[ CAS No. 759-36-4 ] {[proInfo.proName]}

Name: 759-36-4|Diethyl Isopropylmalonate|98%
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SKU: A683609
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Quality Control of [ 759-36-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 759-36-4 ]

Product Details of [ 759-36-4 ]

CAS No. :	759-36-4	MDL No. :	MFCD00040491
Formula :	C₁₀H₁₈O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BYQFBFWERHXONI-UHFFFAOYSA-N
M.W :	202.25	Pubchem ID :	12966
Synonyms :

Calculated chemistry of [ 759-36-4 ] Expand+

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	7
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	52.75
TPSA :	52.6 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.94 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.01
Log Po/w (XLOGP3) :	2.24
Log Po/w (WLOGP) :	1.38
Log Po/w (MLOGP) :	1.55
Log Po/w (SILICOS-IT) :	1.66
Consensus Log Po/w :	1.77

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.04
Solubility :	1.83 mg/ml ; 0.00905 mol/l
Class :	Soluble
Log S (Ali) :	-2.98
Solubility :	0.212 mg/ml ; 0.00105 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.72
Solubility :	3.85 mg/ml ; 0.0191 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.03

Safety of [ 759-36-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H227-H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 759-36-4 ]

* 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.

Upstream synthesis route of [ 759-36-4 ]
Downstream synthetic route of [ 759-36-4 ]

[ 759-36-4 ] Synthesis Path-Upstream 1~4

1
[ 109-72-8 ]
[ 1462-12-0 ]
[ 917-65-7 ]
[ 759-36-4 ]
[ 82297-04-9 ]
[ 133-13-1 ]

Reference： [1] Advanced Synthesis and Catalysis, 2000, vol. 342, # 4, p. 396 - 403

2
[ 1462-12-0 ]
[ 594-19-4 ]
[ 917-65-7 ]
[ 759-36-4 ]
[ 125001-54-9 ]
[ 133-13-1 ]

Reference： [1] Advanced Synthesis and Catalysis, 2000, vol. 342, # 4, p. 396 - 403

3
[ 1462-12-0 ]
[ 759-36-4 ]
[ 82297-04-9 ]
[ 133-13-1 ]

Reference： [1] Advanced Synthesis and Catalysis, 2000, vol. 342, # 4, p. 396 - 403

4
[ 759-36-4 ]
[ 601-79-6 ]

Reference： [1] Journal of the American Chemical Society, 2015, vol. 137, # 51, p. 15992 - 15995

[ 759-36-4 ] Synthesis Path-Downstream 1~51

1
[ 51304-64-4 ]
[ 759-36-4 ]
[ 100454-16-8 ]

Reference： [1]Helvetica Chimica Acta,1959,vol. 42,p. 2013,2016

2
[ 759-36-4 ]
[ 2612-27-3 ]

Yield	Reaction Conditions	Operation in experiment
62%	With lithium aluminium tetrahydride; In tetrahydrofuran; diethyl ether; at 0 - 35℃; for 12h;	To a stirred solution of <strong>[759-36-4]diethyl 2-isopropylmalonate</strong> (2, 4.4 g, 21 .76 mmol) in diethyl ether (50 ml_), was added lithium aluminium hydride solution (45 ml_, 43.53 mmol, 1 M in tetrahydrofuran) drop wise at 0 C and the reaction mixture was allowed to stir at same temperature for 4 h, then heated to 35 C for 8 h. The reaction mixture was cooled to 0 C, quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3 _ 100 ml_). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The crude product was purified by silica gel column chromatography using 40% ethyl acetate in hexane to afford the title compound 2-isopropylpropane-1,3-diol (3, 1 .6 g, 62% yield) as a colorless liquid. _ NMR (DMSO-cfe, 400 MHz) _ (ppm): 4.19 (t, J = 4.8 Hz, 2H), 3.45-3.34 (m, 4H), 1 .78-1 .70 (m, 1H), 1 .28-1 .22 (m, 1H), 0.84 (d, J = 7.2 Hz, 6H).
	With sodium hydroxide; In diethyl ether;	i) A solution of <strong>[759-36-4]diethyl isopropylmalonate</strong> (17 g) in dry diethyl ether (20 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (7 g) in ether (300 ml) at 0 under nitrogen. The resulting mixture was stirred at room temperature for 8 hours when 10% aqueous sodium hydroxide solution (30 ml) was added carefully. The mixture was then filtered and the solid residue washed through with fresh diethyl ether. The combined filtrates were dried over anhydrous magnesium sulphate and then evaporated in vacuo to leave 2-isopropylpropane-1,3-diol as a colourless oil (8.9 g).
	With hydrogenchloride; In tetrahydrofuran;	Reference Example 28 Production of 2-isopropyl-1,3-propanediol To a suspension of 4.17 g of lithium aluminum hydride in tetrahydrofuran being stirred under ice cooling conditions, 15 g of <strong>[759-36-4]diethyl isopropylmalonate</strong> was added dropwise, followed by reaction mixture stirring at 0 C. for 30 minutes and then at room temperature (15 to 20 C.) for 1 hour. To the reaction mixture was added aqueous tetrahydrofuran to decompose excess lithium aluminum hydride, followed by neutralization with 6 N hydrochloric acid; the insoluble substances were filtered off. The filtrate was extracted with ethyl acetate, and the extract was washed with water and dried. The solvent was distilled off under reduced pressure to yield 7.47 g of title compound. NMR (CDCl3)delta: 0.92 (3H, s), 0.95 (3H, s), 1.49-1.65 (1H, m), 1.66-1.86 (1H, m), 2.32 (2H, bs), 3.72-3.93 (4H, m)

With lithium aluminium tetrahydride; In tetrahydrofuran; for 73h;Reflux;

To argon flushed two-neck round-bottomed flask equipped with addition funnel, reflux condenser and drying tube, was added LiAlH4 (1.9 g, 49.5 mmol) and dry THF (60 mL, drop wise addition). To this mixture, <strong>[759-36-4]diethyl isopropylmalonate</strong> 7 (5 g, 24.7 mmol) in dry THF (50 mL) was added over 1 h at room temperature and the mixture was stirred for 3 days at reflux temperature. The mixture was cooled to 0 C and quenched with saturated aq. sodium sulphate (30 mL), filtered, and concentrated under reduced pressure. The obtained crude diol was used for next step, without purification. Diol in CH2Cl2 (60 mL) was added to the stirred solution of imidazole (2.02 g, 44.5 mmol) in CH2Cl2 (30 mL) and stirred at room temperature for 1 h. TBDPSCl (6.79 g, 24.7 mmol) in CH2Cl2 (30 mL) was added drop wise to the reaction mixture and stirring continued for 3 h at room temperature. The mixture was diluted with ether (20 mL), washed successively with aq. saturated K2CO3 (2 x 20 mL) and brine (20 mL). The organic extract was concentrated and the residue was purified by column chromatography (EtOAc:hexanes = 1:3) to give the alcohol 8 (7.47 g, 85%) as colorless liquid.

Reference： [1]European Journal of Organic Chemistry,2008,p. 3461 - 3464
[2]European Journal of Organic Chemistry,2010,p. 4671 - 4686
[3]Journal of Organic Chemistry,1982,vol. 47,p. 2400 - 2404
[4]Journal of Organic Chemistry,1991,vol. 56,p. 6458 - 6467
[5]Patent: WO2018/119374,2018,A1 .Location in patent: Paragraph 00296
[6]Bioscience, Biotechnology and Biochemistry,1992,vol. 56,p. 2023 - 2033
[7]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1957,vol. 77,p. 589,591
Chem.Abstr.,1957,p. 16425
[8]Acta chemica Scandinavica. Series B: Organic chemistry and biochemistry,1986,vol. 40,p. 839 - 854
[9]Journal of the American Chemical Society,2003,vol. 125,p. 7914 - 7922
[10]Synthetic Communications,2003,vol. 33,p. 3761 - 3770
[11]Patent: US5061726,1991,A
[12]Tetrahedron Letters,2008,vol. 49,p. 2446 - 2449
[13]Patent: US5491145,1996,A
[14]Synthetic Communications,2019,vol. 49,p. 1153 - 1158

3
[ 759-36-4 ]
[ 15112-52-4 ]

Reference： [1]Journal of the American Chemical Society,1949,vol. 71,p. 3107
[2]Chemical and pharmaceutical bulletin,1967,vol. 15,p. 549 - 570
[3]Journal of the Chemical Society. Perkin transactions I,1997,p. 1559 - 1570
[4]Angewandte Chemie - International Edition,2012,vol. 51,p. 5727 - 5729
[5]Patent: DE704297,1936,
DRP/DRBP Org.Chem.,

4
[ 759-36-4 ]
[ 17356-08-0 ]
[ 74687-21-1 ]

Reference： [1]Acta Academiae Aboensis, Series B: Mathematica et Physica,1958,vol. 21,p. 7
[2],1935,vol. 13,p. 11
[3]Journal of Medicinal Chemistry,2007,vol. 50,p. 1778 - 1786
[4]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 6477 - 6483
[5]MedChemComm,2014,vol. 5,p. 468 - 473

5
[ 759-36-4 ]
[ 57-13-6 ]
[ 7391-69-7 ]

Yield	Reaction Conditions	Operation in experiment
58%		Step 2 Sodium pieces (11.5 g, 0.5 M) were reacted with ethanol (300 mL) under nitrogen. Diethyl isopropyl malonate (1) (97 g, 0.48 M, crude product) was added to the solution. Urea (30 g, 0.5 M) in hot methanol (100 mL+10 mL for washing) was then added. A yellow precipitate formed immediately. The mixture was heated to reflux and refluxing was continued overnight (-20 hr). The mixture was evaporated in vacuo and the residue was dissolved in water (100 mL) and cooled in an ice bath. Conc. HCl (43 mL, pH paper 3-4) was added to the solution and stirred for 2 hr. The precipitate was collected by filtration, washed with ice-cold water (200 mL) twice, cold ethanol (200 mL), ether (excess), and dried in vacuo to give 49 g (58%) of 5-isopropylbarbituric acid (2) as a white solid. 1H NMR (200 MHz, DMSO-d6) delta 0.98 (6H, d, J=7.0 Hz), 2.41 (4H, m), 3.19 (1H, d, J=3.6 Hz), 11.20 (2H, s).

