 4w and 4x). These products were extracted with ethyl acetate and dried over anhydrous Na2SO4. Evaporation of the solvent gave the pure product as an oil.

91%	at 100℃; for 0.25 h; Green chemistry	General procedure: To a glassy reactor equipped with a magnetic stir bar, amixture of aromatic aldehyde (1.0 mmol), β-keto ester(2 mmol), ammonium acetate (1.5 mmol) and n-Fe₃O₄(at)ZrO₂/HPW (0.003 g, 15 mol percent) was added. The reactorwas put in an oil bath with the temperature of 100 °C andthe reaction was carried out under solvent-free condition.The progress of the reaction was monitored using TLCplates. When the reaction was completed, the mixture wasallowed to cool to room temperature. Afterwards, the mixturewas triturated with 5mL ethyl acetate and the catalystwas separated by the help of an external magnet. Then thesolvent was evaporated and the crude product was recrystallizedfrom EtOH/H₂O to offer the pure product.
90%	With uranyl nitrate hexahydrate; ammonium acetate In ethanol at 20℃; for 0.416667 h; Sonication	General procedure: To a solution of aldehyde (1.0 mmol), ethyl/methyl acetoacetate/acetylacetone (2.0 mmol) and ammonium acetate (1.0 mmol) in ethanol (3 mL), uranyl nitrate (10 molpercent) was added and the resultant reaction mixture was sonicated at room temperature for the required time (Table 1). The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was poured into crushed ice. The obtained solid was filtered, washed thoroughly with water, dried, and purified by recrystallisation in ethanol.

References: [1] RSC Advances, 2014, vol. 4, # 100, p. 56658 - 56664.
[2] Tetrahedron Letters, 2010, vol. 51, # 8, p. 1187 - 1189.
[3] Advanced Synthesis and Catalysis, 2012, vol. 354, # 10, p. 2001 - 2008.
[4] Journal of Molecular Catalysis A: Chemical, 2014, vol. 382, p. 99 - 105.
[5] Patent: CN107141249, 2017, A, . Location in patent: Paragraph 0114; 0115.
[6] Synthetic Communications, 2016, vol. 46, # 24, p. 1989 - 1998.
[7] RSC Advances, 2014, vol. 4, # 21, p. 10514 - 10518.
[8] Journal of the Indian Chemical Society, 2009, vol. 86, # 9, p. 996 - 1000.
[9] New Journal of Chemistry, 2018, vol. 42, # 15, p. 12539 - 12548.
[10] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 3, p. 737 - 739.
[11] Catalysis Letters, 2017, vol. 147, # 6, p. 1551 - 1566.
[12] Chemical Communications, 2011, vol. 47, # 32, p. 9230 - 9232.
[13] Research on Chemical Intermediates, 2015, vol. 41, # 9, p. 6877 - 6883.
[14] Journal of the Chinese Chemical Society, 2016, vol. 63, # 4, p. 336 - 344.
[15] Synthesis, 2007, # 18, p. 2835 - 2838.
[16] Organic Preparations and Procedures International, 2012, vol. 44, # 2, p. 153 - 158.
[17] Synthetic Communications, 2004, vol. 34, # 23, p. 4349 - 4357.
[18] Synthetic Communications, 2009, vol. 39, # 11, p. 1957 - 1965.

7
[ 104-88-1 ]
[ 14205-39-1 ]
[ 105-45-3 ]
[ 73257-49-5 ]

References: [1] Tetrahedron Letters, 1995, vol. 36, # 44, p. 8083 - 8086.

8
[ 104-88-1 ]
[ 105-45-3 ]
[ 14205-39-1 ]
[ 73257-49-5 ]

References: [1] Organic Process Research and Development, 2001, vol. 5, # 4, p. 452 - 455.

9
[ 104-88-1 ]
[ 105-45-3 ]
[ 73257-49-5 ]

References: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 7, p. 652 - 653.

10
[ 504-29-0 ]
[ 105-45-3 ]
[ 943112-78-5 ]

References: [1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 3, p. 364 - 369.
[2] Organic Letters, 2016, vol. 18, # 5, p. 1016 - 1019.
[3] Catalysis Science and Technology, 2019, vol. 9, # 6, p. 1528 - 1534.
[4] Chemical Communications, 2011, vol. 47, # 40, p. 11333 - 11335.
[5] Synthesis, 2011, # 15, p. 2445 - 2453.
[6] Journal of Organic Chemistry, 2016, vol. 81, # 19, p. 9167 - 9174.

11
[ 504-29-0 ]
[ 105-45-3 ]
[ 5231-96-9 ]
[ 943112-78-5 ]

References: [1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 3, p. 364 - 369.

