[ CAS No. 636-61-3 ] {[proInfo.proName]}

Name: 636-61-3|(R)-2-Hydroxysuccinic acid|98%
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3d Animation Molecule Structure of 636-61-3

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Quality Control of [ 636-61-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 636-61-3 ]

SDS Specification

Alternatived Products of [ 636-61-3 ]

Product Details of [ 636-61-3 ]

CAS No. :	636-61-3	MDL No. :	MFCD00004245
Formula :	C₄H₆O₅	Boiling Point :	-
Linear Structure Formula :	HO₂CCH₂CH(OH)CO₂H	InChI Key :	BJEPYKJPYRNKOW-UWTATZPHSA-N
M.W :	134.09	Pubchem ID :	92824
Synonyms :		Chemical Name :	(R)-2-Hydroxysuccinic acid

Calculated chemistry of [ 636-61-3 ] Expand+

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.5
Num. rotatable bonds :	3
Num. H-bond acceptors :	5.0
Num. H-bond donors :	3.0
Molar Refractivity :	26.05
TPSA :	94.83 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-8.01 cm/s

Lipophilicity

Log Po/w (iLOGP) :	-0.07
Log Po/w (XLOGP3) :	-1.26
Log Po/w (WLOGP) :	-1.09
Log Po/w (MLOGP) :	-1.37
Log Po/w (SILICOS-IT) :	-1.25
Consensus Log Po/w :	-1.01

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	0.32
Solubility :	280.0 mg/ml ; 2.09 mol/l
Class :	Highly soluble
Log S (Ali) :	-0.24
Solubility :	78.0 mg/ml ; 0.582 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	1.53
Solubility :	4510.0 mg/ml ; 33.7 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.27

Safety of [ 636-61-3 ]

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

Application In Synthesis of [ 636-61-3 ]

* 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 [ 636-61-3 ]
Downstream synthetic route of [ 636-61-3 ]

[ 636-61-3 ] Synthesis Path-Upstream 1~2

1
[ 64-17-5 ]
[ 636-61-3 ]
[ 7554-28-1 ]

Reference： [1] Journal of Organic Chemistry, 1999, vol. 64, # 22, p. 8267 - 8274
[2] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 8, p. 2696 - 2706
[3] Organic Letters, 2005, vol. 7, # 11, p. 2261 - 2264
[4] Tetrahedron Asymmetry, 1997, vol. 8, # 3, p. 417 - 423
[5] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 22, p. 4936 - 4943
[6] Journal of Biological Chemistry, 1947, vol. 169, p. 183,184
[7] Journal of the American Chemical Society, 1966, vol. 88, # 22, p. 5306 - 5315
[8] Tetrahedron Letters, 1992, vol. 33, # 11, p. 1415 - 1418
[9] Tetrahedron Letters, 2002, vol. 43, # 48, p. 8657 - 8660
[10] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 963 - 968

2
[ 636-61-3 ]
[ 67-63-0 ]
[ 83540-97-0 ]

Reference： [1] Journal of Organic Chemistry, 1982, vol. 47, # 25, p. 4928 - 4933

[ 636-61-3 ] Synthesis Path-Downstream 1~61

1
[ 64-17-5 ]
[ 636-61-3 ]
[ 7554-28-1 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; at 100℃; for 0.5h;Microwave irradiation;	Compound 5 was prepared as previously reported [1] or using the microwave conditions as described below. (R)-Malic acid (1.0 g, 7.5 mmol) was weighed into a microwave tube equipped with a stir bar before addition of anhydrous ethanol (5 mL). Thionyl chloride (0.25 mL, 3.4 mmol) was next added dropwise, and the tube was sealed. The resulting light yellow mixture was allowed to react in a microwave reactor for 30 min at 100 C. Then the yellow reaction mixture was diluted in diethyl ether (40 mL) and washed with a saturated solution of NaHCO3 (20 mL). The organic layer was dried over anhydrous Na2SO4. The white solid was filtered off and the solution concentrated in vacuo by rotary evaporation. The crude product was obtained as a clear, light-yellow oil, which was used directly in the next step. Yield: 1.3 g, 90%. Characterization matched previous report of this known compound [1].

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 8267 - 8274
[2]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2696 - 2706
[3]Organic Letters,2005,vol. 7,p. 2261 - 2264
[4]Tetrahedron Asymmetry,1997,vol. 8,p. 417 - 423
[5]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4936 - 4943
[6]Journal of Biological Chemistry,1947,vol. 169,p. 183,184
[7]Journal of the American Chemical Society,1966,vol. 88,p. 5306 - 5315
[8]Tetrahedron Letters,1992,vol. 33,p. 1415 - 1418
[9]Tetrahedron Letters,2002,vol. 43,p. 8657 - 8660
[10]Beilstein Journal of Organic Chemistry,2016,vol. 12,p. 963 - 968

2
[ 2058-58-4 ]
[ 636-61-3 ]

Reference： [1]Chemische Berichte,1886,vol. 19,p. 1694
Gazzetta Chimica Italiana,1887,vol. 17,p. 127,186

3
[ 67-56-1 ]
[ 636-61-3 ]
[ 70681-41-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride; at 0 - 20℃;Inert atmosphere;	SOCl2 (2.40 mL) was added dropwise to a solution of (R)-malic acid 4 (2.0024 g, 15 mmol) in MeOH (20 mL) at 0oC. The solution was stirred at room temperature for 24 hours then concentrated under reduced pressure. Flash chromatography (1:1 EtOAc:Pet ether) gave 5 (2.4034 g, 99%) as a light yellow oil, with spectral data in accordance with the literature [6, 7]. Rf (1:1 EtOAc:Pet ether): 0.30. 1H NMR (500 MHz, CDCl3) ppm 4.52 (q, J = 5.5 Hz, 1H, H2), 3.82 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 2.95-2.74 (m, 2H, H3). 13C NMR (126 MHz, CDCl3) d ppm 173.9, 171.2, 67.4, 53.1, 52.2, 38.6. HRMS (ESI): Calcd. for C6H10NaO5 [M+Na]+: 185.0420; found: 185.0427.
98%	With boron trifluoride diethyl etherate; at 0℃; for 12h;Inert atmosphere;	To a solution of the (R)-malic acid (1.5 g, 11.2 mmol) in MeOH (20 mL) at 0 C was slowly added BF3·Et2O (0.4 mL) dropwise at 0 C. After being stirred for 12 h, the solvent was removed under reduced pressure and dissolved in ethyl acetate. The organic layer was then washed with a saturated NaHCO3 solution and dried over Na2SO4. Removal of the solvent afforded the crude product, which was purified by silica column chromatography (30% ethyl acetate hexane) to afford (R)-dimethyl malate (1.6 g, 98%). (c 1.12, CH3OH). 1H NMR (300 MHz, acetone-d6): delta = 4.56-4.48 (m, 1H), 3.71 (s, 3H), 3.64 (s, 3H), 2.84-2.62 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3): delta = 173.6, 170.9, 67.1, 52.7, 51.9, 38.3 ppm. To a solution of (R)-dimethyl malate (6 g, 37.0 mmol) in dry THF (60 mL) was added the BH3DMS complex (2 M solution in THF 15 mL, 37.0 mmol) at room temperature and the reaction was stirred for 30 min. The reaction mixture was then cooled to 0 C after which a catalytic amount of NaBH4 (ca. 16 mg) was added under N2 and allowed to stir for an additional 30 min at 0 C. After being stirred, the reaction was slowly warmed to rt and stirring continued over night. The reaction mixture was quenched with methanol (15 mL) and then stirred for 0.5 h. The solvent was removed and the crude product was purified by flash column chromatography (25% acetone-hexane) to afford 34 (1.2 g, 89%) as a colourless oil. (c 1.08, CH3OH). 1H NMR (300 MHz, acetone-d6): delta = 4.09-3.99 (m, 1H), 3.82 (t, J = 4.9 Hz, 1H), 3.63 (s, 3H), 3.50 (t, J = 5.2 Hz, 1H), 2.62-2.51 (m, 1H), 2.42-2.31 (m, 1H) ppm. 13C NMR (75 MHz, acetone-d6): delta = 173.7, 70.6, 67.4, 59.7, 40.2 ppm. ESI-MS: m/z = 257 [M+Na]+.
59%		Acetyl bromide (2.2mL, 0.031mol) was added dropwise to 20mL cold methanol. The solution was stirred for 30min in ice. Then R-malic acid, R-3, (12.5g, 93.28mmol) was added. The acid dissolved in about 5min, and the resulting solution was stirred at ambient temperature. After 18h, sodium bicarbonate (4.00g, 0.048mol) was added to the pale yellow solution. After 15min of stirring, the mixture was filtered, the filtrate collected, and all volatile compounds evaporated in vacuum, yielding a sticky, oily raw material containing a white precipitate. The desired ester was distilled from this mixture in vacuum yielding 8.88g of R-5 (54.77mmol, 59%) of a colorless liquid; bp 65-80C (0.9torr); [alpha]23.5D=+9.7[alpha]D23.5=+9.7 (c 0.288, EtOH) (lit. [44] [alpha]25D=+9.6[alpha]D25=+9.6 (c 2.3, EtOH); deltaH (CDCl3) 4.51 (dd, 6.0, 4.3, 1H), 3.81 (s, 3H), 3.71 (s, 3H), 3.28 (br. s, 1H), 2.87 (dd, 16.6, 4.5, 1H), 2.79 (dd, 16.3, 6.0, 1H); deltaC (CDCl3) 173.6, 170.9, 67.1, 52.6, 51.9, 38.3; numaxcm-1 (thin film on KBr) 3470 (br), 2958, 1737 (s), 1442, 1220. The NMR, IR and optical rotation data agree well with literature data [43,44].