Reference： [1]Molecules,2011,vol. 16,p. 4764 - 4774
[2]Patent: US2009/163712,2009,A1 .Location in patent: Page/Page column 13-14
[3],1935,vol. 13,p. 9
[4]Organic Preparations and Procedures International,1993,vol. 25,p. 563 - 568
[5]Chemical and Pharmaceutical Bulletin,2006,vol. 54,p. 1248 - 1253

6
[ 75-30-9 ]
[ 105-53-3 ]
[ 759-36-4 ]

Reference： [1]Journal of Organic Chemistry,1998,vol. 63,p. 3677 - 3679
[2]Justus Liebigs Annalen der Chemie,1880,vol. 204,p. 151
[3]Journal of the Chemical Society. Perkin transactions I,1977,p. 1743 - 1745

7
[ 759-36-4 ]
[ 28509-46-8 ]
[ 13387-67-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium In ethanol

Reference： [1]Stepanov,F.N.; Myrsina,R.A. [Journal of general chemistry of the USSR, 1964, vol. 34, # 9, p. 3131 - 3134][Zhurnal Obshchei Khimii, 1964, vol. 34, # 9, p. 3092 - 3096]

8
[ 759-36-4 ]
[ 24124-04-7 ]

Yield	Reaction Conditions	Operation in experiment
	With nitric acid;	EXAMPLE 2 Isopropyl-tartronic acid diethyl ester 400 g (6.3 mols) of 98 % to 100 % nitric acid are placed in a sulphonating flask, and 10 g (0.05 mols) of isopropyl-malonic acid diethyl ester are added dropwise within 15 minutes at room temperature while stirring. The clear solution is allowed to stand at room temperature for 48 hours. Most of the nitric acid is then carefully removed by evaporation on a rotary evaporator under a water pump vacuum, the residue is distributed between an aqueous potassium hydrogen carbonate solution and a sufficient amount of methylene chloride and is worked up in the usual manner. The methylene chloride phases are again extracted with a small amount of water, dried over sodium sulphate, and the solvent is carefully removed by evaporation in a vacuum. The resulting crude product is distilled in a high vacuum and yields isopropyl-tartronic acid diethyl ester having a B.P. of 65-67 (0.05 mm of Hg), nD20 = 1.4289.

Reference： [1]Helvetica chimica acta,1969,vol. 52,p. 1549 - 1564
[2]Patent: US3997593,1976,A
[3]Bioscience, Biotechnology and Biochemistry,2019,vol. 83,p. 763 - 767

9
[ 6802-75-1 ]
[ 759-36-4 ]

Yield	Reaction Conditions	Operation in experiment
>= 99%	With C40H56N2RuSi4; hydrogen; In toluene; at 25℃; under 7600.51 Torr; for 9h;Schlenk technique; Autoclave;	A magnetic stirrer was placed in a 20 mE Schlenk tube and the tube was dried by heating under a reduced pressureof 5 Pa, after which the tube interior was purged with argon.Ruthenium Complex C (7.7 mg, 0.010 mmol) was added asthe catalyst to this Schlenk tube and dissolved in toluene (2 mE). To this solution was added diethyl isopropylidenemalonate (200 mg, 1.0 mmol). The resulting solution wastransferred to an autoclave and the interior of the autoclavewas purged with hydrogen. Next, the solution was stirred forhours at room temperature under a hydrogen atmospherea pressure of 10 atmospheres. Anisole was added as an internal reference, the ?H-NMR spectrum was measured,and the structure and yield of the product were determined.The structure of the resulting compound was confirmed fromthe ?H and ?3C-NMR spectra. These results are shown as Entry 8 in Table 6.?H-NMR (400 MHz, CDC13) oe=0.99 (d, JHH=6.3 Hz, 3H,CH3), 1.26 (t, Hz, 3H, CH3), 2.38 (doublet ofseptet, JHH=6.3, 8.7 Hz, 1H, CHMe2), 3.10 (d, JHH=8.7 Hz,1H, Me2CH-CH----), 4.82 (q, Hz, 2H, CH2).?3C-NMR (100 MHz, CDC13) oe=14.3, 20.5, 28.9, 59.3, 61.3, 169.0

Reference： [1]Patent: US9884316,2018,B2 .Location in patent: Page/Page column 44; 46
[2]Journal of the American Chemical Society,2018,vol. 140,p. 4119 - 4134
[3]Synthetic Communications,1987,vol. 17,p. 1007 - 1014
[4]Russian Journal of General Chemistry,1997,vol. 67,p. 396 - 399
[5]Journal of the American Chemical Society,1969,vol. 91,p. 2703 - 2715
[6]Journal of Organic Chemistry,1965,vol. 30,p. 2748 - 2754
[7]Journal of Organic Chemistry,1976,vol. 41,p. 3328 - 3329

10
[ 759-36-4 ]
[ 94-36-0 ]
[ 60807-00-3 ]

Yield	Reaction Conditions	Operation in experiment
29 g		To a suspension of NaH (4.80 g, 0.120 mmol, 60% oildispersion) in anhydrous toluene (150 mL). The mixturewas stirred well and cooled to 15 C, 4 (20.2 g,0.100 mmol) was added dropwise. Then the reactionmixture was stirred at 50 C for 1 h. After no obviousbubbles released, the reaction mixture was cooled to5 C. A solution of benzoyl peroxide (24.2 g,0.100 mmol) dissolved in anhydrous toluene (200 mL)was added dropwise via an addition funnel maintainingtemperature below 10 C. After the completion of theaddition, the reaction mixture was stirred at 40 C for 1 h. Activated carbon (2.00 g) was added in batches underice-bath and then themixture was stirred at 40 C for 1 hand stirred at 20 C overnight. The reaction mixture wasfiltered and the wet cake was washed with toluene andwater, the filtrate was collected together and washed toneutral with water, the organic phase was dried overanhydrous sodium sulfate and concentrated. Then theresidue was distilled under reduced pressure at 80 C, 26Pa to obtain 29.0 g crude product. The material wasready for the next step without purification. 1H NMR(400 MHz, CDCl3): delta 8.10-8.06 (2H, m), 7.57 (1H, t, J= 7.5 Hz), 7.46 (2H, t, J = 7.7 Hz), 4.28 (2H, q, J = 7.1Hz),2.69-2.56 (1H, m), 1.27 (6H, t, J = 7.1 Hz), 1.2 (6H, d, J= 6.9Hz).

Reference： [1]Journal of Heterocyclic Chemistry,1976,vol. 13,p. 781 - 788
[2]Bioscience, Biotechnology and Biochemistry,2019,vol. 83,p. 763 - 767

11
[ 759-36-4 ]
[ 691-60-1 ]
[ 7770-84-5 ]

Reference： [1]Journal of the American Chemical Society,1987,vol. 109,p. 466 - 476

12
[ 75-26-3 ]
[ 105-53-3 ]
[ 759-36-4 ]