12
[ 105-45-3 ]
[ 943112-78-5 ]

References: [1] Tetrahedron Letters, 2017, vol. 58, # 37, p. 3662 - 3666.

[ 105-45-3 ] Synthesis Path-Downstream 1~35

1
[ 101166-65-8 ]
[ 105-45-3 ]
[ 116585-05-8 ]

Yield	Reaction Conditions	Operation in experiment
77%		A solution of TBSCl (30.1 g, 200 mmol) in DCM (50 mL) was added dropwise over 15 min to a stirred solution of 2-chloroethanol (16.0 g, 200 mmol), imidazole (20.4 g, 300 mmol) and DMAP (0.244 g, 2.0 mmol) in DCM (200 mL) at 0 °C under an argon atmosphere, and the resulting mixture was warmed to room temperature where it was stirred for 12 h. The mixture was quenched with saturated aqueous NH4Cl (200 mL) and the separated aqueous layer was then washed with DCM (2*100 mL). The combined organic extracts were washed with saturated aqueous NH4Cl (100 mL) and brine (100 mL), then dried over MgSO4 and concentrated to leave 2-chloroethoxy tert-butyl dimethylsilane (37.1 g, 95percent) as a colourless oil. A solution of the silyl ether (3.88g, 20.0mmol) and sodium iodide (8.94g, 60 mmol) in acetone (10mL) was sealed in a microwave vial and heated at 120°C for 4h in a microwave reactor. The vial was cooled to room temperature and the reaction mixture was then diluted with diethyl ether (80mL) and filtered through silica. The filtrate was concentrated to leave 2-iodoethoxy tert-butyl dimethylsilane (5.72g, quant.) as a pale yellow oil, which was used without further purification. A solution of methyl acetoacetate (2.55g, 22.0mmol) in 79 THF (10mL) was added over 10 min to a stirred suspension of sodium hydride (0.88g, 22.0 mmol, 60percent) in THF (50mL) at 0°C under argon. The mixture was stirred for 15 min, and then a solution of n-butyl lithium (11.0 mL, 22.0 mmol, 2.0M in hexane) was added dropwise over 10 min and the mixture was stirred at 0°C for 15 min. A solution of the above, crude iodide (ca. 20 mmol) in THF (10 mL) was added dropwise over 10 min, and the resulting yellow mixture was then warmed to room temperature where it was stirred for 12 h. The mixture was quenched with saturated aqueous NH4Cl (100 mL) and diethyl ether (100mL), and the separated aqueous layer was then washed with diethyl ether (2×100mL). The combined organic extracts were washed with brine (100 mL), then dried over MgSO4 and concentrated to leave a pale yellow gum. Purification by column chromatography (25:1, petrol/Et2O) gave the keto ester (5.05 g, 77percent) as a pale yellow oil (10percent enol form): deltaH (400 MHz, CDCl3) 3.73 (3H, s, CO2CH3), 3.61 (2H, t, J=6.0, CH2O), 3.46 (2H, s, CH2), 2.62 (2H, t, J=7.1, CH2C(O)), 1.80 (2H, tt, J=6.0, 7.1, CH2), 0.87 (9H, s, SiC(CH3)3), 0.03 (6H, s, SiCH3); deltaC (100 MHz, CDCl3) 202.6 (C=O), 167.6 (CO2CH3), 61.8 (CH2O), 52.2 (CO2CH3), 49.0 (CH2), 39.4 (CH2), 26.5 (CH2), 25.9 (SiC(CH3)3), 18.2 (SiC(CH3)3), ?5.4 (2×SiCH3); HRMS m/z C13H26O4SiNa+ (MNa+) requires 297.1498, found 297.1498.

References: [1]Tetrahedron,2014,vol. 70,p. 7229 - 7240.
[2]Journal of the Chemical Society. Perkin transactions I,1988,p. 1417 - 1424.

2
[ 5779-93-1 ]
[ 105-45-3 ]
[ 75-05-8 ]
2-[acetylamino-(2,3-dimethyl-phenyl)-methyl]-3-oxo-butyric acid methyl ester [ No CAS ]

References: [1]Tetrahedron Letters,2005,vol. 46,p. 2137 - 2140.

3
[ 1454-85-9 ]
[ 105-45-3 ]
[ 57582-42-0 ]

References: [1]Synthesis,2007,p. 61 - 64.