59%		Acetyl bromide (2.2 mL, 0.031 mol) was added dropwise to 20 mL cold methanol. The solution was stirred for 30 minutes in ice. Then R-malic acid R-3, (12.5 g, 93.28 mmol) was added. The acid dissolved in about 5 min, and the resulting solution was stirred at ambient temperature. After 18 h, sodium bicarbonate (4.00 g, 0.048 mol) was added to the pale yellow solution. After 15 min of stirring, the mixture was filtered, the filtrate collected, and all volatile compounds evaporated in vacuum, yielding a sticky, oily raw material containing a white precipitate. The desired ester was distilled from this mixture in vacuum yielding 8.88 g of (R)-methyl malate (R-5) (54.77 mmol, 59%) of a colorless liquid
	With thionyl chloride; at 20℃; for 12h;	General procedure: Compounds 1-6 and 10-11 (3.0 mg each) were, respectively, dissolved in 100 muL methanol and added to 100 muL 10% K2CO3 (methanol/water 2: 1, v/v). After hydrolysis at 60C for 2 h, the reaction mixtures were blow-dried, then acidified by 0.1 M HCl (500 muL) and extracted with EtOAc (500 muL×3). The aqueous layers were blow-dried and dissolved in methanol (200 muL). A drop of SOCl2 was added to the solution to catalyze the esterification (room temperature, 12 h). After evaporation, the mixed methyl esters of 4-hydroxytiglic acid and malic acid (or tartaric acid) were dissolved in dry pyridine (100 muL) and reacted with (S)-MTPA chloride (2 muL) overnight to obtain the final products. The corresponding authentic (R)-MTPA esters were also prepared from the commercial <strong>[636-61-3]D-malic acid</strong>, L-malic acid, D-tartaric acid and L-tartaric acid. The 1H NMR data of the authentic (R)-MTPA esters of dimethyl malates were in accord with the reported.8

Reference： [1]Bioorganic and medicinal chemistry,2002,vol. 10,p. 1829 - 1839
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 5387 - 5396
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6838 - 6841
[4]European Journal of Organic Chemistry,2013,p. 376 - 388
[5]Tetrahedron Asymmetry,2013,vol. 24,p. 1010 - 1022
[6]Journal of the American Chemical Society,1997,vol. 119,p. 7483 - 7498
[7]Synthetic Communications,2014,vol. 44,p. 500 - 506
[8]Journal of Catalysis,2016,vol. 338,p. 349 - 364
[9]Patent: US2017/275303,2017,A1 .Location in patent: Paragraph 0044; 0045
[10]Tetrahedron,1979,vol. 35,p. 933 - 940
[11]Tetrahedron Letters,1993,vol. 34,p. 8439 - 8442
[12]Journal of Medicinal Chemistry,2003,vol. 46,p. 3985 - 4001
[13]Tetrahedron,2015,vol. 71,p. 5362 - 5370

4
[ 1783-96-6 ]
[ 636-61-3 ]

Reference： [1]Tetrahedron Letters,1984,vol. 25,p. 3705 - 3706

5
[ 636-61-3 ]
[ 70005-88-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	With Trimethyl borate; dimethylsulfide borane complex; In tetrahydrofuran;	To a mixture of BH3SMe2 (2 M in THF, 60 mL, 120 mmol) and B(OMe)3 (13.5 g, 130 mmol) in THF (30 mL) at 0C was added a solution of (R)-malic acid (5.0 g, 37.3 mmol) in THF (30 mL). The mixture was stirred at r.t. for 16 hr then quenched with MeOH (75 mL) and concentrated under reduced pressure. The residue was purified by flash column chromatography to give afford the desired product (3.5 g, 89 % yield). LC-MS: m/z 107 (M+H)+.
85%	With Trimethyl borate; dimethylsulfide borane complex; In tetrahydrofuran; at 20℃; for 22h;	[[2R]-BUTANE-1,] 2, [4-TRIOL.] To a dry 1L two-necked flask equipped with a pressure-equalizing addition funnel, a magnetic stirring bar and a reflux condenser was added THF (200 mL), B (OMe) 3 (100 mL), and [(R)- (+)-MALIC] acid (40.0 g, 0.30 mol). To this solution was added dropwise BH3-SMe2 (100 mL, 1.0 mol) over 2 h in a water bath as instantaneous H2 evolution occurred throughout the addition. After stirring for 20 h at rt, MeOH (200 mL) was added dropwise, and the resulting solution was filtered through a glass frit funnel charged with Celite to remove any solids. The clear, yellow filtrate was concentrated [IRA] vacuo to give a yellow oil. The residue was dissolved in MeOH (100 mL) and concentrated in vacuo. This was repeated 5 times giving 26.9 g of the triol [(85%).] The spectral data matched that of the known compound.