Yield	Reaction Conditions	Operation in experiment
97%		Example 1; Step 1:; To a stirred solution of 21 wt. % sodium ethoxide (245 mL, 0.6 M), was added diethyl malonate (80 mL, 0.5 M). Immediately, a white precipitate formed. The mixture was then heated to reflux (the white precipitate dissolved during this process) and 2-bromopropane (70 mL, 0.75 M) was added dropwise during 30-45 min. Refluxing was continued for over 10 hr. After cooling to room temperature, the mixture was evaporated in vacuo. The residue was dissolved in ether, washed with saturated NH4Cl solution, dried with MgSO4, filtered, and evaporated in vacuo to give 98 g (97%) of diethyl isopropyl malonate (1) as a pale brown oil. The crude product was used directly in the next reaction.1H NMR (200 MHz, CDCl3) delta 0.98 (6H, d, J=6.6 Hz), 1.25 (6H, t, J=7.2 Hz), 2.32-2.43 (1H, m), 3.09 (1H, d, J=8.6 Hz), 4.17 (4H, q, J=7.2 Hz).
87%		To a stirred solution of diethyl malonate (1 , 4 g, 24.97 mmol) in ethanol (5 mL), was added 21 % sodium ethoxide in ethanol (12.25 mL, 29.96 mmol) and allowed to stir at room temperature for 30 min. Then 2-bromopropane (3.5 mL, 37.46 mmol) was added to the reaction mixture and allowed to stir at 85 C for 9.5 h. The reaction mixture was concentrated, the residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The crude product was purified by silica gel column chromatography using 5% ethyl acetate in hexane to afford the title compound diethyl 2-isopropylmalonate (2, 4.4 g, 87%) as colorless liquid. Calculated (M+H): 203.12; Found (M+H): 203.1
81.46%		Diethyl malonate 1 (12 g, 75 mmol) was added to ethanolic NaOEt and the resulting mixture was boiled under reflux for 2 h in the presence of dry nitrogen. Isopropyl bromide (13.84 g, 112.5 mmol) was then added dropwise and the mixture was extracted with 50 mL ethyl acetate thrice. The extracts were combined, washed with brine and dried over anhyd. MgSO4. The solvent was evaporated in vacuum to obtain the crude product, which was then distilled in vacuum using a fractionating column to obtain 21.85 g diethyl isopropylmalonate in 81.46% yield as a colorless oil, bp 92-95 C/ca 20 mmHg. 1H-NMR (400 MHz, CDCl3): delta 4.20 (q, J=7.1 Hz, 4H),3.12 (d, J=8.8 Hz, 1H), 2.49-2.33 (m, 1H), 1.28 (t, J=7.1 Hz, 6H), 1.01 (d, J=6.8 Hz,6H).

81.46%		1. Preparation of Diethyl IsopropylmalonateSodium ethoxide (5.61g, 82.5mmoL) was dissolved in absolute ethanol (80mL), and diethyl malonate (12g, 75mmoL) was added dropwise thereto under constant stirring. After the addition was complete, the temperature was raised to reflux for 2 hours; the temperature was lowered and stirring was continued. Isopropyl bromide (13.84 g, 112.5 mmoL) was added dropwise. After the addition was completed, the temperature was raised and refluxed for 6 hours.After TLC tracking, after the reaction was completed, the temperature was reduced, and the filtrate was collected to collect the filtrate.The pH was adjusted to 5-6 on an ice bath and the mixture was evaporated and the solvent removed.Dissolve with 100 mL of ethyl acetate, wash 100 mL of saturated sodium chloride three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase, and distill off under reduced pressure to obtain 17.80 g of a colorless, transparent liquid, ie compound isopropyl. Diethyl malonate, yield 81.46%.NMR spectra of the compound diethyl isopropylmalonate: 1H NMR (400 MHz, CDCL3) delta 4.20 (q, J=7.1 Hz, 4H), 3.12 (d, J=8.8 Hz, 1H), 2.49-2.33(m,1H),1.28(t,J=7.1Hz,6H),1.01(d,J=6.8Hz,6H).A nuclear magnetic resonance spectrum of diethyl isopropyl malonate can be seen in FIG.
	With sodium ethanolate; In ethanol; water;	a. Preparation of 2-isopropyl-4-methylpent-4-enoic acid Diethylmalonate (80.0g) in ethyl alcohol (50 ml) was added to a solution of sodium ethoxide (prepared from sodium metal (13.0g) and absolute alcohol (400 ml)) over 15 minutes whilst gently refluxing the mixture. After stirring under reflux for 1 hour a solution of 2-bromopropane (74.5g) in alcohol (50 ml) was added over 1 hour and the mixture stirred under reflux overnight. The reaction mixture was cooled in ice and inorganic material removed by filtration and the filtrate concentrated. Water was added to the concentrate which was extracted with ether, the ethereal extracts washed with 2N sodium hydroxide solution (X2) and dried over magnesium sulphate. Removal of solvent gave an almost colourless liquid which was further purified by distillation to give diethyl isopropylmalonate b.p. 62-65 C./0.7 mm Hg.

Reference： [1]Patent: US2009/163712,2009,A1 .Location in patent: Page/Page column 13-14
[2]Patent: WO2018/119374,2018,A1 .Location in patent: Paragraph 00295
[3]Natural Product Research,2018,vol. 32,p. 128 - 132
[4]Patent: CN104693205,2017,B .Location in patent: Paragraph 0039; 0040; 0041; 0042
[5]Mendeleev Communications,2002,vol. 12,p. 57 - 59
[6]Journal of the Chemical Society. Perkin transactions I,1997,p. 1559 - 1570
[7]Journal of Fluorine Chemistry,1989,vol. 42,p. 179 - 186
[8]Patent: US4042710,1977,A
[9]Journal of the American Chemical Society,2015,vol. 137,p. 15992 - 15995
[10],2019,p. 663 - 671

13
[ 759-36-4 ]
potassium 2-(ethoxycarbonyl)-3-methylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In ethanol; at 20℃;Inert atmosphere;	General procedure: To a solution of diethyl 2-ethylmalonate (5600 mg, 29 mmol) in anhydrous EtOH (20 mL) was added KOH (1500 mg, 29 mmol). The resulting mixture was stirred at rt overnight and then concentrated. The solid was filtrated, rinsed with Et2O (20 mL x 2), and resuspended in anhydrous CH3CN (20 mL). To this was added TEA (3200 mg, 32 mmol) and MgCl2 (2380 mg, 25 mmol) and the mixture was stirred at rt for 2 h. Then a solution of 2-cyclohexyl-1-(1H-imidazol-1-yl)ethan-1-one (10 mmol), which was freshly prepared from 2-cyclohexylacetic acid (5) (1420 mg, 10 mmol) and CDI (1620 mg, 10 mmol) in hydrous CH3CN (20 mL), was added. The reaction mixture was stirred overnight at rt then heated under refluxing for 2 h and cooled to 0 C. 13 % HCl (50 mL) was added slowly and the resulting clear mixture was stirred at rt for 15 min. The organic phase was collected and water phase was extracted with EtOAc (2 x 50 mL). Combined organic phases were washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated in vaccu to give the crude product. The subsequent purification by combiflash (Hex / EtOAc, 10:1) gave the desired compound as clear oil.

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 2119 - 2129
[2]European Journal of Medicinal Chemistry,2017,vol. 128,p. 168 - 179

14
[ 109-72-8 ]
[ 1462-12-0 ]
[ 917-65-7 ]
[ 759-36-4 ]
[ 82297-04-9 ]
[ 133-13-1 ]

Reference： [1]Advanced Synthesis and Catalysis,2000,vol. 342,p. 396 - 403

15
[ 1462-12-0 ]
[ 594-19-4 ]
[ 917-65-7 ]
[ 759-36-4 ]
[ 125001-54-9 ]
[ 133-13-1 ]

Reference： [1]Advanced Synthesis and Catalysis,2000,vol. 342,p. 396 - 403

16
[ 759-36-4 ]
[ 106-47-8 ]
[ 345913-37-3 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 5912 - 5922
[2]Journal of Medicinal Chemistry,2004,vol. 47,p. 5923 - 5936

17
[ 759-36-4 ]
[ 836-42-0 ]
[ 710326-80-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 2419 - 2439

18
[ 759-36-4 ]
[ 3473-63-0 ]
[ 90345-37-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol; at 60℃; for 4h;	Method 00 Preparation of 5 -Alkyl-4,6-dihydroxypyrimidine To a diethyl 2-alkylmalonate or a dimethyl 2-alkylmalonate (1.0 eq) was added formamidine acetate (1.0 eq) and 25% sodium methoxide in methanol (3.3 eq). The resulting slurry was stirred vigorously and heated to 60C for 4 h, and then allowed to cool. The slurry was diluted with water, and acidified to pH = 2 by addition of HCI. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum, to afford a 5-alkyl-4,6-dihydroxypyrimidine of sufficient purity for immediate conversion to a 5-alkyl-4,6-dichloropyrimidine.

Reference： [1]Patent: WO2005/97162,2005,A2 .Location in patent: Page/Page column 536-537; 557

19
[ 759-36-4 ]
[ 14287-61-7 ]

Reference： [1]Helvetica Chimica Acta,1986,vol. 69,p. 374 - 388
[2]Recueil des Travaux Chimiques des Pays-Bas,1886,vol. 5,p. 236

20
[ 759-36-4 ]
[ 1780-42-3 ]

Reference： [1]Journal of Fluorine Chemistry,1989,vol. 42,p. 179 - 186
[2]Molecules,2011,vol. 16,p. 4764 - 4774

21
[ 759-36-4 ]
methanolic sodium methoxide [ No CAS ]
[ 7391-69-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	With urea; In methanol; water;	EXAMPLE 1 Preparation of 5-(1-methylethyl)pyrimidine-2,4,6 (1H,3H,5H)-trione 456 g (2.25 mol) of <strong>[759-36-4]diethyl isopropylmalonate</strong>, 650 ml of a 30% methanolic sodium methoxide solution and 910 ml of methanol are charged to a 2 liter reactor equipped with an anchor stirrer. The mixture is brought to reflux for thirty minutes before adding 135 g (2.25 mol) of urea in the solid form while maintaining the reflux. The reaction mixture at the end of the reaction is a thick white suspension which is brought to dryness by evaporation of the methanol under vacuum. The residue is taken up in 1370 ml of water and then filtered after cooling to 20 C. The filtrate is treated by addition of the amount of hydrochloric acid needed to bring the pH to 2-3, and the precipitate obtained is filtered off under cold conditions and washed with ice-cold water in order to obtain 267 g of 5-(1-methylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione. (Yield=69%) Melting point: 215 C.