4
[ 615-43-0 ]
[ 105-45-3 ]
[ 65417-22-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	With copper(l) iodide; 1H-tetrazol-1-ylacetic acid; caesium carbonate; In dimethyl sulfoxide; at 80℃; for 12h;Sealed tube;	General procedure: To a 10mL sealed tube was added CuI (0.05mmol), L4 (0.1mmol), ortho-iodo/bromoaniline (0.5mmol), beta-keto ester/beta-diketone (3.0mmol), Cs2CO3 (1.0mmol), and DMSO (1mL). The reaction mixture was reacted at 80C in a preheated oil bath for 12h (for ortho-iodoanilines) or 36h (for ortho-bromoanilines). The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×20mL). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatograph on silica gel (ethyl acetate/petroleum ether as the eluent) to afford the target products 3a-3s.
85%	With cetyltrimethylammonim bromide; potassium carbonate; In water; at 50℃; for 3h;Green chemistry;Catalytic behavior;	A mixture of the appropriate 1,3-dicarbonyl compound 3 (1.1equiv), 2-iodoaniline (1 equiv), CTAB (10 mol%), K2CO3 (1equiv), and magnetic catalyst (20 mg) in H2O (4 mL) was stirredat 50 C for 3 h then cooled to r.t. The catalyst was removed byusing an external magnet, and the solution was extracted withEtOAc (3 × 10 mL). The extracts were dried (MgSO4), filtered,and concentrated under vacuum to give a crude product thatwas purified by column chromatography.Methyl 2-Methyl-1H-indole-3-carboxylate (4a)Beige solid; yield: 160 mg (85%); mp 164-166 C. IR (KBr):3016, 1690, 1449, 1209, 10905 cm-1. 1H NMR (400 MHz, CDCl3):delta = 2.72 (s, 3 H), 3.93 (s, 3 H), 7.16-7.30 (m, 3 H), 8.08 (d, J= 7.7Hz, 1 H), 8.67 (br s, 1 H). 13C NMR (100 MHz, CDCl3): delta = 14.2,50.8, 104.3, 110.4, 121.2, 121.7, 122.3, 127.2, 134.5, 144.2,166.7.

References: [1]Tetrahedron,2016,vol. 72,p. 653 - 657.
[2]Synlett,2016,vol. 27,p. 1665 - 1668.
[3]Synlett,2011,p. 623 - 626.
[4]European Journal of Organic Chemistry,2007,p. 3977 - 3980.
[5]Research on Chemical Intermediates,2014,vol. 40,p. 2157 - 2164.

5
[ 105-45-3 ]
[ 65417-22-3 ]

References: [1]Synthesis,1990,p. 215 - 218.
[2]ACS Catalysis,2015,vol. 5,p. 4751 - 4755.
[3]Organic and Biomolecular Chemistry,2017,vol. 15,p. 8054 - 8058.
[4]Organic Letters,2020,vol. 22,p. 3397 - 3401.

6
[ 110-89-4 ]
[ 83279-38-3 ]
[ 105-45-3 ]
methyl 2-acetyl-3-(3-chloro-4-trifluoromethylphenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; acetic acid;	EXAMPLE 1 Methyl 2-acetyl-3-(3-chloro-4-trifluoromethylphenyl)acrylate STR48 32.3 g (155 mol) of <strong>[83279-38-3]3-chloro-4-trifluoromethylbenzaldehyde</strong> and 18.0 g (155 mmol) of methyl acetoacetate are dissolved in 200 ml of methylene chloride, and 1.2 ml of piperidine and 1 ml of glacial acetic acid are added. The mixture is heated for 5 hours, using a water separator. It is then washed with water, dried over MgSO4 and concentrated. The product is recrystallized twice from methanol. 25.6 g (54percent of theory) of the title compound are obtained.

References: [1]Patent: US5652251,1997,A .

7
[ 57297-29-7 ]
[ 105-45-3 ]
[ 7043-10-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium methylate; In methanol; water;	(a) The 2-cyclopropyl-4-hydroxy-6-methylpyrimidine to be employed as a starting material could be prepared, for example, as follows: STR6 78.3 g (0.65 mol) of cyclopropylamidine hydrochloride and then 76.4 g (0.65 mol) of acetoacetic acid methyl ester were added to a solution of 70 g (1.3 mol) of sodium methylate in 400 ml of methanol at room temperature. The mixture was stirred at room temperature for 18 hours, the solvent was then distilled off in vacuo and the residue was dissolved in 400 ml of water. The solution was adjusted to pH 4 by adding concentrated hydrochloric acid and, after cooling to 5°-10° C., the product which had precipitated was filtered off. 75 g (77percent of theory) of 2-cyclopropyl-4-hydroxy-6-methylpyrimidine were obtained in this manner in the form of a colorless powder with the melting point 187° C. STR7
	With sodium methylate; In methanol; at 20℃; for 18h;	2-Cyclopropyl-6-methylpyrimidin-4-ol (B8.1) (0372) A mixture of <strong>[57297-29-7]cyclopropane-carboximidamide hydrochloride</strong> (2.0 g, 16.7 mmol), methyl 3-oxobutanoate (1.9 g, 16.7 mmol) and CH3ONa (1.8 g, 33.4 mmol) in MeOH (200 mL) was stirred at rt for 18 h. Then the mixture was diluted with Sat. Na2SO3 (50 mL), then concentrated under reduced pressure. The residue was dissolved in 50 mL water, adjusted pH to 4. After cooling to 5° C., the solid was collected and dried in vacuum to give the title compound (2.0 g, 98percent) as a yellow solid. The crude product was used in the next step without further purification. LC-MS: [M+H]+=151.2.
	With sodium methylate; In methanol; at 20℃; for 18h;	A mixture of cyclo propanecarboximidamide hydrochloride (2.0 g, 16.7 mmol), methyl 3-oxobutanoate (1.9 g, 16.7 mmol) and CH3ONa (1 .8 g, 33.4 mmol) in MeOH (200 mL) was stirred at rt for 18 h.Then the mixture was diluted with Sat. Na2503 (50 mL), then concentrated under reduced pressure. The residue was dissolved in 50 mL water, adjusted pH to 4. After cooling to 5°C, the solid was collected and dried in vaccum to give the title compound (2.0 g, 98percent) as a yellow solid. The crude product was used in the next step without further purification. LC-MS: [M+H] = 151.2.