Reference： [1]Tetrahedron,2011,vol. 67,p. 5083 - 5097
[2]Tetrahedron,1990,vol. 46,p. 6731 - 6740
[3]Tetrahedron Asymmetry,1991,vol. 2,p. 191 - 194
[4]Tetrahedron Asymmetry,1996,vol. 7,p. 3209 - 3246
[5]Patent: WO2016/112088,2016,A1 .Location in patent: Paragraph 0486
[6]Patent: WO2004/22552,2004,A1 .Location in patent: Page 81
[7]Bioscience, Biotechnology and Biochemistry,1995,vol. 59,p. 497 - 500
[8]Tetrahedron Letters,1997,vol. 38,p. 603 - 606
[9]Journal of Organic Chemistry,2004,vol. 69,p. 8694 - 8701
[10]Journal of the American Chemical Society,2005,vol. 127,p. 10396 - 10399
[11]Australian Journal of Chemistry,1990,vol. 43,p. 1391 - 1405
[12]Organic and biomolecular chemistry,2003,vol. 1,p. 4173 - 4208
[13]Letters in Organic Chemistry,2011,vol. 8,p. 143 - 149
[14]Tetrahedron Letters,2016,vol. 57,p. 4670 - 4672
[15]Organic and Biomolecular Chemistry,2016,vol. 14,p. 9554 - 9559
[16]Angewandte Chemie - International Edition,2017,vol. 56,p. 14883 - 14887
Angew. Chem.,2017,vol. 129,p. 15079 - 15083,5
[17]Angewandte Chemie - International Edition,2018,vol. 57,p. 5147 - 5150
Angew. Chem.,2018,vol. 130,p. 5241 - 5244,4

6
[ 636-61-3 ]
[ 42890-76-6 ]

Reference： [1]Australian Journal of Chemistry,1990,vol. 43,p. 1391 - 1405

7
[ 80513-23-1 ]
[ 636-61-3 ]
[ 110-17-8 ]

Reference： [1]Journal of the American Chemical Society,1982,vol. 104,p. 166 - 168

8
[ 636-61-3 ]
[ 67-63-0 ]
[ 83540-97-0 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 4928 - 4933

9
[ 636-61-3 ]
[ 77-76-9 ]
[ 73991-95-4 ]

Yield	Reaction Conditions	Operation in experiment
79%	In toluene; for 2.5h;Heating / reflux;	Preparation 1 f(4R)-2,2-Dimethvl-5-oxo-1 ,3-dioxolan-4-vllacetic acid2,2-Dimethoxypropane (75mL, 610mmol) was added to,a suspension of D(+)malic acid (19.8g, 148mmol) in toluene (20OmL) and the mixture was heated under reflux for 2.5 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with diethyl ether. The appropriate fractions were evaporated under reduced pressure and the residue was further purified by column chromatography on silica gel, eluting with heptane:diethyl ether, 66:33 to 50:50 to 0:100, to afford the title compound in 79% yield, 20.2g.1HNMR(400MHz, CDCI3) delta: 1.58(s, 3H), 1.63(s, 3H), 2.80-3.05(m, 2H), 4.70(m, 1 H)
79%	In toluene; for 2.5h;Heating / reflux;	Preparation 1; ff4R)-2.2-Diotamethyl-5-oxo-1,3-diotaoxolan-4-y)1acetiotac acid; 2,2-Diotamefhoxypropane (75mL, 610mmol) was added to a solution of D(+)maliotac acid (19 8g, 148mmol) in toluene (20OmL) and the mixture was heated under reflux for 2.5 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with diethyl ether The appropriate fractions were evaporated under reduced pressure and the residue was further purified by column chromatography on silica gel, eluting with heptane diethyl ether, 66:33 to 50 50 to 0:100, to afford the title compound in 79% yield, 20.2g.1HNMR(400MHz, CDCI3) delta 1 58(S, 3H), 1 63(S, 3H), 2 80-3 05(m, 2H), 4 70(m, 1 H)
	With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 4h;	Step 1: [(4R)-2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid To a suspension of D-(+)-malic acid (10 g, 75 mmol) in CH2Cl2 (100 mL) was added 2,2-dimethoxypropane (23 g, 225 mmol) and p-toluenesulfonic acid (0.129 g, 0.75 mmol). The reaction mixture was stirred at rt for 4 h, filtered through silica gel (50% EtOAc/hexane) and concentrated to give the title compound. 1H NMR (300 MHz, CDCl3): delta9.70 (s, 1H), 4.69-4.73 (m, 1H), 2.97-3.04 (m, 1H), 2.81-2.89 (m, 1H), 1.62 (s, 3H), 1.57 (s, 3H).

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 5313 - 5316
[2]Tetrahedron Letters,1987,vol. 28,p. 1685 - 1688
[3]Journal of Medicinal Chemistry,1998,vol. 41,p. 199 - 223
[4]Organic Letters,2012,vol. 14,p. 3648 - 3651
[5]Angewandte Chemie - International Edition,2011,vol. 50,p. 8739 - 8744
[6]Journal of Medicinal Chemistry,2008,vol. 51,p. 5387 - 5396
[7]Patent: WO2007/57767,2007,A2 .Location in patent: Page/Page column 30
[8]Patent: WO2007/57756,2007,A2 .Location in patent: Page/Page column 29
[9]Organic and Biomolecular Chemistry,2012,vol. 10,p. 5861 - 5872
[10]Tetrahedron Letters,1997,vol. 38,p. 4935 - 4938
[11]Patent: US2008/132542,2008,A1 .Location in patent: Page/Page column 30
[12]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9212 - 9216

10
[ 3068-00-6 ]
[ 636-61-3 ]
benzylating reagent [ No CAS ]
[ 115114-87-9 ]
[ 85960-55-0 ]

Reference： [1]Journal of Organic Chemistry,1991,vol. 56,p. 2262 - 2264

11
[ 3068-00-6 ]
[ 636-61-3 ]
benzylating reagent [ No CAS ]
[ 71998-70-4 ]
[ 69985-32-6 ]

Reference： [1]Journal of Organic Chemistry,1991,vol. 56,p. 2262 - 2264

12
[ 3068-00-6 ]
[ 636-61-3 ]
benzylating reagent [ No CAS ]
[ 132980-10-0 ]
[ 132980-11-1 ]
[ 132980-09-7 ]

Reference： [1]Journal of Organic Chemistry,1991,vol. 56,p. 2262 - 2264

13
[ 636-61-3 ]
[ 630-19-3 ]
[ 186906-71-8 ]

Yield	Reaction Conditions	Operation in experiment
79.3%	With sulfuric acid; toluene-4-sulfonic acid; In pentane; at 48 - 53℃; for 72h;Dean-Stark;	Pivalaldehyde (25 ml, 19.5 g, MW 86.13, 226.4 mmol, 1.1 eq) was dissolved in n-Pentane (270 ml). D-(+)-malic acid (27.6 g, MW 134.08, 205.82 mmol, 1 eq.), PTSA (3.9 g, MW 190, 20.6 mmol, 0.1 eq.) and H2SO4 (98 %, 0.2 ml) were added. The reaction mixture was heated at 48-53 C under stirring for 72 hours removing water with a Dean-Stark apparatus. The reaction mixture was filtered, the residue solubilized in DCM (1L) and washed twice with aqueous PO4 (8 %, 2 x 100 ml) dried (Na2SO4) and evaporated till dryness (40 g). The residue was crystallized from DCM (120 mL) at - 22C. Dioxolanone (XIII) was isolated as a white solid (33 g, MW 202.21 , 163.2 mmol, reaction yield 79.3%).
64%	With sulfuric acid; toluene-4-sulfonic acid; In pentane; for 40h;Reflux; Inert atmosphere;	To a suspension of D-(+)-malic acid (10 g, 74.58 mmol) and pivalaldehyde (13.2 mL, 116.1 mmol) in pentane (150 mL),PTSA (1.1 g, 6.39 mmol) and concentrated H2SO4 (2 drops) were added. The mixture was heatedunder reflux for 40 h with azeotropic removal of water. The resulting suspension was filtered.The solid cake was dissolved in CH2Cl2, and washed with 8% aqueous H3PO4 (2×40 mL). Thecombined organic phases were dried with Na2SO4. The solvent was removed under vacuum,giving 9.554 g of the product as a white solid (yield 64%). [alpha]D24 +2.20 (c 1.00, MeOH). 1HNMR (300 MHz, CDCl3): deltaH 5.33 (m, 1H), 4.77 - 4.54 (m, 1H), 3.08 - 2.77 (m, 2H), 0.98 (s,9H). 13C NMR (75 MHz, CDCl3): deltac 1745.0, 172.4, 111.4, 71.4, 35.9, 35.4, 23.4.
64%	With sulfuric acid; toluene-4-sulfonic acid; In pentane; for 40h;Reflux; Inert atmosphere;	To a suspension of D- (+)-malic acid (10 g, 74.58 mmol) and pivalaldehyde (13.2 mL, 116.1 mmol) in pentane (150 mL), PTSA (1.1 g,6.39 mmol) and concentrated H2SO4 (2 drops) were added.The mixture was heated under reflux for 40 hours with azeotropic removal of water. The resulting suspension was filtered. The solid cake was dissolved in CH2Cl2, and washed with 8% aqueous H3PO4(2×40 mL). The combined organic phases were dried with Na2SO4.The solvent was removed under vacuum, giving 9.554 g of the product as a white solid (yield 64%). [alpha]D24 +2.20 (c 1.00, MeOH). 1H NMR (500MHz, CDCl3): deltaH 5.33 (m,1H), 4.77 - 4.54 (m, 1H), 3.08 - 2.77 (m, 2H), 0.98 (s, 9H). 13C NMR(126 MHz, CDCl3): deltac 1745.0, 172.4, 111.4, 71.4, 35.9,35.4, 23.4.