Reference： [1]Patent: US6452006,2002,B1

22
[ 759-36-4 ]
[ 128227-95-2 ]
[ 141891-90-9 ]

Yield	Reaction Conditions	Operation in experiment
64.7%	In N,N-dimethyl-formamide;	(1) 6.0 g of <strong>[759-36-4]diethyl 2-isopropylmalonate</strong>, 1.2 g of 60% sodium hydride and 50 ml of N,N-dimethylformamide were placed in a round bottom flask, and are stirred at 60 C. for 30 minutes. Thereafter, 4.7 g of 4,6-dimethoxy-2-fluoropyrimidine was added thereto. After stirring for further 5 hours, 100 ml of water was added to the resultant reaction liquor, and the reaction liquor was extracted twice with 100 ml of ether. This extracted liquor was washed with water, and was dried with anhydrous sodium sulfate for one night. After filtrating the inorganic salt, the solvent was distilled off under reduced pressure to obtain 7.2 g of a viscous liquid. The viscous liquor thus obtained was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=5/1) to obtain 6.6 g of diethyl 2-(4,6-dimethoxypyrimidin-2-yl)-2-isopropylmalonate (yield=64.7%). Light yellow liquid, refractive index (n20/D)=1.4808.

Reference： [1]Patent: US5411934,1995,A

23
[ 759-36-4 ]
[ 538-32-9 ]
3-benzyl-5-isopropylpyrimidine-2,4,6(1H,3H)-trione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.96 g (89.5%, white crystal)	With hydrogenchloride; sodium methylate; In methanol; water;	i) Synthesis of 3-benzyl-5-isopropylpyrimidine-2,4,6(1H,3H)-trione To a suspension of 22.53 g (150 mmol) of benzylurea and 30.34 g (150 mmol) of <strong>[759-36-4]diethyl isopropylmalonate</strong> in 77 ml of methanol, 36.6 ml (150 mmol) of a 4.1M sodium methylate solution was added at room temperature, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. After the residue was dissolved in water and insoluble substances were filtered out, the filtrate was adjusted to pH 3-4 by adding concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and n-hexane-diethyl ether and dried to yield 34.96 g (89.5%, white crystal) of the desired product. 1 H-NMR (CDCl3, 200 MHz) delta 1.02 (6H, d, J=7.0 Hz), 2.58 (1H, d, quint., J=4.0, 7.0 Hz), 3.29 (1H, d, J=4.0 Hz), 5.02 (2H, s), 7.28-7.46 (5H, m), 8.95 (1H, s); IR (KBr) 1684, 1441, 1375, 1120, 700 cm-1

Reference： [1]Patent: US5840732,1998,A

24
[ 759-36-4 ]
[ 118040-79-2 ]
[ 196706-22-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In ethanol;	EXAMPLE 3 6-cyclohexyl-2-isopropyl-4-hexenoic acid 23.15 g (0.15 mol) of 1-cyclohexyl-3-buten-2-ol, 6.85 g (0.03 mol) of tetraethyl orthotitanate and 61.5 ml (0.30 mol) of <strong>[759-36-4]isopropylmalonic acid diethyl ester</strong> are placed in a flask and stirred for 1 hour at 170 and then for 24 hours at 200. Excess malonic acid ester is distilled off at 20 mbar, and the residue is dissolved in 120 ml of ethanol and, after the addition of 120 ml of 6N KOH, stirred under reflux for 7 hours. After cooling, the reaction mixture is filtered and the filtrate is extensively concentrated by evaporation in a rotary evaporator. The aqueous phase is extracted once with ether, acidified to pH 1 with 6N HCl while cooling with ice and then extracted three times with ether. The combined organic phases are washed with brine, dried with MgSO4 and concentrated by evaporation in a rotary evaporator. The residue is distilled at 137-140/0.025 mbar. C15 H26 O2 (238.37): calc. C 75.58 H 11.00%; found C 75.49 H 10.91%. 1 H-NMR (CDCl3): 5.28-5.55 (m, 2H, HC=CH).

Reference： [1]Patent: US4898977,1990,A

25
[ 759-36-4 ]
[ 2567-14-8 ]
diethyl isopropyl-(3,3-dichloro-2-propenyl)malonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol; toluene; mineral oil;	Part A: diethyl isopropyl-(3,3-dichloro-2-propenyl)malonate A 1 liter flask was equipped with a mechanical stirrer, reflux condenser, addition funnel, thermometer, and nitrogen inlet. The flask was charged with 20.06 g (0.418 mol) of 50% sodium hydride dispersion in mineral oil. The oil was washed off the sodium hydride with two 50 ml portions of toluene, then 200 ml of toluene added to the flask and the mixture warmed to 50 C. To the reaction mixture was added dropwise 84.54 g (0.418 mol) of <strong>[759-36-4]diethyl isopropylmalonate</strong>. If the evolution of hydrogen gas was not observed after a few grams of diethyl isopropylmolonate had been added, then a few drops of absolute ethanol were added to initiate the reaction. When all of the <strong>[759-36-4]diethyl isopropylmalonate</strong> had been added, then a few drops of absolute ethanol were added to initiate the reaction. When all of the <strong>[759-36-4]diethyl isopropylmalonate</strong> had been added, the reaction mixture was warmed to 75 C. until the evolution of hydrogen gas gas had cesed. While maintaining the temperature at 75 C., 60.78 g (0.418 mol) of 1,1,3-trichloropropene was added dropwise. When all the halide had been added, the reaction mixture was refluxed overnight. The reaction mixture was then cooled to room temperature, and 25 ml of ice water added dropwise. The reaction mixture was poured into 500 ml of ice water, and extracted into ether. The combined ether extracts were washed twice with water, dried (MgSO4), and the ether removed. The residue was vacuum distilled through a vigreux column to give 111.7 g (86% yield) of the desired malonate, b.p. 115-130 C./0.20 mm. IR(neat, cm-1): 2970(s), 2930(m), 2900(m), 2880(m), 1730(s), 1620(m), 1550(m), 1500(m), 1390(m), 1370(m), 1320(w), 1270(m), 1230(s), 1195(s), 1130(m), 1095(m), 1040(m), 915(w), 895(w), 880(w), 855(m). NMR(CDCl3, delta): 1.02 (d,6H); 1.29(t,6H); 2.30(m,1H); 2.75(d,2H); 4.20(q,4H); 5.95(t,1H).

Reference： [1]Patent: US4338326,1982,A

26
[ 759-36-4 ]
1,1-dichloro-3-bromo-1-propane [ No CAS ]
diethyl isopropyl-(3,3-dichloro-2-propenyl)malonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	In benzene;	SYNTHESIS EXAMPLE 3 10.5 g of sodium hydride (ca. 50%) were washed with n-hexane and suspended in 430 g of benzene with stirring. To this suspension were added 36.8 of <strong>[759-36-4]diethyl isopropylmalonate</strong> and the mixture was refluxed for about 40 minutes. The reaction mixture was then allowed to stand and cool for about 20 minutes, after which 37.9 g of 1,1-dichloro-3-bromo-1-propane were added in several increments. The mixture was then stirred under reflux for 1.5 hours. After cooling, the reaction mixture was washed with water and dilute hydrochloric acid, dried over anhydrous magnesium sulfate and distilled to remove the low-boiling fraction. The resultant oil was further distilled under reduced pressure to obtain 52.3 g of diethyl isopropyl-(3,3-dichloroallyl)malonate which was shown to have the following NMR spectrum [yield: 92% based on <strong>[759-36-4]diethyl isopropylmalonate</strong>].

Reference： [1]Patent: US4409238,1983,A

27
[ 759-36-4 ]
[ 43153-03-3 ]
[ 60726-40-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In N-methyl-acetamide; ice-water; mineral oil;	(1) Ethyl 2-[4-(2,2-diethoxycarbonyl-3-methylbutyl)phenyl]propionate (V) To a mixture of 8.5g. of a 50% suspension of sodium hydride in mineral oil and 180 ml. of dimethylformamide was added dropwise 70g. of <strong>[759-36-4]diethyl isopropylmalonate</strong> below 30 C. To the solution was added dropwise 40G. of ethyl 2-(4-chloromethylphenyl)propionate at 20 - 30 C., followed by stirring at 40 C. for 2 hours. The reaction mixture was poured into 500 ml. of ice-water, made acidic by addition of hydrochloric acid and extracted with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was distilled under reduced pressure to give 41g. of the desired product boiling at 159 - 160 C./0.005 mmHg as a colorless oil. Analysis for C22 H32 O6 Calcd. (%): C, 67.32; H, 8.22. Found (%): C, 67.82; H, 8.47.