References: [1]Patent: US4254113,1981,A .
[2]Patent: US2016/176882,2016,A1 .Location in patent: Paragraph 0371; 0372.
[3]Patent: WO2017/221100,2017,A1 .Location in patent: Paragraph 00177.

8
ethyl aminocrotonate [ No CAS ]
[ 105-45-3 ]
[ 6334-18-5 ]
[ 72509-76-3 ]
[ 91189-59-2 ]
[ 79925-38-5 ]

Yield	Reaction Conditions	Operation in experiment
66%		To a solution of 2,3-dichlorobenzaldehyde (8.76 g, 0.05 mol) in isopropanol (80 mL) is added picolinic acid (0.65 g, 5.4 mmol), piperidine (0.45 g, 5.4 mmol) and methyl acetoacetate (86.3 g, 0.06 mol). The solution is stirred at 40-45 C. for 6 h, and then isopropanol is distilled under vacuum. The residue is dissolved in ethyl acetate (80 mL) and washed with water (60 mL). Ethyl acetate is then removed under vacuum. To the residue is added ethyl aminocrotonate (7.74 g, 0.06 mol) and isopropanol (60 mL). The mixture is heated under reflux for 4 hours. Isopropanol is distilled and heptanes (60 mL) is added. The resulting solid is filtered and washed with heptanes. After drying 12.7 g (66%) felodipine is obtained as pale yellow solid with a purity of 94.4% (diethyl and dimethyl have a concentration of 2.02% and 3.38% (a/a), respectively).

References: [1]Patent: US2004/204604,2004,A1 .Location in patent: Page 5.

9
[ 874-42-0 ]
[ 105-45-3 ]
[ 4922-98-9 ]
[ 512838-68-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 4395 - 4398.

10
[ 103646-82-8 ]
[ 105-45-3 ]
[ 1269662-35-2 ]

References: [1]Molecules,2011,vol. 16,p. 1878 - 1887.

11
[ 105-45-3 ]
[ 615-36-1 ]
[ 65417-22-3 ]

Yield	Reaction Conditions	Operation in experiment
71%	With copper(l) iodide; 1H-tetrazol-1-ylacetic acid; caesium carbonate; In dimethyl sulfoxide; at 80℃; for 36h;Sealed tube;	General procedure: To a 10mL sealed tube was added CuI (0.05mmol), L4 (0.1mmol), ortho-iodo/bromoaniline (0.5mmol), beta-keto ester/beta-diketone (3.0mmol), Cs2CO3 (1.0mmol), and DMSO (1mL). The reaction mixture was reacted at 80C in a preheated oil bath for 12h (for ortho-iodoanilines) or 36h (for ortho-bromoanilines). The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×20mL). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatograph on silica gel (ethyl acetate/petroleum ether as the eluent) to afford the target products 3a-3s.

References: [1]Tetrahedron,2016,vol. 72,p. 653 - 657.
[2]Synlett,2011,p. 623 - 626.
[3]Organic Letters,2013,vol. 15,p. 362 - 365.

12
[ 105-45-3 ]
[ 62-53-3 ]
[ 65417-22-3 ]

References: [1]Chemistry - A European Journal,2011,vol. 17,p. 7298 - 7303.
[2]Journal of Organic Chemistry,2019,vol. 84,p. 4017 - 4024.

13
[ 105-45-3 ]
[ 191171-55-8 ]
[ 65417-22-3 ]

References: [1]Synthesis,2012,vol. 44,p. 3811 - 3814.