Reference： [1]Tetrahedron Letters,2005,vol. 46,p. 3815 - 3818
[2]European Journal of Organic Chemistry,2005,p. 2965 - 2972
[3]Chemistry - A European Journal,2008,vol. 14,p. 4293 - 4306
[4]Patent: WO2018/19549,2018,A1 .Location in patent: Page/Page column 12-13
[5]ARKIVOC,2014,vol. 2014,p. 206 - 212
[6]Tetrahedron Letters,2016,vol. 57,p. 216 - 218
[7]Angewandte Chemie - International Edition,2000,vol. 39,p. 4339 - 4341

14
[ 636-61-3 ]
[ 108-94-1 ]
[ 632357-87-0 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 4 (5.31 g, 39.63 mmol) in Et2O (60 mL) cooled to 0 C was added first BF3·OEt2 (7.1 mL, 57.46 mmol) and then distilled cyclohexanone (4.5 mL, 43.59 mmol). The mixture was stirred at 0 C for 1 hour and then at room temperature for 4 days. The reaction mixture was quenched with aq. 10% NaOAc (150 mL), the solution was stirred for 2 hours, and then extracted with CH2Cl2 (3x 100 mL). The combined organic phases were dried (Na2SO4), filtered and the solvent evaporated under reduced pressure to yield acid 6. (R)-2-(3-Oxo-1,4-dioxaspiro[4.5]decan-2-yl)acetic Acid (6). Rf = 0.78 (EtOAc); [alphaD]25 -16.9 (c 0.6, CHCl3). IR (NaCl, neat): 3035, 2943, 2866, 1793, 1724 cm-1. 1H NMR (400 MHz, CDCl3): delta = 4.71 (dd, J = 3.9, 6.5 Hz, 1 H, H-2); 2.98 (dd, J = 3.9, 17.2 Hz, 1 H, H-1?); 2.83 (dd, J = 6.5, 17.2 Hz, 1 H, H-1?); 1.83 (m, 2 H, CHeq-6, CHeq-10 ); 1.6-1.77 (m, 6 H, CHax-6, CHax-10, CH2-7, CH2-9); 1.44 (m, 2 H, CH2-8). 13C NMR (100 MHz, CDCl3): delta = 174.46 (C-2?); 171.92 (C-3); 121.12 (C-5); 70.01 (CH-2); 36.19 (CH2-1?); 36.15, 35.33 (CH2-6, CH2-10); 24.40 (CH2-8); 22.93 (CH2-7, CH2-9). MS (ESI+): m/z (%) = 237.07 ([M + Na] +, 100), 215.2 ([M] +, 12), 201.04 (13), 179.01 (21), 157.01 (27). HRMS (ESI+): m/z calcd for C10H14O5 + Na: 237.0739; found: 237.0733.

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 19 - 27
[2]Journal of Organic Chemistry,2003,vol. 68,p. 8080 - 8087
[3]Organic Letters,2006,vol. 8,p. 5601 - 5604
[4]Journal of the American Chemical Society,2002,vol. 124,p. 384 - 385
[5]Tetrahedron Letters,2011,vol. 52,p. 5983 - 5986

15
[ 636-61-3 ]
[ 100-51-6 ]
[ 83477-74-1 ]

Yield	Reaction Conditions	Operation in experiment
28 g		To (R)-2-Hydroxy-succinic acid (10 g) was added under cooling trifluoracetic acid anhydride (25 mL) and the mixture is stirred at ambient temperature. After 4 h the solution was concentrated under vacuum to which benzyl alcohol was added and the mixture was stirred over night. The solution was concentrated under vaccum (3 mbar, 6000) and the residual oil (28 g) was used without further purification in the next step.Analysis: HPLC-MS: R1 = 0.99 mm (method E), M+H = 225

Reference： [1]Journal of Natural Products,2019,vol. 82,p. 417 - 421
[2]Journal of the American Chemical Society,2001,vol. 123,p. 9935 - 9946
[3]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 239 - 252
[4]Patent: WO2017/42100,2017,A1 .Location in patent: Page/Page column 41

16
[ 636-61-3 ]
[ 43200-80-2 ]
[ 863393-46-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	In methanol; acetone at 10 - 48℃; for 4h;	8.a Example 8: Preparation of Eszopiclone starting from zopiclone a) Preparation of eszopiclone D-(+)-malate[0071 ] To the mixture of zopiclone prepared according to the example 2 (15g) in methanol (152ml) and acetone (283ml) was added D-(+)-mah'c acid (5.27g) and the mixture was heated to 48°C. Complete dissolution was obtained. After seeding with D-(+)-eszopiclone rnalate, the reaction mixture was cooled over four hours to about 1O0C. The obtained solid was filtrated and washed with methanol. After drying in vacuum oven at 400C the product eszopiclone D-(+)-malate was obtained (8.73g; yield 88.0%; optical purity 98.2% eszopiclone).
41%	In methanol; acetone at 55 - 56℃; for 0.5h;	1 A three-neck 3.0 L flask was charged with zopiclone (50 g, 0.126 mol), D-malic acid (16.7 g, 0.125 mol), 508 mL MeOH and 945 mL acetone. The reaction mixture was heated to 55-56 °C for about 30 min and gradually cooled to 45-47 °C over approximately 30 minutes. (S)-zopiclone D-malate seeds (0.18 g, 0.3 %) were added at 45-47 °C. The reaction mixture was cooled to 40 °C over 1 h and then cooled to 10-15 °C over 3 h. The slurry was held at 10-15 °C for 30 minutes. The product was isolated by filtration, washed with 150 mL of cold methanol and dried at 40 °C over 6-16 h to give (S)-zopiclone D-malate (27.0 g, 41 %, 98.5 % ee)

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/2629, 2008, A1 Location in patent: Page/Page column 15
[2]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2345655, 2011, A1 Location in patent: Page/Page column 11

17
[ 636-61-3 ]
[ 71432-55-8 ]
[ 157594-60-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	In dichloromethane; at 20℃; for 48h;Inert atmosphere;	N,N'-Diisopropyl-O-tert-butylisourea (30.00?g, 149.90?mmol, 6.7 eq.) was added to the suspension of (R)-malic acid (3.00?g, 22.40?mmol, 1.0 eq.) in DCM (150.0?mL). After stirring at rt for 48?h, the mixture was filtered through a short pad of celite. The filtrate was concentrated in vacuo and dissolved in EtOAc (100.0?mL). The solution was washed with 1?M HCl (aq.), sat. NaHCO3 (aq.), brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Cyh:EtOAc?=?9:1, v/v) to obtain ester 7 as colorless oil (4.06?g, 16.50?mmol, 74%). [alpha]25D +6.2 (c 0.87, CHCl3); IR (ATR) numax 3500, 2979, 2935, 1727, 1367, 1252, 1144, 1101?cm-1; 1H NMR (400?MHz, CDCl3) delta 4.29 (dd, J?=?5.9, 4.5?Hz, 1H), 2.71 (dd, J?=?16.3, 4.5?Hz, 1H), 2.63 (dd, J?=?16.3, 5.9?Hz, 1H), 1.45 (s, 9H), 1.44 (s, 9H); 13C NMR (100?MHz, CDCl3) delta 172.8, 169.8, 82.6, 81.3, 67.6, 39.9, 28.1, 28.0; EIMS m/z (%) 269.1 [M+Na]+ (52), 515.3 [2M + Na]+ (40); HREIMS m/z 269.1359 [M+Na]+ (calcd for C12H22NaO5+, 269.1365); Rf?=?0.51 (Cyh:EtOAc?=?4:1, v/v).