Reference： [1]Patent: US4007179,1977,A

28
[ 759-36-4 ]
HMPT (hexamethylphosphorus triamide) [ No CAS ]
[ 563-47-3 ]
[ 62391-92-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In N,N,N,N,N,N-hexamethylphosphoric triamide; toluene;	A solution of <strong>[759-36-4]diethyl isopropylmalonate</strong> (8.1g) in 25 ml of a 25% solution of HMPT (hexamethylphosphorus triamide) in toluene was added dropwise over 15 minutes to a suspension of sodium hydride (50 mM) in 25% HMPT/toluene (50 ml) at room temperature. The mixture was then stirred at 60 C. for 1/2 hour, cooled to 25 C. and methallyl chloride (4.0g) in 25% HMPT/toluene was added over 10 minutes. The mixture was stirred at 80-85 C. overnight, cooled to room temperature and poured onto a mixture of ice/hydrochloric acid. The product was extracted with ether, the ethereal extracts washed with water, followed by 2N sodium hydroxide and then water, and dried over magnesium sulphate. Removal of solvent gave diethyl isopropyl-2-methylprop-2-enylmalonate as a pale yellow liquid. R.I. nD21 1.4467.

Reference： [1]Patent: US4042710,1977,A

29
[ 759-36-4 ]
HMPT (hexamethylphosphorus triamide) [ No CAS ]
[ 107-08-4 ]
[ 62391-98-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	In N,N,N,N,N,N-hexamethylphosphoric triamide; toluene;	A solution of diethylisopropylmalonate (10.1g) in 15 ml of a 25% solution of HMPT (hexamethylphosphorus triamide) in toluene was added dropwise over 15 minutes to a suspension of sodium hydride (70 mM) in 25% HMPT/toluene (15 ml) at 50-70 C. N-propyl iodide (17.0g) was then added over 30 minutes at 70-100 C. and the mixture stirred at 120-130 C. for 11/2 hours. After cooling, methylated spirits (10 ml) was added and the mixture poured onto a mixture of ice/hydrochloric acid. The product was extracted with ether, the ethereal extracts washed with sodium bicarbonate (X2), then water and dried over anhydrous magnesium sulphate. Removal of the solvent gave diethyl 2-isopropyl-2-propylmalonate as a yellow liquid b.p. 92-94/1 mm Hg. 87% yield. Analysis: Calculated for C13 H24 O4: C 63.9; H 9.8%. Found: C 63.1; H 10.1%.

Reference： [1]Patent: US4042710,1977,A

30
[ 759-36-4 ]
[ 2270-59-9 ]
[ 1008776-37-1 ]

Reference： [1]Angewandte Chemie - International Edition,2008,vol. 47,p. 1469 - 1472

31
[ 759-36-4 ]
[ 20038-12-4 ]
[ 1008776-35-9 ]

Yield	Reaction Conditions	Operation in experiment
33%	Stage #1: diethyl isopropylmalonate With sodium hydride In N,N-dimethyl-formamide for 0.5h; Stage #2: 4-bromo-2-methylbut-1-ene In N,N-dimethyl-formamide for 18h; Further stages.;

Reference： [1]Grachan, Melissa L.; Tudge, Matthew T.; Jacobsen, Eric N. [Angewandte Chemie - International Edition, 2008, vol. 47, # 8, p. 1469 - 1472]

32
[ 759-36-4 ]
[ 50-00-0 ]
[ 321-98-2 ]
[ 507-09-5 ]
(S)-2-acetylthiomethyl-3-methylbutanoic acid (+)-ephedrine salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[(S)-2-ACETYLTHIOMETHYL-3-METHYLBUTANOIC ACID] (+) -ephedrine salt Intermediate 24: A mixture of [DIETHYL ISOPROPYLMALONATE (1WT)] and 2M aqueous sodium hydroxide (2. 2equivalents, 5. 45volumes) was heated at 80 [+] [5C] for 2 hours. Upon completion of the reaction the contents were acidified with conc HCI (1.13 wt). 60% aqueous dimethylamine (0.41 Wt) was added followed by 37% wt/wt aqueous formaldehyde (0.49 Wt) and the reaction was then stirred at [905C] for 16 hours. The solution was cooled to [205C] and conc HCI (0.83 Wt) and MIBK (4volumes) were added. The layers were separated and the organic layer was washed with water (1 volume). The MIBK layer was then concentrated under reduced pressure to about 1. 4volumes. Cesium carbonate (0.039wt) was then added and the mixture was heated at [405C.] Thioacetic acid (0.36 Wt) was added and the mixture was stirred for at least 12 hours at [405C.] The reaction mixture was cooled to [205C] and 20% potassium bicarbonate (2. 25volumes) was added. The layers were separated and the organic layer was washed with 20% potassium bicarbonate (0. 9volumes). The combined aqueous layers were adjusted to pH 1 with conc HCI (1.18 Wt) then the acidified layer was extracted with isopropyl acetate (2x2volumes). The combined organic layers were then washed with water [(1VOLUMES)] and the mixture concentrated to 2volumes by vacuum distillation then isopropyl acetate (4. 9volumes) was added. (+) -Ephedrine hydrochloride (0.86 Wt) was suspended in isopropyl acetate (4. 2volumes) and water (0.7 volumes). 10.8M sodium hydroxide (0.58 Wt) was added and stirred to give a biphasic solution. The phases were separated and organic phase was washed with water (0. 35volumes) and the solvent reduced to 3.5 volumes by vacuum distillation. 40% of the ephedrine solution (1. 4volumes) was added to the racemate solution. The crystallisation was seeded and stirred for an hour at [20C,] then the remaining ephedrine was added over 2-3 hours. The crystallisation was cooled to 0 [5C] and stirred for at least 2 hours. The slurry was filtered and the filter cake was washed with isopropyl acetate (2x2. 8volumes) and dried in a vacuum oven at [50+5C.] Expected yield: 33% theory; 58% [W/W.] HPLC (2minute method) RT 0.86minute 27. [1%] area, 1.34minute 71.9% area

Reference： [1]Patent: WO2003/104200,2003,A1 .Location in patent: Page 23-24

33
[ 759-36-4 ]
[ 1462-37-9 ]
[ 1123787-27-8 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: To a solution of sodium hydride 60% in oil (5.93 g, 148 mmol) in DMSO (124 mL) previously stirred for 10 minutes at room temperature was added dropwise diethyl 2- isopropylmalonate (25.3 mL, 124 mmol). The reaction was allowed to stir for 1 hour at RT, then, ((2-bromoethoxy)methyl)benzene (19.55 mL, 124 mmol) was added, and the reaction mixture was allowed to stir at room temperature for about 15 hours and at 60C for 2 hours. The reaction mixture was quenched with saturated aqueous H4CI solution and extracted with Et20. The organic layer was washed with deionized water, dried over MgS04, filtered, and concentrated in vacuo. The crude residue obtained was purified using flash chromatography on silica gel (hexane/EtOAc: 90/10) to provide the product as oil. LC/MS: [(M+l)]+ = 337.0.

Reference： [1]Russian Journal of Bioorganic Chemistry,2008,vol. 34,p. 660 - 667
[2]Journal of the American Chemical Society,2009,vol. 131,p. 2786 - 2787
[3]Organic Letters,2013,vol. 15,p. 1266 - 1269
[4]Patent: WO2017/223020,2017,A1 .Location in patent: Page/Page column 34-35

34
[ 759-36-4 ]
[ 17356-08-0 ]
[ 74-88-4 ]
[ 1111757-42-6 ]

Yield	Reaction Conditions	Operation in experiment
92%		To a solution of thiourea (9.3 g, 121 mmol) in MeOH (100 ml) was slowly added NaOMe (21.8 g, 121 mmol) and the mixture was stirred for 10 min. Subsequently, a solution of <strong>[759-36-4]diethyl isopropylmalonate</strong> (25.0 g, 121 mmol) in MeOH (100 ml) was added drop wise and stirring continued overnight. Additional NaOMe (43.6 g, 242 mmol) was added and the reaction mixture was heated at reflux for 6 h. Upon cooling down to room temperature, iodomethane was added and stirring was continued overnight. The solvent was removed under reduced pressure to afford a solid residue. The latter was dissolved in water (500 ml) and the solution was acidified using cone. HCI, resulting in the formation of a precipitate. The solid was collected and washed with water (3x100 ml), followed by diisopropylether (200 ml). The precipitate collected was dried in a vacuum oven at 500C to afford the desired product (22.4 g, 112 mmol, 92%) as a white solid.