14
[ 13726-16-4 ]
[ 105-45-3 ]
[ 17356-08-0 ]
[ 1443743-40-5 ]

References: [1]Phosphorus, Sulfur and Silicon and the Related Elements,2013,vol. 188,p. 596 - 608.

15
[ 36193-65-4 ]
manganese(III) acetate dihydrate [ No CAS ]
[ 105-45-3 ]
methyl 2-acetoxy-2-(2-cyano-1H-indol-3-yl)-3-oxobutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With acetic acid; for 4h;Reflux;	General procedure: Cyanoindole 6 (40 mg, 0.256 mmol, 1 equiv.), Mn(OAc)3.2H2O (345 mg, 1.29 mmol, 5 equiv),and diethyl malonate (205 mg, 1.28 mmol, 5 equiv) were dissolved in aceticacid (10 mL) and heated to reflux for 2 h. After TLC indicated complete consumption of the starting indole, the reaction was poured into water (200 mL) and extracted with ethyl acetate (3 50 mL). The combined organic extracts were washed with water (3 100 mL), brine (1 100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. The product was purified via flash chromatography (silica gel, hexanes:EtOAc 4:1)to afford 15 as a white solid (90%);20

References: [1]Tetrahedron Letters,2013,vol. 54,p. 6142 - 6145.

16
[ 89891-69-0 ]
[ 1736-70-5 ]
[ 105-45-3 ]
[ 1613621-56-9 ]

Yield	Reaction Conditions	Operation in experiment
22.2 g	With Tris(trimethylsilyl) phosphate; In tetrahydrofuran; at 75℃; for 17.0h;Inert atmosphere;	3-Trifluoromethylphenylthiourea (12.8 g, 87 mmol), <strong>[89891-69-0]2-bromo-4-cyanobenzaldehyde</strong> (18.3 g, 87 mmol), and methyl acetoacetate (10.4 mL, 96 mmol) were dissolved in THF (300 mL) under an atmosphere of N2 and then trimethylsilylphosphate (18 g) in THF (50 mL) was added, and the mixture heated at 75° C. After 17 hours the reaction mixture was allowed to cool, poured onto 0.5 M HCl (600 mL) and stirred for 30 minutes. The mixture was extracted into EtOAc. The organic phase was washed with water, then brine and dried (Na2SO4) before being concentrated in vacuo. The resulting solid was triturated with Et2O (50 mL), filtered and the solid collected to yield the title compound as a white solid (22.2 g). LC-MS (Method 2): Rt=4.03 min, m/z=432 [M(79Br)+H]+
22.2 g	With Tris(trimethylsilyl) phosphate; In tetrahydrofuran; at 75℃; for 17.0h;Inert atmosphere;	3-Trifluoromethylphenylthiourea (12.8 g, 87 mmol), 2-bromo-4- cyanobenzaldehyde (18.3 g, 87 mmol) and methyl acetoacetate (10.4 mL, 96 mmol) were dissolved in THF (300 mL) under an atmosphere of N2 and then trimethylsilylphosphate (18 g) in THF (50 mL) was added and the mixture heated at 75 °C. After 17 hours the reaction mixture was allowed to cool, poured onto 0.5 M HC1 (600 mL) and stirred for 30 mins. The mixture was extracted into EtOAc. The organic phase was washed with water, then brine and dried (Na2S04) before being concentrated in vacuo. The resulting solid was triturated with Et20 (50 mL), filtered and the solid collected to yield the title compound as a white solid (22.2 g). LC-MS (Method 2): Rt = 4.03 min, m/z = 432 [M(79Br) +H]+

References: [1]Patent: US2014/171414,2014,A1 .Location in patent: Paragraph 0446; 0447; 0448.
[2]Patent: WO2014/95700,2014,A1 .Location in patent: Page/Page column 61-62.

17
[ 91760-66-6 ]
[ 1736-70-5 ]
[ 105-45-3 ]
[ 1613621-85-4 ]