Reference： [1]Australian Journal of Chemistry,2009,vol. 62,p. 676 - 682
[2]Tetrahedron,2019,vol. 75,p. 4479 - 4485
[3]Synthetic Communications,2013,vol. 43,p. 1345 - 1350
[4]Heterocycles,2007,vol. 72,p. 181 - 185
[5]Journal of Organic Chemistry,2008,vol. 73,p. 9692 - 9697

18
[ 56-84-8 ]
[ 636-61-3 ]
[ 4198-33-8 ]
[ 6915-18-0 ]

Yield	Reaction Conditions	Operation in experiment
0.1% - 0.4%Spectr.; 86 - 87%; 0.1% - 0.2%Spectr.	With hydrogenchloride; sodium nitrite; In water; at -15 - 0℃; for 8h;	To a vigorously stirred mixture of mother waters and washing waters (approximately 650 ml) from the previous reaction are added 200 g (1.50 mol) of L-aspartic acid, 360 ml (428.4 g) of 37% HCl (158.51 g of HCl, 4.35 mol) and 100 ml of demineralised water; 184 g (2.66 mol) of solid sodium nitrite are then added in approximately 2 hours at a temperature of ?5 C. under nitrogen blanket. Stirring is continued at the same temperature for 2.5 hours, the temperature is raised to +0 C. in the space of approximately 1 hour, the mixture is left at this temperature for another period of 1 hour, and the temperature then lowered to ?15 C. After 1.5 hours at this temperature, the mixture is vacuum filtered on Buchner filters and left to drain under vacuum pump aspiration for approximately 0.5 hours. The solid is then washed with 80 ml of water at 0 C. and left on a vacuum filter for another 1.5 hours. [00082] The crude product is vacuum dried in an oven at 40 C. It presents approximately 15-20% sodium chloride contamination. [00083] The molar percentages of the impurities present, calculated on the basis of the NMR spectrum, are the following: [TABLE-US-00002] fumaric acid 0.1-0.2% w/w malic acid 0.1-0.4% w/w aspartic acid 0.1-0.2% w/w [00084] The yield of S-(?)-chlorosuccinic acid, calculated 100% pure, is 86-87%. [00085] The pure product, obtained by means of a further crystallisation of a sample of the crude product with water, has a melting point of 180-182 C. [00086] The overall yield of reactions A+B is 83-84%.
0.1 - 0.4%Spectr.; 80 - 81%; 0.1% - 0.2%Spectr.	With hydrogenchloride; sodium chloride; sodium nitrite; In water; at -15 - 0℃; for 7h;	To a vigorously stirred mixture of 200 g (1.50 mol) of L-aspartic acid, 40 g of sodium chloride (0.68 mol), 440 ml (523.6 g) of 37% HCl (193.74 g of HCl, 5.32 mol), 200 ml of demineralised water, 100 ml of washing waters of the solid obtained in REACTION B (see Example 2), are added 184 g (2.66 mol) of solid sodium nitrite in approximately 2 hours at a temperature of -5 C. under nitrogen blanket. Stirring is continued at the same temperature for 2.5 hours, the temperature is raised to +0 C. in the space of approximately 1 hour, the mixture is left at this temperature for another period of 1 hour and then the temperature is lowered to ?15 C. After 1.5 hours at that temperature, the mixture is vacuum filtered on Buchner filters and left to drain under vacuum pump aspiration for approximately 0.5 hours. The solid is then washed with 80 ml of water at 0 C. and left on a vacuum filter for another 1.5 hours. [00078] The crude product is vacuum dried in an oven at 40 C. It presents approximately 15-20% sodium chloride contamination. [00079] The molar percentages of the impurities present, calculated on the basis of the NMR spectrum, are the following: [TABLE-US-00001] fumaric acid 0.1-0.2% w/w malic acid 0.1-0.4% w/w aspartic acid 0.1-0.2% w/w [00080] The yield of chlorosuccinic acid, calculated 100% pure, is 80-81%.

Reference： [1]Patent: US6677476,2004,B1 .Location in patent: Page column 9
[2]Patent: US6677476,2004,B1 .Location in patent: Page column 9

19
[ 636-61-3 ]
[ 43200-80-2 ]
[ 1094726-30-3 ]
[ 863393-46-8 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; acetone Resolution of racemate;	In the synthetic route shown above, (RS)-Zopiclone and D-malic acid are dissolved ., in a mixture of acetone and methanol to form (S)-zopiclone D-malate and (R)-zopiclone D- malate. The two diastereomeric salts are resolved in-site by selective crystallization, filtration and rinsing to produce highly (S)-enriched zopiclone D-malate salt. In this process, the majority of (R)-zopiclone D-malate remains in the mother liquors. In this method, the use of an acetone/methanol co-solvent system results in a highly diastereoselective salt crystallization, and preferably, the co-solvent ratio used should be in the range of approximately 1.9/1 to 2.3/1 w/w acetone in methanol. Preferably, this stage of the process may also include cooling the reaction mixture during the isolation step to a temperature in the inclusive range of about 10°C to 15°C, and washing or rinsing the wet cake obtained after filtration with cold solvent, such as cold methanol.
	In methanol; aceone Resolution of racemate;	In the synthetic route shown above, (RS)-zopiclone and D-malic acid are dissolved in a mixture of acetone and methanol to form (S)-zopiclone D-malate and (R)-zopiclone D-malate. The two diastereomeric salts are resolved in-situ by selective crystallization, filtration and rinsing to produce highly (S)-enriched zopiclone D-malate salt. In this process, the majority of (R)-zopiclone D-malate remains in the mother liquors. In this method, the use of an acetone/methanol co-solvent system results in a highly diastereoselective salt crystallization, and preferably, the co-solvent ratio used should be in the range of approximately 1.9/1 to 2.3/1 w/w acetone in methanol. Preferably, this stage of the process may also include cooling the reaction mixture during the isolation step to a temperature in the inclusive range of about 10° C. to 15° C., and washing or rinsing the wet cake obtained after filtration with cold solvent, such as cold methanol. The resulting (S)-zopiclone D-malate salt is converted to optically pure (S)-zopiclone free base by treatment with aqueous potassium carbonate and ethyl acetate, followed by phase separation and crystallization. In this process, once a solution of (S)-zopiclone free-base is obtained, additional enantiomeric enrichment (typically 1 to 4%) can be achieved by crystallization from ethyl acetate of low water content. The water content can be controlled, e.g., by azeotropic distillation, and incorporating an in-process control of water content into the crystallization process can further improve the robustness of enantiomeric purity. Preferably, the water level during this step is 2% or less, more preferably 1% or less, and most preferably 0.6% or less. The resulting optically pure eszopiclone free base can then be milled to a desired size for use as an active ingredient in a pharmaceutical composition according to the present invention. These compositions are useful in treating disorders that are affected by the binding of agonists to central nervous system and peripheral benzodiazepine receptors while avoiding the adverse effects associated with the administration of the racemic mixture of zopiclone.