Reference： [1]Patent: WO2009/19099,2009,A1 .Location in patent: Page/Page column 63-65

35
[ 759-36-4 ]
[ 87884-39-7 ]

Yield	Reaction Conditions	Operation in experiment
		Diisobutylaluminum hydride (38 mL of a 1.0 M solution in toluene, 38 mmol) was added over 5 min to a solution of 2-isopropyl-malonic acid diethyl ester (3.84 g, 19.0 mmol) in dichloromethane (33 mL) at -78 C. The reaction mixture was stirred at that temperature for 3.5 h, and then was quenched with saturated aqueous ammonium chloride (33 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25 C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford crude product (1.92 g, 12.14 mmol, 64%). This material was dissolved in ethanol (40 mL) at 25 C. and 4-fluorobenzylamine (1.39 mL, 12.2 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.52 g, 24.2 mmol) were added sequentially. The mixture was stirred at 25 C. for 17 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-80% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-3-methyl-butyric acid ethyl ester (1.36 g, 5.09 mmol, 42%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) delta: 0.93 (6H, d, J=7.2 Hz), 1.27 (3H, t, J=7.0 Hz), 1.92-2.01 (1H, m), 2.35-2.46 (1H, m), 2.73 (1H, dd, J=3.8 Hz, J2=11.6 Hz), 2.90 (1H, dd, J=10.2 Hz, J2=11.7 Hz), 3.74 (1H, d, J=13.2 Hz), 3.82 (1H, d, J=13.5 Hz), 4.15-4.21 (2H, m), 6.97-7.01 (2H, m), 7.26-7.30 (2H, m).

Reference： [1]Patent: US2009/306057,2009,A1 .Location in patent: Page/Page column 62

36
[ 759-36-4 ]
[ 3433-80-5 ]
C₁₇H₂₃BrO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 99.1 g (0.49 mol) of <strong>[759-36-4]diethyl isopropylmalonate</strong> in500 ml of THF, 11.7 g (0.49 mol) of sodium hydride was added. This mixture was refluxed for 1 h and then cooled to room temperature. Next, 120 g (0.49 mol) of 2- bromobenzylbromide was added, and the resulting mixture was refluxed for 3 h. This mixture was cooled to ambient temperature and filtered through a glass frit (G2). The precipitate (NaBr) was additionally washed with 3 x 100 ml of THF. The combined filtrate was evaporated to dryness. The residue was dissolved in 400 ml of ethanol and 160 g of potassium hydroxide and 50 ml of water were added. The resulting mixture was refluxed for 4 h, and then 200 ml of water was added. Ethanol was distilled off at atmospheric pressure. The resulting aqueous solution was acidified with 5 M HCl to pH 1. The precipitate obtained at -3O0C was filtered off, washed with 100 ml of water, and dried in air. The dibasic acid was decarboxylated by heating for 2 h at 16O0C. The product obtained was dissolved in 600 ml of dichloromethane, and 600 ml of SOCl2 was added. The mixture was refluxed for 3 h and then evaporated to dryness. The residue was dissolved in 270 ml of dry dichloromethane, and the solution obtained was added dropwise to a suspension of 136 g (1.02 mol) of AlCl3 in 1350 ml of dichloromethane for 1 h at O0C, while vigorously stirring. Next, the reaction mixture was refluxed for 3 h, cooled to ambient temperature, poured on 500 cm3 <n="125"/>of ice, and, finally, acidified with 8M HCl to pH 3. The organic layer was separated, the aqueous layer was washed with 3 x 300 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The product was isolated by vacuum distillation (bp 154-157C/3 mm Hg). Yield 73.4 g (60%).Anal. calc. for C2Hi3BrO: C, 56.94; H, 5.18. Found: C, 56.78; H, 5.02.1H NMR (CDCl3): delta 7.73 (d, J= 7.7 Hz, IH, 7-H), 7.67 (d, J= 7.7 Hz, IH, 5-H), 7.25 (t, J=7.7 Hz, IH, 6-H), 3.09 (dd, J= 17.7 Hz, J= 8.0 Hz, IH, 3-H), 2.66- 2.72 (m, IH, 2-H), 2.66 (dd, J= 17.7 Hz, J= 4.2 Hz, IH, 3'-H), 2.36-2.46 (m, IH, CHMe2), 1.07 (d, J= 6.7 Hz, 3H, CH3), 0.80 (d, J= 6.6 Hz, 3H, CH3').13C NMR (CDCl3): delta 207.6, 153.6, 139.4, 137.1 , 128.9, 122.3, 122.0, 53.0, 29.4, 29.0, 20.6, 17.3.

Reference： [1]Patent: WO2007/70041,2007,A1 .Location in patent: Page/Page column 123-124

37
[ 759-36-4 ]
[ 50-01-1 ]
[ 500161-23-9 ]

Yield	Reaction Conditions	Operation in experiment
93%		General procedure: Metallic sodium (12.9 g, 0.56 mol) was dissolved in absolute ethanol (300 mL) under argon while being intensively stirred with a mechanical stirrer. The reaction flask was equipped with a reflux condenser with a chlorocalcium tube. After all the sodium was dissolved and the reaction mixture was cooled to room temperature; guanidine hydrochloride(21.02 g, 0.22 mol) was added under intensive stirring, followed by the corresponding monosubstituted malonic acid diester (0.2 mol). The reaction mixture was further intensively stirred due to the production of the solid product,which is so massive that after 2 h it already practically precludes stirring. After another 2 h, absolute ethanol (200 mL) was added and the reaction mixture was refluxed for 1 h while being stirred. Afterward, ethanol (ca200-300 mL) was evaporated on a vacuum rotary evaporatorand water (500 mL) was added to the reaction mixture. After stirring, the product (in the form of sodium salt) was almost dissolved. The obtained mixture was subsequently neutralized by dropwise addition of acetic acid, resulting in immediate and quantitative precipitation of the desired product in the form of a fine solid. This mixture was subsequently heated under reflux for 10 min and then cooled to laboratory temperature. This heating and cooling was repeated twice to get a well-filterable solid product. The solid product was filtered off, washed with water (2 x 50 mL),ethanol (2 x 50 mL), and acetone (2 x 50 mL). The product was dried under high vacuum at 60 C for 2 days. The obtained purity of the product prepared in this manner is sufficient for the following reaction and based on analyses contains only crystalline water.
93%	With sodium; In ethanol;Inert atmosphere;	General procedure: Metallic sodium (12.9 g, 0.56 mol) was dissolved in absolute ethanol (300 mL) under argon while being intensively stirred with a mechanical stirrer. The reaction flask was equipped with a reflux condenser with a chlorocalcium tube. After all the sodium was dissolved and the reaction mixture was cooled to room temperature; guanidine hydrochloride (21.02 g, 0.22 mol) was added under intensive stirring, followed by the corresponding monosubstituted malonicacid diester (0.2 mol). The reaction mixture was further intensively stirred due to the production of the solid product, which is so massive that after 2 h it already practically precludes stirring. After another 2 h, absolute ethanol (200 mL) was added and the reaction mixture was refluxed for 1 h while being stirred. Afterward, ethanol (ca 200-300 mL) was evaporated on a vacuum rotary evaporator and water (500 mL) was added to the reaction mixture. After stirring, the product (in the form of sodium salt) was almost dissolved. The obtained mixture was subsequently neutralized by dropwise addition of acetic acid, resulting in immediate and quantitative precipitation of the desired product in the form of a fine solid. This mixture was subsequently heated under reflux for 10 min and then cooled to laboratory temperature. This heating and cooling was repeated twice to get a well-filterable solid product. The solid product was filtered off, washed with water (2 9 50 mL), ethanol (2 9 50 mL), and acetone (2 9 50 mL). The product was dried under high vacuum at 60 C for 2 days. The obtained purity of the product prepared in this manner is sufficient for the following reaction and based on analyses contains only crystalline water.

Reference： [1]Medicinal Chemistry Research,2014,vol. 23,p. 4482 - 4490
[2]Medicinal Chemistry Research,2014,vol. 23,p. 4482 - 4490

38
[ 759-36-4 ]
[ 16617-46-2 ]
6-isopropyl-5,7-dioxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium ethanolate; In ethanol; N,N-dimethyl-formamide; at 160℃; for 0.5h;	A solution of <strong>[759-36-4]diethyl isopropylmalonate</strong> (2.1?mL, 10?mmol), 3-amino-4-pyrazolecarbonitrile (1.1?g, 10?mmol), and NaOEt (20% in EtOH, 10?mL) in EtOH (5?mL) was heated by MW at 160?C for 0.5?h. MeOH was added to the reaction mixture and the reaction mixture was acidified with 4?N HCl in AcOEt to adjust the pH to 1. The precipitate was collected by filtration and washed with Et2O to give 28 (2.18?g, quant.): 1H NMR (DMSO-d6, 300?MHz, delta; ppm), 8.21 (1H, s), 3.21 (1H, m), 1.21 (6H, d, J?=?6.6?Hz).
74%	With ethanol; sodium; for 16h;Reflux;	Sodium (9.0 g, 391 mmol) was added slowly to EtOH (400 mL), and the mixture was stirred at 26 C for 1.5 hours until sodium was consumed completely. To the resultant NaOEt solution was added 5-amino-lH-pyrazole-4-carbonitrile (20 g, 185 mmol), followed by <strong>[759-36-4]diethyl 2-isopropylmalonate</strong> (37.5 g, 185 mmol). The reaction mixture was refluxed for 16 hours. Then the reaction mixture was cooled to room temperature and diluted with MTBE (200 mL). The precipitate was collected by filtration and dissovled in water. The solution was acidified with concentrated HC1 to pH 2-3 to afford an off-white precipitate, which was filtered and dried under reduced pressure to afford the desired product as a white solid (30 g, 74% yield). 1H NMR (400MHz, DMSO- ) delta 8.23 (s, 1H), 3.23 (q, / = 6.8 Hz, 1H), 1.20 (d, J = 6.8 Hz, 6H).