Yield	Reaction Conditions	Operation in experiment
754 g	With polyphosphoric acid; In tetrahydrofuran; diethyl ether; at -10 - 75℃; for 20h;Inert atmosphere;	Intermediate 34 (458 g, 2 mol, 1.0 eq.), methyl acetoacetate (274.4 g, 255 mL, 2.36 mol, 1.18 eq.) and 3-trifluoromethylphenyl thiourea (519 g, 2.36 mol, 1.18 eq.), were charged to a 10 L jacketed reactor under a N2 atmosphere, and suspended in THF (4.6 L) and while stirring, was cooled to -10 C. (internal temperature -3 C.). Polyphosphoric acid (1650 g, 3.6 wt eq.), was prewarmed in a water bath at 50 C., then added in one portion, resulting in an immediate exotherm, and the internal temperature rose to 19 C. The resulting orange mixture was then warmed to 75 C. in 10 C. increments to a gentle reflux, and the reaction stirred at this temperature for 20 hours. The reaction was then cooled to 20 C. and the bulk of THF removed in vacuo to give a dark orange viscous oil, which was then diluted with water (5 L) and Et2O (5 L).The aqueous layer was separated and extracted again with Et2O (2*2 L) and the combined organics were subsequently washed with water (1 L), brine (1 L) and dried (Na2SO4) and filtered through Celite to remove any fine particulates. The filtered solution was then concentrated in vacuo to give a viscous orange gum which was resuspended in Et2O (ca. 1.5 L) and left to stand overnight. The resulting suspension was filtered and the solid collected was rinsed with Et2O (0.5 L) and dried in a vacuum oven at 50 C. (8 mbar) for 4 days to afford the title compound (754 g). LCMS (Method 1): Rt 3.52 min, m/z 529, 531 [M+H]+ 1H NMR (300 MHz, DMSO): delta 10.15 (1H, d, J=3.5 Hz), 8.11 (1H, d, J=1.6 Hz), 8.05 (1H, dd, J=8.1, 1.7 Hz), 7.92-7.64 (5H, m), 5.80 (1H, d, J=2.9 Hz), 3.53 (3H, s), 2.07 (3H, s).
754 g	With polyphosphoric acid; In tetrahydrofuran; at -10 - 75℃; for 20h;Inert atmosphere;	Intermediate 34 (458 g, 2 mol, 1.0 eq.), methyl acetoacetate (274.4 g, 255 mL, 2.36 mol, 1.18 eq.) and 3-trifluoromethylphenyl thiourea (519 g, 2.36 mol, 1.18 eq.), were charged to a 10 L jacketed reactor under a N2 atmosphere, and suspended in THF (4.6 L) and while stirring, was cooled to -10C (internal temperature -3C). Polyphosphoric acid (1650 g, 3.6 wt eq.), was prewarmed in a water bath at 50C, then added in one portion, resulting in an immediate exotherm, and the internal temperature rose to 19C. The resulting orange mixture was then warmed to 75C in 10C increments to a gentle reflux, and the reaction stirred at this temperature for 20 h. The reaction was then cooled to 20C and the bulk of THF removed in vacuo to give a dark orange viscous oil, which was then diluted with water (5 L) and Et20 (5 L). The aqueous layer was separated and extracted again with Et20 (2 x 2 L) and the combined organics were subsequently washed with water (1 L), brine (1 L) and dried (Na2S04) and filtered through Celite to remove any fine particulates. The filtered solution was then concentrated in vacuo to give a viscous orange gum which was resuspended in Et20 (ca. 1.5 L) and left to stand overnight. The resulting suspension was filtered and the solid collected was rinsed with Et20 (0.5 L) and dried in a vacuum oven at 50C (8 mbar) for 4 days to afford the title compound (754 g). LCMS (Method l):Rt 3.52 min, m/z 529, 531 [M+H]+ 1H NMR (300 MHz, DMSO): delta 10.15 (1H, d, J = 3.5 Hz), 8.11 (1H, d, J = 1.6 Hz), 8.05 (1H, dd, J = 8.1, 1.7 Hz), 7.92-7.64 (5H, m), 5.80 (1H, d, J = 2.9 Hz), 3.53 (3H, s), 2.07 (3H, s).
754 g	With Polyphosphoric acid; In tetrahydrofuran; at -10 - 75℃; for 20h;Inert atmosphere; Industrial scale;	Intermediate 2 (458 g, 2 mol, 1.0 eq.), methyl acetoacetate (274.4 g, 255 mL, 2.36 mol, 1.18 eq.) and 3-trifluoromethylphenyl thiourea (519 g, 2.36 mol, 1.18 eq.), were charged to a 10 L jacketed reactor under a N2 atmosphere, and suspended in THF (4.6 L) and while stirring, was cooled to -10 C. (internal temperature -3 C.). Polyphosphoric acid (1650 g, 3.6 wt eq.), was prewarmed in a water bath at 50 C., then added in one portion, resulting in an immediate exotherm, and the internal temperature rose to 19 C. The resulting orange mixture was then warmed to 75 C. in 10 C. increments to a gentle reflux, and the reaction stirred at this temperature for 20 h. The reaction was then cooled to 20 C. and the bulk of THF removed in vacuo to give a dark orange viscous oil, which was then diluted with water (5 L) and Et2O (5 L). The aqueous layer was separated and extracted again with Et2O (2×2 L) and the combined organics were subsequently washed with water (1 L), brine (1 L) and dried (Na2SO4) and filtered through Celite to remove any fine particulates. The filtered solution was then concentrated in vacuo to give a viscous orange gum which was resuspended in Et2O (ca. 1.5 L) and left to stand overnight. The resulting suspension was filtered and the solid collected was rinsed with Et2O (0.5 L) and dried in a vacuum oven at 50 C. (8 mbar) for 4 days to afford the title compound (754 g). LCMS (Method 1): Rt 3.52 min, m/z 529, 531 [M+H]+ 1H NMR (300 MHz, DMSO): delta 10.15 (1H, d, J=3.5 Hz), 8.11 (1H, d, J=1.6 Hz), 8.05 (1H, dd, J=8.1, 1.7 Hz), 7.92-7.64 (5H, m), 5.80 (1H, d, J=2.9 Hz), 3.53 (3H, s), 2.07 (3H, s).