Reference： [1]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Pharma (in: Sumitomo Chemical); Sumitomo Chemical (w/o Dongwoo Fine-Chem) - WO2005/63297, 2005, A2 Location in patent: Page/Page column 22
[2]Current Patent Assignee: WOODWARD SPECIALTY - US2005/222156, 2005, A1 Location in patent: Page/Page column 3

20
[ 636-61-3 ]
[ 152459-95-5 ]
[ 862366-42-5 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol at 20 - 90℃;	19 Example 19; 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl] amino] phenyl]-benzamide, malate; A solution of (2R)- (-)-hydroxybutanedioic acid ( (D)-malic acid; Fluka, Buchs, Switzerland; 553 mg, 2. 83 mmol) in ethanol (60 mL) is added to a solution of 4- [ (4-methyl-1- piperazinyl) methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino] phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol (150 mL at 90°C). The hot solution is reduced in volume to 80 mL by rotary evaporation at 90°C and 400 mbar and then slowly cooled to 20°C to afford, after filtering and drying, 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl] amino] phenyl]-benzamide, malate as a crystalline solid, having the following analytical properties: Analysis found: C, 62.14 ; H, 6.33 ; N, 15. 48 ; O, 16.18%. H20, 1. 99%. Calculated for C33H37N706-0. 71 H2O : C, 61.88 ; H, 6.05 ; N, 15.31 ; O, 16.76%. H2O, 2.00%.

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2005/75454, 2005, A2 Location in patent: Page/Page column 11

21
[ 636-61-3 ]
[ 75-36-5 ]
[ 14189-99-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 45℃; for 6h;	hi accordance with Naylor et al, 4-[(Alkylamino)methyl]furo[3,2-c]pyridines: A New Series of Selective kappa-Receptor Agonists. J. Med. Chem. 1994, 37, 2138-2144, successive treatment of the corresponding free base of (32) with (i?)-(+)-2-acetoxysuccinic anhydride (95a) Step 6A: (jR)-(+)-2-Acetoxysuccinic anhydride (95a).A mixture of <strong>[636-61-3]D-malic acid</strong> (10 g, 75 mmol, Major Chemicals Co. Ltd. lot No.KS00404) in acetyl chloride (30 mL, Aldrich cat No.11 ,418-9) was heated to 45C for 6 h. The excess acetyl chloride was evaporated in vacuo and the residue was taken up in dichloromethane (10-15 mL). The volatiles were removed in vacuo and the residual oil was stored at 4C for 18 h. Under cold storage, the oil crystallized, giving rise to (R)- (+)-2-acetoxysuccinic anhydride (95a) as a white solid (11.7 g, quant yield); m.p. 52C; [CC]D +23.82 (c 5.44, acetone); 1H-NMR (300 MHz, CDCl3) delta: 5.51 (dd, IH, J6 Hz, 9 Hz), 3.36 (dd, IH, J 19 Hz, 9 Hz), 3.00 (dd, IH, J 19 Hz, 6 Hz), 2.17 (s, 3H); 13C-NMR (75 MHz, CDCl3) delta: 169.61 (+), 167.66 (+), 166.21 (+), 67.51 (-), 35.10 (+), 20.16 (-).
90%	at 45℃; for 6h;	20 ml of acetyl chloride (Compound C-2) was added to a 100 ml single-necked flask,6.7 kg of <strong>[636-61-3]D-malic acid</strong> (Compound C-1) was added with stirring, and the reaction solution was heated to 45 C and stirred for 6 hours.Acetyl chloride was distilled off under reduced pressure to give a colorless oil, which was placed after seeding and precipitated as colorless crystals.Filtration gave a white solid, petroleum ether was added, stirred for 4 hours,Again filtered to give 7.11 g of (R) - (+) - 2-acetoxysuccinic anhydride as a white solid,The yield was 90%. HPLC purity was 97.4%
90%	at 45℃; for 6h;	Acetyl chloride (Compound C-2) 20 ml was added to a 100 ml jar and <strong>[636-61-3]D-malic acid</strong> was added with stirring (Compound C-1) 6.7 kg, the reaction solution was warmed to 45C and stirred for 6 hours. Acetyl chloride was distilled off under reduced pressure to give a colorless oil which was added after seedingPlace, precipitate colorless crystals. Filter to give a white solid, add petroleum ether, stir for 4 hours, and filter again to give (3R)-2,5-dioxooxolan-3-yl acetate 7.11 g as a white solid, yield 90%, HPLC purity 97.4%.

80%	at 50℃; for 16h;Inert atmosphere;	A suspension of R-Malic acid (100 g) in acetyl chloride (265 mL, 5 equiv) was heated to 50 C under nitrogen for 16 h or until >95% conversion to the anhydride was observed by GC. At this point, the volatiles were distilled off. The resulting oil was dissolved in iPrOAc (200 mL), filtered. The filtrate was concentrated, dissolved in iPrOAc (290 mL). MTBE (750 mL) was slowly added to induce crystallization of the -acetoxy malic acid anhydride (v). After cooling to 0 C in an ice bath, the slurry was filtered and dried under N2 vacuum sweep to give 95 g (80% yield) of the R- acetoxy malic acid anhydride(v) as a colorless, crystalline solid.
	at 40℃; for 4h;	General procedure: (S)- and (R)-3-hydroxy-gamma-butyrolactone were synthesized using D- and L-malic acid as starting materials, respectively (Scheme 1). To a 100 mL flask was added L-malic acid (3, 13.4 g, 0.1 mol) and redistilled acetyl chloride (60 mL). The mixture was stirred at 40 C for 4 h. Excess solvent was evaporated with added 1,4-dioxane and white solid 4 (15.6 g, 0.0987 mol) was obtained from the residue via recrystallization with a chloroform and petroleum ether system (v/v = 1:1, CHCl3/PE). Compound 4 was then dissolved in redistilled methanol (120 mL) and stirred 30 min at room temperature. Excess methanol was evaporated to yield the crude product monomethyl ester 5 (18.6 g,0.0979 mol). After refluxing of NaBH4 (9.5 g, 0.245 mol) in t-BuOH (125 mL) for 2 h, a mixture of t-BuOH (150 mL) and MeOH (10 mL) containing compound 5 (18.6 g) was added dropwise to the mixture and then reflux was continued for 2 h. A white solid 6 was obtained by rotary evaporation. Amixed solvent of HCl/H2O/1,4-dioxane (v/v/v = 55:165:290) was added dropwise to the white solid at 70 C to prepare (S)-3-hydroxy-gamma-butyrolactone (7). After evaporation of the solvents, the white residue was extracted with THF (200 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under vacuum to yield the crude product, which was further purified by flash chromatography on silica gel using petroleum ether/ethyl acetate (4:1) as the eluent to afford(S)-3-hydroxy-gamma-butyrolactone (7.67 g, 75%) as a colorless or yellowish oil.