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1119 - 1129
[2]Patent: WO2015/135094,2015,A1 .Location in patent: Page/Page column 48
[3]Angewandte Chemie - International Edition,2019,vol. 58,p. 515 - 519
Angew. Chem.,2019,vol. 131,p. 525 - 529,5

39
[ 759-36-4 ]
[ 601-79-6 ]

Reference： [1]Journal of the American Chemical Society,2015,vol. 137,p. 15992 - 15995
[2]ChemBioChem,2019,vol. 20,p. 1183 - 1189
[3]Chemical Communications,2019,vol. 55,p. 755 - 758

40
[ 759-36-4 ]
[ 622-06-0 ]
(+)-1,2-dibenzyl 3,3-diethyl 4-methylpentane-1,2,3,3-tetracarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With (R)-3,3?-dichloro-1,1?-binaphthalene-2,2?-diol; n-butyllithium; In hexane; tert-butyl methyl ether; at 50℃; for 17h;Inert atmosphere;	General procedure: Under argon atmosphere, n-Butyllithium (0.1 mmol, 20 mol %) in hexane (0.15 M, 0.67 mL)was added to the solution of (R)-Cl2BINOL (17.8 mg, 0.05 mmol, 10 mol %) in TBME at rt.After stirring for 1 min, dibenzyl malonate (0.13 mL, 0.5 mmol, 1.0 equiv.) and diethylmaleate (0.1 mL, 0.6 mmol, 1.2 equiv.) were successively added to the reaction mixture. Afterstirring for 1 h, the reaction was quenched with sat. NH4Cl aq (2 mL). The aqueous layer wasextracted by EtOAc (20 mL) and the combined organic layers were washed with brine (20mL). After drying over Na2SO4, filtration and concentration, the crude product was purifiedby column chromatography.
79%	With (R)-3,3?-dichloro-1,1?-binaphthalene-2,2?-diol; n-butyllithium; In hexane; tert-butyl methyl ether; at 50℃; for 17h;Inert atmosphere;	General procedure: Under argon atmosphere, n-butyllithium (0.10 mmol,20 mol%) in hexane (0.15 M, 0.67 mL) was added to a solutionof (R)-3,3-Cl2-BINOL (17.8 mg, 0.05 mmol, 10 mol%)in TBME (5.0 mL) at 0C. After stirring for 1 min, dibenzylmalonate (1a) (0.125 mL, 0.5 mmol, 1.0 eq) and diethyl maleate(2a) (0.096 mL, 0.6 mmol, 1.2 eq) was successively added tothe mixture at room temperature (r.t.). After 1 h, the reactionwas quenched with sat. NH4Cl aq. (2 mL) and stirred for 0.5 h.The aqueous layer was extracted with EtOAc (3 × 10 mL). Thecombined organic layers were washed with brine (20 mL),and dried over Na2SO4. After filtration and concentration, thecrude product was purified by column chromatography (hexane-EtOAc = 9 : 1, SiO2: 10 g) to give product 3aa as a colorless oil (214 mg, 94% yield, 90% ee)

Reference： [1]Synlett,2016,vol. 27,p. 2477 - 2480
[2]Chemical and Pharmaceutical Bulletin,2019,vol. 67,p. 452 - 460

41
[ 759-36-4 ]
5-aminodihydropyrrole [ No CAS ]
(-)-3-(isopropyl)tetrahydropyrrolo[1,2-a]pyrimidine-2,4-(1H,3H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31.08%		Liquid sodium ethoxide (1.36 g, 20 mmol) was added into pyrrolidin-2-amine(1.33 g, 10 mmol) to form a reaction mixture which was then dissolved in absolute ethanol and the resultant mixture was stirred for 45 min at ambient temperature and then <strong>[759-36-4]diethyl isopropylmalonate</strong> (2.0 g, 10 mmol) was added to the solution within 20 min. The resulting residue was extracted and dissolved in water while the solvent was made to evacuate under reflux for 15 h. The total residue was successively extracted with ethyl acetate, n-butyl alcohol and methylene chloride and the remaining solvent was eliminated under reduced pressure. Finally, the residue was distilled to give 1.94 g white solid in a yield of 31.08%. Spectroscopic data of ITPD was presented as follows. [alpha]25D =-4.3 (c 0.27, MeOH). mp: 104-107 C. MS (ESI): 196.93. 1H-NMR(400 MHz, CDCl3): delta 4.17-4.11 (m, 1H), 3.63 (t, J=7.1 Hz, 2H), 2.96 (d, J=9.7 Hz,1H), 2.85 (t, J=8.1 Hz, 2H), 2.33-2.24 (m, 1H), 2.18-2.12 (m, 2H), 1.02 (d, J=6.7 Hz,3H), 0.95 (d, J=6.6 Hz, 3H). 13C-NMR (100 MHz, CDCl3): delta 172.53, 171.75, 63.62,60.37, 47.24, 30.47, 29.58, 20.95, 20.66, 14.24.

Reference： [1]Natural Product Research,2018,vol. 32,p. 128 - 132

42
[ 759-36-4 ]
2,3,4,5-tetrahydro-1H-pyrrol-2-amino hydrochloride [ No CAS ]
3-isopropyltetrahydropyrrole[1,2-a]pyrimidine-2,4(1H,3H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31.08%		2-aminotetrahydropyrrolidine hydrochloride (1.33 g, 10 mmoL) was dissolved in 60 mL of anhydrous ethanol, and 1.33 mL of triethylamine was added dropwise with constant stirring, and the reaction was carried out for 10 min at room temperature.A solution of sodium ethoxide (1.36 g, 20 mmoL) in absolute ethanol (20 mL) was added dropwise on an ice bath and allowed to react for 45 min at room temperature after the addition was complete.A solution of <strong>[759-36-4]diethyl isopropylmalonate</strong> (2.0 g, 10 mmoL) in absolute ethanol (20 mL) was added dropwise with constant stirring, and the temperature was raised to reflux for 15 hours.After TLC tracking, after the reaction was completed, the mixture was filtered by suction and the filtrate was collected. The filtrate was evaporated and the solvent was removed to give a yellow solid.100 mL of water was dissolved and 100 mL of ethyl acetate was extracted three times. Fat-soluble impurities were removed and the aqueous phases were combined.Butanol was extracted and the n-butanol layer was collected, rotary evaporated and the solvent removed to give a pale yellow solid.The trichloromethane was dissolved and suction filtered to remove impurities that were insoluble in chloroform. The filtrate was collected and spin-dried to give a white solid, 0.603 g, which was compound 3-isopropyl-tetrahydropyrrole [1,2-a]pyrimidine- 2,4(1H,3H)-dione, yield 31.08%.Nuclear magnetic resonance spectrum data of the compound 3-isopropyl-tetrahydropyrrolo[1,2-a]pyrimidine-2,4(1H,3H)-dione: 1H NMR (400 MHz, CDCL3) delta 4.17-4.11 ( m, 1H), 3.63 (t, J=7.1Hz, 2H), 2.96 (d, J=9.7Hz, 1H), 2.85 (t, J=8.1Hz, 2H), 2.33-2.24 (m, 1H), 2.18-2.12(dt,2H), 1.02(d,J=6.7Hz,3H),0.95(d,J=6.6Hz,3H).The nuclear magnetic hydrogen spectrum of 3-isopropyl-tetrahydropyrrolo[1,2-a]pyrimidine-2,4(1H,3H)-dione is shown in FIG. The NMR carbon spectrum data were: 13C NMR (400 MHz, CDCL3) delta 172.53, 171.75, 63.62, 60.37, 47.24, 30.47, 29.58, 20.95, 20.66, 14.24.The nuclear magnetic carbon spectrum of 3-isopropyl-tetrahydropyrrolo[1,2-a]pyrimidine-2,4(1H,3H)-dione is shown in FIG.

Reference： [1]Patent: CN104693205,2017,B .Location in patent: Paragraph 0047; 0048; 0049; 0050

43
[ 759-36-4 ]
[ 30405-75-5 ]
diethyl 2-(2-(3,4-dimethoxyphenyl)allyl)-2-isopropylmalonate [ No CAS ]

Reference： [1]Organic Letters,2018,vol. 20,p. 4032 - 4035

44
[ 759-36-4 ]
[ 17356-08-0 ]
[ 74-88-4 ]
6-hydroxy-5-isopropyl-2-(methylthio)pyrimidin-4(1H) -one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%		To a solution of thiourea (1.71 g, 22.5 mmol) in MeOH (15 mL) was addedfreshly prepared NaOMe (NaH in 60% in mineral oil (0.99 g, 24.8 mmol) and MeOH (5 mL)were stirred at RT for 15 min). To this mixture diethyl2-isopropylmalonate (4.56 g, 22.5mmol) was added in MeOH (15 mL). The resulting mixture was heated at reflux overnight.The reaction was allowed to cool toRT, additional NaOMe (NaH (60% in mineral oil; 0.99 g,24.8 mmol) and MeOH (5 mL)) was added and the reaction was heated at reflux for 1.5 h.The reaction was allowed to cool toRT, Mel (1.55 mL, 24.8 mmol) was added and thereaction was heated at reflux overnight. The reaction was concentrated, ice-water was addedand then acidified with cone HCl. The resulting mixture was filtered, washed with water,diethyl ether, and hexanes to give the product (3.78 g, 18.9 mmol, 84% yield) as a whitesolid.[0199] MS (ES+) CsH12N202S requires: 200, found: 201 [M+H]+.