754 g	With Polyphosphoric acid; In tetrahydrofuran; at -3℃; for 20h;Inert atmosphere; Reflux;	Intermediate 2 (458 g, 2 mol, 1.0 eq.), methyl acetoacetate (274.4 g, 255 mL, 2.36 mol, 1.18 eq.) and 3-trifluoromethylphenyl thiourea (519 g, 2.36 mol, 1.18 eq.), were charged to a 10 L jacketed reactor under a N2 atmosphere, and suspended in THF (4.6 L) and while stirring, was cooled to -10C (internal temperature -3C). Polyphosphoric acid (1650 g, 3.6 wt eq.), was prewarmed in a water bath at 50C, then added in one portion, resulting in an immediate exotherm, and the internal temperature rose to 19C. The resulting orange mixture was then warmed to 75C in 10C increments to a gentle reflux, and the reaction stirred at this temperature for 20 h. The reaction was then cooled to 20C and the bulk of THF removed in vacuo to give a dark orange viscous oil, which was then diluted with water (5 L) and Et20 (5 L). The aqueous layer was separated and extracted again with Et20 (2 x 2 L) and the combined organics were subsequently washed with water (1 L), brine (1 L) and dried (Na2S04) and filtered through C elite to remove any fine particulates. The filtered solution was then concentrated in vacuo to give a viscous orange gum which was resuspended in Et20 (ca. 1.5 L) and left to stand overnight. The resulting suspension was filtered and the solid collected was rinsed with Et20 (0.5 L) and dried in a vacuum oven at 50 C (8 mbar) for 4 days to afford the title compound (754 g). LCMS (Method 1): Rt 3.52 min, m/z 529, 531 [M+H]+ 1HNuMuR delta(300 MHz, DMSO): delta 10.15 (1H, d, J = 3.5 Hz), 8.11 (1H, d, J = 1.6 Hz), 8.05 (1H, dd, J = 8.1, 1.7 Hz), 7.92-7.64 (5H, m), 5.80 (1H, d, J = 2.9 Hz), 3.53 (3H, s), 2.07 (3H, s).
754 g	With polyphosphoric acid; In tetrahydrofuran; at -10 - 75℃; for 20h;Inert atmosphere;	Intermediate 2 (458 g, 2 mol, 1.0 eq.), methyl acetoacetate (274.4 g, 255 mL, 2.36 mol, 1.18 eq.) and 3-trifluoromethylphenyl thiourea (519 g, 2.36 mol, 1.18 eq.), were charged to a 10 L jacketed reactor under a N2 atmosphere, and suspended in THF (4.6 L) and while stirring, was cooled to -10C (internal temperature -3C). Polyphosphoric acid (1650 g, 3.6 wt eq.), was prewarmed in a water bath at 50C, then added in one portion, resulting in an immediate exotherm, and the internal temperature rose to 19C. The resulting orange mixture was then warmed to 75C in 10C increments to a gentle reflux, and the reaction stirred at this temperature for 20 h. The reaction was then cooled to 20C and the bulk of THF removed in vacuo to give a dark orange viscous oil, which was then diluted with water (5 L) and Et20 (5 L). The aqueous layer was separated and extracted again with Et20 (2 x 2 L) and the combined organics were subsequently washed with water (1 L), brine (1 L) and dried (Na2S04) and filtered through C elite to remove any fine particulates. The filtered solution was then concentrated in vacuo to give a viscous orange gum which was resuspended in Et20 (ca. 1.5 L) and left to stand overnight. The resulting suspension was filtered and the solid collected was rinsed with Et20 (0.5 L) and dried in a vacuum oven at 50C (8 mbar) for 4 days to afford the title compound (754 g). LCMS (Method 1): Rt 3.52 min, m/z 529 [M(79Br)+H]+ 1H NMR (300 MHz, DMSO): delta 10.15 (1H, d, J = 3.5 Hz), 8.11 (1H, d, J = 1.6 Hz), 8.05 (1H, dd, J = 8.1, 1.7 Hz), 7.92-7.64 (5H, m), 5.80 (1H, d, J = 2.9 Hz), 3.53 (3H, s), 2.07 (3H, s).
754 g	With polyphosphoric acid; In tetrahydrofuran; at -10 - 75℃; for 20h;Inert atmosphere;	Intermediate 2 (458 g, 2 mol, 1.0 eq.), methyl acetoacetate (274.4 g, 255 mL, 2.36 mol, 1.18 eq.) and 3-trifluoromethylphenyl thiourea (519 g, 2.36 mol, 1.18 eq.), were charged to a 10 L jacketed reactor under a N2 atmosphere, and suspended in THF (4.6 L) and while stirring, was cooled to -10 C. (internal temperature -3 C.). Polyphosphoric acid (1650 g, 3.6 wt eq.), was prewarmed in a water bath at 50 C., then added in one portion, resulting in an immediate exotherm, and the internal temperature rose to 19 C. The resulting orange mixture was then warmed to 75 C. in 10 C. increments to a gentle reflux, and the reaction stirred at this temperature for 20 h. The reaction was then cooled to 20 C. and the bulk of THF removed in vacuo to give a dark orange viscous oil, which was then diluted with water (5 L) and Et2O (5 L). The aqueous layer was separated and extracted again with Et2O (2×2 L) and the combined organics were subsequently washed with water (1 L), brine (1 L) and dried (Na2SO4) and filtered through Celite to remove any fine particulates. The filtered solution was then concentrated in vacuo to give a viscous orange gum which was resuspended in Et2O (ca. 1.5 L) and left to stand overnight. The resulting suspension was filtered and the solid collected was rinsed with Et2O (0.5 L) and dried in a vacuum oven at 50 C. (8 mbar) for 4 days to afford the title compound (754 g). (0253) LCMS (Method 1): Rt 3.52 min, m/z 529 [M(79Br)+H]+ (0254) 1H NMR (300 MHz, d6-DMSO): delta10.15 (1H, d, J=3.5 Hz), 8.11 (1H, d, J=1.6 Hz), 8.05 (1H, dd, J=8.1, 1.7 Hz), 7.92-7.64 (5H, m), 5.80 (1H, d, J=2.9 Hz), 3.53 (3H, s), 2.07 (3H, s).