Reference： [1]Patent: WO2006/88525,2006,A1 .Location in patent: Page/Page column 126
[2]Patent: CN105294530,2016,A .Location in patent: Paragraph 0063-0065
[3]Patent: CN104610121,2017,B .Location in patent: Paragraph 0066-0068
[4]Patent: WO2012/24100,2012,A2 .Location in patent: Page/Page column 81-82
[5]Chemistry - A European Journal,2009,vol. 15,p. 12754 - 12763
[6]Molecules,2014,vol. 19,p. 16950 - 16958
[7]Synthetic Communications,2018,vol. 48,p. 2382 - 2390

22
[ 636-61-3 ]
[ 75-36-5 ]
[ 70681-41-3 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol	A Step (A): Step (A): (R)-2-Hydroxysuccinic acid dimethyl ester To an ice cooled solution of methanol (250 mL) was added acetyl chloride (12.5 mL), and the solution was stirred for 1 hour at 0° C. (R)-Malic acid (20.0 g) was added, and the solution was stirred for 16 hours at room temperature. Solvent was removed by evaporation in vacuo leaving a quantitative yield of (R)-2-hydroxysuccinic acid dimethyl ester as an oil. 1H-NMR (CDCl3): δ4.52 (dd, 1H), 3.80 (s, 3H), 3.71 (s, 3H), 3.55 (bs, 1H), 2.88 (dd, 1H), 2.80 (dd, 1H).

Reference： [1]Current Patent Assignee: PFIZER INC - US2002/143186, 2002, A1

23
[ 617-48-1 ]
[ 636-61-3 ]
[ 32082-74-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	With hydrogenchloride; sodium borohydrid; lithium chloride; In tetrahydrofuran; methanol;	EXAMPLE 2 Direct Reduction of Malic Acid to Lactone (R)-Isomer <strong>[636-61-3]D-Malic acid</strong> (1 gram, 0.0075 moles) was refluxed for 3 hours with 10 ml of anhydrous methanol containing 1% hydrogen chloride to form the dimethyl ester (Scheme II). The solution was concentrated to a syrup and dissolved in 4 ml of tetrahydrofuran. Anhydrous lithium chloride (0.6 grams. 0.014 moles) was added followed by sodium borohydride (0.32 grams, 0.0084 moles) and methanol (2 ml) to provide the reducing agent. The mixture was stirred at room temperature(25 C.) for 6 hours, filtered, concentrated to dryness, treated with methanol (10 ml) containing hydrochloric acid (1 ml) and concentrated to dryness on a rotary evaporator at a bath temperature of 35 C. A further 10 ml of methanol was added and the solution concentrated again. The process was repeated twice again and the final syrup partitioned between ethyl acetate and water 0.4 ml: 8 ml. The ethyl acetate layer was recovered, dried and concentrated to yield (R)-3-hydroxybutyrolactone (0.6 grams, 88%).

Reference： [1]Patent: US5808107,1998,A

24
[ 636-61-3 ]
[ 104-15-4 ]
[ 70681-41-3 ]

Yield	Reaction Conditions	Operation in experiment
86%		[00199] (R)-Dimethyl 2-hydroxysuccinateTo a solution of (R)-2-hydroxysuccinic acid (134 g, 1 mol) in CH3OH (500 niL) was added toluene-4-sulfonic acid (9.5 g, 0.05 mol). The mixture was heated to reflux overnight. Methanol was evaporated, and then water (250 mL) was added to the residue. The mixture was basified with sat. NaHCO3 solution to pH 7-8 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give (R)-dimethyl 2-hydroxysuccinate (140 g, 86%). 1HNMR (300 MHz, CDCl3) ? 4.46 (dd, J= 6 Hz, 4.8 Hz, 1 H), 3.74 (s, 3 H), 3.64 (s, 3 H), 3.42 (s, 1 H), 2.69-2.85 (m, 2 H).

Reference： [1]Patent: WO2007/21982,2007,A2 .Location in patent: Page/Page column 67

25
azithromycin dihydrate [ No CAS ]
[ 636-61-3 ]
azithromycin D-malate anhydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	In isopropyl alcohol; at 0 - 20℃;	Example 2: Preparation of azithromycin D-malate anhydrate 10.Og of azithromycin dihydrate (12.7mmol) was dissolved in 100mL of anhydrous 2-propanol, and 3.4 Ig of <strong>[636-61-3]D-malic acid</strong> (25.4mmol) having an optical purity of 98.2% ee was added thereto, followed by stirring over night at room temperature, and then, for 2 hours at 0 to 5 C . The precipitate formed was filtered, washed with cold 2-propanol, and dried at 45 C5 to obtain 10.4 g of the title compound (yield: 79%) as a white crystal.M.P.: 160-163 CSpecific rotation, [?]25: -39.5 (c=l, methanol) Optical purity of <strong>[636-61-3]D-malic acid</strong> after salt formation (HPLC): 98.9% ee Moisture content (Karl-Fisher titrator): 0.4% or less (after drying) IR (KBr5 cm'1): 3427, 2974, 2937, 2882, 1735, 1598, 1466, 1385, 1179, 1171, 1080, 1060, 1013, 1002, 899, 726.The azithromycin D-malate compound obtained above was subjected to X-ray diffraction analysis, and the result showed that it had a crystal structure showing major peaks (1/I0 values of at least 10%) at 2?+-0.2 of 5.7, 9.9, 10.9, 11.3, 12.3, 15.9, 17.1, 17.8, 18.2, 19.9, 20.6, 22.2. Its anhydrate form was confirmed by the result of moisture content measurement. However, it showed an increase of moisture content of 8% or higher when exposed at 40 C and 75% relative humidity for 10 hours.The azithromycin D-malate anhydrate obtained above did not convert to a hydrate form under the aqueous solvent condition employed in Examples 1 to 8.

Reference： [1]Patent: WO2006/132486,2006,A1 .Location in patent: Page/Page column 16 - 17

26
[ 636-61-3 ]
[ 17875-18-2 ]
[ 75-36-5 ]
(3R)-3-acetoxy-1-(3-buten-1-yl)pyrrolidine-2,5-dione [ No CAS ]

Reference： [1]Organic Letters,2009,vol. 11,p. 1179 - 1181

27
[ 636-61-3 ]
[ 138729-47-2 ]
[ 863393-46-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	In ethyl acetate for 18h;	6 [00108] A 250 mL reactor was charged with 1.5 g (,S)-zopiclone and 90 mL ethyl acetate, and heated to 40 0C to dissolve. A 125 mL reactor was charged with 540 mg D-malic acid and 60 mL ethyl acetate. The acid solution was transferred to the zopiclone solution, seeded with D-Malate salt and mixed for 18 hours. The reactor slurry was filtered and washed with ethyl acetate in a filter. The wet cake was dried under vacuum and isolated at 45-50 °C to provide the titled compound in 89% yield.

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Pharma (in: Sumitomo Chemical) - WO2009/85988, 2009, A1 Location in patent: Page/Page column 29-30

28
[ 636-61-3 ]
[ 83905-01-5 ]
azithromycin D-malate anhydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	In isopropyl alcohol; at 0 - 20℃;	10.0 g of azithromycin dihydrate (12.7 mmol) was dissolved in 100 ml of anhydrous 2-propanol, and 3.41 g of <strong>[636-61-3]D-malic acid</strong> (25.4 mmol) having an optical purity of 98.2% ee was added thereto, followed by stirring over night at room temperature, and then, for 2 hours at 0 to 5 C. The precipitate formed was filtered, washed with cold 2-propanol, and dried at 45 C., to obtain 10.4 g of the title compound (yield: 79%) as a white crystal.M.P.: 160163 C.Specific rotation, [alpha]D25: -39.5 (c=1, methanol)Optical purity of <strong>[636-61-3]D-malic acid</strong> after salt formation (HPLC): 98.9% eeMoisture content (Karl-Fisher titrator): 0.4% or less (after drying)IR (KBr, cm-): 3427, 2974, 2937, 2882, 1735, 1598, 1466, 1385, 1179, 1171, 1080, 1060, 1013, 1002, 899, 726.The azithromycin D-malate compound obtained above was subjected to X-ray diffraction analysis, and the result showed that it had a crystal structure showing major peaks (I/Io values of at least 10%) at 2theta+/-0.2 of 5.7, 9.9, 10.9, 11.3, 12.3, 15.9, 17.1, 17.8, 18.2, 19.9, 20.6, 22.2. Its anhydrate form was confirmed by the result of moisture content measurement. However, it showed an increase of moisture content of 8% or higher when exposed at 40 C. and 75% relative humidity for 10 hours.