Reference： [1]Patent: WO2018/213777,2018,A1 .Location in patent: Paragraph 0198; 0199

45
[ 759-36-4 ]
thiazole-5-carboxamidine [ No CAS ]
5-isopropyl-2-(thiazol-5-yl)pyrimidine-4,6(1H,5H)dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium ethanolate; In ethanol; at 55℃;	To a solution of the material from the previous step (300 mg, 1.24 mmol) inethanol (3 mL) were added NaOEt in EtOH (1.86 mL, 4.98 mmol; 21% w.t.) and diethyl2-isopropylmalonate (302 mg, 1.49 mmol) and the resulting mixture was stirred at 55 ocovernight. The volatiles were removed under reduced pressure. The residue was treated with1M HCl, whereupon a brown precipitate was formed. DCM was added and the layers wereseparated. The brown precipitate was removed by filtration, and after filtration, the solid wasconfirmed to be product. The aqueous phase was extracted with DCM (3x), and the combinedorganic layers and the solid were combined, concentrated under reduced pressure andpurified via silica gel chromatography (0-20% MeOH in DCM) to give the product (194 mg,0. 818 mmol, 66% yield) as a yellow solid. MS (ES+) CwHuN302S requires: 237, found: 238 [M+Ht.

Reference： [1]Patent: WO2018/213777,2018,A1 .Location in patent: Paragraph 0286; 0287

46
[ 759-36-4 ]
[ 106-95-6 ]
[ 59726-39-5 ]

Yield	Reaction Conditions	Operation in experiment
97%		To a suspension of NaH (6.23 g, 260 mmol, 1.05 equiv) in anhyd THF (1000 mL), <strong>[759-36-4]diethyl 2-isopropylmalonate</strong> (50.0 g, 247 mmol, 1 equiv) was added dropwise for 10 min at 0 C. The resulting mixture was stirred at this temperature for 30 min, then allyl bromide (31.5 g, 260 mmol, 1.05 equiv) was added dropwise, and the reaction mixture was stirred overnight at r.t. Thereafter the resulting mixture was carefully poured into water (2000 mL), and the obtained two-phase mixture was extracted with Et2O (3 × 300 mL). The combined organic extractwas dried over Na2SO4 and then evaporated to dryness. This procedure gave 7; yield: 58.5 g (97%); colorless oil. IR (neat): 3080w, 2980w, 2939w, 2880w, 1724s, 1640w, 1465w,1369w, 1275m, 1226s, 1136m, 1042s, 918m, 858w cm-1. 1H NMR (400 MHz, CDCl3): delta = 5.74 (ddt, J = 17.1, 10.0, 7.2 Hz, 1 H), 4.91-5.16 (m, 2 H), 4.17 (q, J = 7.1 Hz, 4 H), 2.64 (d, J = 7.2 Hz, 2 H), 2.30 (spt, J = 6.9 Hz, 1 H), 1.24 (t, J = 7.2 Hz, 6 H), 0.98 (d, J = 6.9 Hz, 6H). 13C NMR (101 MHz, CDCl3): delta = 170.7, 133.5, 118.1, 61.7, 60.7, 38.1, 31.7, 18.4, 14.1. HRMS: m/z calcd for C13H22O4: 242.1518; found: 242.1533.

Reference： [1]Synthesis,2019,vol. 51,p. 1399 - 1407
[2]Patent: JP2020/59693,2020,A .Location in patent: Paragraph 0065

47
[ 759-36-4 ]
[ 61-82-5 ]
6-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ethanol; sodium; at 15 - 95℃; for 24h;	To a mixture of sodium (5.5 g, 239 mmol) and ethanol (135 ml) which was stirred at 15 oC for 1 hour was added successively <strong>[759-36-4]diethyl 2-isopropylmalonate</strong> (32 ml, 155 mmol) and 1H- 1,2,4-triazol-5-amine (9.06 g, 108 mmol). The resulting mixture was stirred at 95 C for 24 hours to form a white solution. After cooling to room temperature, the precipitates were collected by filtration and dissolved in water. The aqueous solution was acidified with 2N HCl (pH~2). The resulting precipitates were collected by filtration, washed with petroleum ether, water and dried under vacuum to afford 6-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione as a white powder.1H NMR (400 MHz, methanol-d4) delta 8.40 (s, 1 H); 3.38-3.32 (m, 1 H); 1.29 (d, J = 7.1 Hz, 6 H), 1.18-1.02 (m, 1 H).

Reference： [1]Patent: WO2018/71283,2018,A1 .Location in patent: Page/Page column 78-79

48
[ 759-36-4 ]
[ 64-17-5 ]
[ 15112-52-4 ]

Reference： [1]Organic Letters,2019,vol. 21,p. 6135 - 6139

49
[ 2403-88-5 ]
[ 759-36-4 ]
C₂₄H₄₄N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With di(n-butyl)tin oxide; In 5,5-dimethyl-1,3-cyclohexadiene; for 48h;Dean-Stark; Reflux; Inert atmosphere;	In a reaction vessel with a stirring device, thermometer, cooling tube, Dean Stark (Dean Stark) tube,Make 5.0g (0.025mol) of 1,3-Diethyl 2-isopropanylmalonate 3.8.5g (0.054mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine 2And 0.06g (0.241mmol) of dibutyltin oxide dissolved in xylene (25mL),And heated to reflux under nitrogen atmosphere for 48 hours.The methanol produced on the way is separated by Dean Stark.After cooling at room temperature, the reaction solution was diluted with water and dichloromethane, and multiple phases were separated.Thereafter, after extracting the organic layer, it was washed with distilled water and dried in magnesium sulfate.Using a solution in which n-heptane: ethyl acetate = 1: 1 and 5% by weight of triethylamine is dissolved,Elution was performed in a silica gel column to obtain compound Y (10.3 g, 58% yield).

Reference： [1]Patent: CN110835317,2020,A .Location in patent: Paragraph 0288-0292

50
[ 759-36-4 ]
[ 528-92-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 20 - 25 °C 1.2: 20 - 45 °C 2.1: sodium bromide / water; dimethyl sulfoxide / 12 h / 140 - 160 °C 3.1: sodium hydride / N,N-dimethyl-formamide / 4 h / 10 - 15 °C 3.2: 10 h / 10 - 15 °C

Reference： [1]Current Patent Assignee: VENKATA NARAYANA ACTIVE INGREDIENTS PRIVATE - JP2020/59693, 2020, A

51
[ 759-36-4 ]
[ 382-14-9 ]
C₁₄H₂₀F₆O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%	With N,N,N-tributylbutan-1-aminium fluoride In acetonitrile at -20℃; for 2.5h;

Reference： [1]Delamare, Aline; Naulet, Guillaume; Kauffmann, Brice; Guichard, Gilles; Compain, Guillaume [Chemical Science, 2022, vol. 13, # 33, p. 9507 - 9514]

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Technical Information

• Acyl Group Substitution • Alcohols Convert Acyl Chlorides into Esters • Alcoholysis of Anhydrides • Amines Convert Esters into Amides • Bouveault-Blanc Reduction • Catalytic Hydrogenation • Claisen Condensations Produce β-Dicarbonyl Compounds • Claisen Condensations Produce β-Dicarbonyl Compounds • Complex Metal Hydride Reductions • Convert Esters into Aldehydes Using a Milder Reducing Agent • Decarboxylation of 3-Ketoacids Yields Ketones • Deprotection of Cbz-Amino Acids • Ester Cleavage • Ester Hydrolysis • Grignard Reagents Transform Esters into Alcohols • Hantzsch Pyridine Synthesis • Heat of Combustion • Ketones Undergo Mixed Claisen Reactions to Form β-Dicarbonyl Compounds • Reactions with Organometallic Reagents • Reduction of an Ester to an Alcohol • Reduction of an Ester to an Aldehyde • Specialized Acylation Reagents-Carbodiimides and Related Reagents • The Cycloaddition of Dienes to Alkenes Gives Cyclohexenes • Transesterification

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Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 759-36-4 ] {[proInfo.proName]}

Quality Control of [ 759-36-4 ]

Related Doc. of [ 759-36-4 ]

Product Details of [ 759-36-4 ]

Calculated chemistry of [ 759-36-4 ] Expand+

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 759-36-4 ]

Application In Synthesis of [ 759-36-4 ]

[ 759-36-4 ] Synthesis Path-Upstream 1~4

[ 759-36-4 ] Synthesis Path-Downstream 1~51

Technical Information

Related Functional Groups of [ 759-36-4 ]

Aliphatic Chain Hydrocarbons

Esters

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 759-36-4 ]