References: [1]Patent: US2014/171414,2014,A1 .Location in patent: Paragraph 0723; 0724; 0725; 0726.
[2]Patent: WO2014/95700,2014,A1 .Location in patent: Page/Page column 157-158.
[3]Patent: US2015/166548,2015,A1 .Location in patent: Paragraph 0233; 0234; 0235; 0236.
[4]Patent: WO2015/91281,2015,A1 .Location in patent: Page/Page column 51; 52.
[5]Patent: WO2015/188866,2015,A1 .Location in patent: Page/Page column 29.
[6]Patent: US2015/353561,2015,A1 .Location in patent: Paragraph 0251; 0252; 0253; 0254.

18
[ 141-97-9 ]
[ 105-45-3 ]
[ 6334-18-5 ]
[ 72509-76-3 ]

References: [1]Chinese Journal of Chemistry,2014,vol. 32,p. 1245 - 1250.

19
[ 4313-03-5 ]
[ 105-45-3 ]
methyl (6E,8E)-5-hydroxy-3-oxoundeca-6,8-dienoate [ No CAS ]

References: [1]Organic and Biomolecular Chemistry,2017,vol. 15,p. 9408 - 9414.

20
[ 626-34-6 ]
[ 105-45-3 ]
[ 6334-18-5 ]
[ 72509-76-3 ]

Yield	Reaction Conditions	Operation in experiment
94.3%		20.0-dichlorobenzaldehyde 70.0 g (0.40 mol), beta-aminocrotonate ethyl ester in a 500 mL round bottom flask55.8g (0.48mol),62.0 g (0.48 mol) of methyl acetoacetate, followed by 4.5 g (0.053 mol) of piperidine and 4.2 g (0.053 mol) of pyridine.The heating was started slowly and the temperature was raised. The reaction was maintained at 75-80 C for 9 h, and 200 g of absolute ethanol was added while heating, and the mixture was heated to reflux for 1 h, and filtered while hot.The mixture was cooled to 15 C and stirred for 1 h, and suction filtered. The filter cake was washed with a small amount of dry ethanol and dried to give 145 g of pale yellow solid.Yield: 94.3%, purity 99.1%

References: [1]Patent: CN108840819,2018,A .Location in patent: Paragraph 0014; 0040-0042; 0045-0048; 0051-0053.

21
[ 120-72-9 ]
[ 105-45-3 ]
[ 621-63-6 ]
methyl 4-(1H-indol-3-yl)-2-methyl-4,5-dihydrofuran-3-carboxylate [ No CAS ]