Reference： [1]Patent: US2009/318375,2009,A1 .Location in patent: Page/Page column 6

29
[ 390800-88-1 ]
[ 636-61-3 ]
[ 1201902-99-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	In acetone; at 25℃;Heating;	Example 25: Synthesis of 2-((R)-2-((R)-3-methyl- 1 -((S)-3-phenyl-2-(pyrazine-2- carboxamido)propanamido)butyl)-5-oxo-l ,3.2-dioxaborolan-4-yl)acetic acid (1-21)[0358] A mixture of N,N',N"-(boroxin-2,4,6-triyltris{ [(lR)-3-methylbutane-l,l-diyl]imino[(2S)-l- oxo-3-phenylpropane-l,2-diyl] })tripyrazine-2-carboxamide (0.305 g, 0.278 mmol) and <strong>[636-61-3]D-malic acid</strong> (130.3 mg, 0.33 mmol) were mixed in acetone (3 mL). The mixture was heated to form a solution. The solution was cooled uncontrolled until the internal temperature was about 25 0C. White solid precipitated out and the resultant slurry was agitated at ambient temperature for 3 h. The slurry was filtered to collect solid 2-((R)-2-((R)-3-methyl-l-((S)-3-phenyl-2-(pyrazine-2- <n="78"/>carboxamido)propanamido)butyl)-5-oxo-l ,3,2-dioxaborolan-4-yl)acetic acid (0.410 g, 100%). [M+H] calculated for C23H28BN4O7, 483.2051 ; found, 483.2.

Reference： [1]Patent: WO2009/154737,2009,A1 .Location in patent: Page/Page column 76-77

30
[ 636-61-3 ]
[ 93413-62-8 ]
4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol D-malate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 20℃;Reflux;	Example 12[00153] A 100 ml flask equipped with a magnetic stirrer was charged with ODV base (3 g, 11.39 mmol) and EtOH 95% (9ml), the suspension being stirred at reflux. D-Malic acid (1.68g 12.53 mmol) was added and a clear solution was obtained. After stirring overnight at room temperature, the mixture was cooled to -1O0C. Cyclohexanane (6 ml) was added and a clear solution appeared. The mixture was evaporated to dryness to get amorphous ODV Malic. X-ray powder diffraction pattern is depicted in Figure 12.

Reference： [1]Patent: WO2010/8735,2010,A2 .Location in patent: Page/Page column 18

31
[ 636-61-3 ]
[ 1130137-76-6 ]
(R,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (R)-malate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	In methanol; water; at 20 - 50℃;Darkness;	Example 24 (R,Z)-2-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one malate 2-Hydroxy-succinic acid (231 mg, 1.72 mmol) was dissolved in 100 mL of methanol under stirring at room temperature, and (R,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 1 (560 mg, 1.233 mmol), 200 mL of methanol and 100 mL of water was then added to the solution in batch. Upon completion of the addition, the reaction system was heated at 50 C. in an oil bath in dark until a clear solution was obtained. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove the solvent to give a yellow solid. The resulting solid was dissolved in 100 mL of acetonitrile, and the mixture was heated to reflux in dark for 1.5 hours. The oil bath was removed. The reaction system was naturally cooled down to room temperature and filtered to give the title compound (R,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one malate 24 (718 mg, yield 99%) as a yellow solid.

Reference： [1]Patent: US2010/160317,2010,A1 .Location in patent: Page/Page column 28

32
[ 67-56-1 ]
[ 636-61-3 ]
[ 83540-94-7 ]

Yield	Reaction Conditions	Operation in experiment
99%		trifluoroacetic anhydride (55 ml) was added to <strong>[636-61-3]D-Malic acid</strong> (1)(13.4 g, 100 mmol), and stirred at room temperature under argon atmosphere for 40 mi Volatileswere removed, 80 ml of anhydrous methanol was added and stirred at room temperature for 1 h 30mm. Concentrated and the residue was crystallized from diethyl ether / hexanes to obtain 14.7 g(yield, 99%) of 2 as a white solid. This material was used for the next without further processing.
		<strong>[636-61-3]D-Malic acid</strong> (5.48 g, 40.1 mmol) in trifluoroacetic anhydride (24 mL, 173 mmol) was stirred for 3 h at room temperature. The excess trifluoroacetic anhydride and acid were removed in vacuo. The <strong>[636-61-3]D-Malic acid</strong> anhydrate was opened by MeOH (40 mL) to the monoacid 5, dried, and lyophilized from H2O. The resulting powder was dissolved in THF (40 mL) and cooled to 0 C, and 60 mL of a BH3-THF solution (55.8 mmol, 0.93 M) was added dropwise. After 4 h, the reaction was quenched with MeOH, THF and MeOH were removed in vacuo, and product 6 was evaporated from MeOH several times to remove methyl borate. A mixture of the remaining solid, benzaldehyde dimethyl acetal (9 mL, 58.7 mmol), and catalytic quantity of p-toluenesulfonic acid in DMF (60 mL) was heated at 50 C under reduced pressure. After 5 h, the reaction was stopped by cooling and adding an excess of Et3N (0.3 mL). DMF was removed in vacuo, and AcOEt was added to the residue. The organic layer was washed in the usual manner. Purification by flash column chromatography (hexane: ether = 4:1 to 1:1) yielded 7 (5.80 g, 63%) as a colorless oil.

Reference： [1]Patent: WO2016/145417,2016,A1 .Location in patent: Paragraph 274; 278; 279
[2]Journal of Organic Chemistry,2010,vol. 75,p. 7580 - 7587
[3]Tetrahedron Letters,2011,vol. 52,p. 6504 - 6507

33
[ 636-61-3 ]
[ 1360617-31-7 ]
[ 1360728-99-9 ]

Yield	Reaction Conditions	Operation in experiment
80%		The transaminase polypeptide SEQ ID NO: 206 (1.25 g, 5 wt% relative to alkoxy ketone) and pyridoxal 5 '-phosphate (250 mg, 1 wt%) were charged to a 3 -neck RB flask. Borate buffer (0.2 M, 225 mL, 9 vol) with 1M iPrNH2 at pH 10.5 was added. Dimethyl sulfoxide (12.5 mL, 0.5 vol) was added, and the resulting slurry was heated to 45 C in a closed system. Once at 45 C, the pH of the slurry was adjusted to 10.5 using 4 M isopropylamine and a free standing titrating unit.Alkoxyketone, which was prepared as described in Example 1, (26.6 g, 89 wt%, 85 mmol) was dissolved in dimethyl sulfoxide (12.5 mL, 0.5 vol). The alkoxy ketone solution was added to the hot transaminase polypeptide slurry over 3 minutes. The resulting milky yellow slurry was aged 20 h while the pH was maintained at 10.5 by addition of isopropylamine (95% conversion by HPLC).The mixture was then allowed to cool to ambient temperature, after which the slurry was extracted with a mixture of 107 mL tert-butyl methyl ether and 80 mL isopropanol. The aqueous phase was extracted with a mixture of 80 mL tert-butyl methyl ether and 53 mL isopropanol followed by the third extraction using 80 mL fert-butyl methyl ether and 40 mL isopropanol. The combined organic extracts (83% assay, 99.2:0.8 dr) were concentrated, diluted with isopropyl acetate (133 mL) and washed with 1 M K3PO4 CI (133 mL). Organic layer was concentrated and diluted with isopropanol (67 mL).Solution of D-(+)-malic acid (10.3 g, 77 mmol) in isopropanol (67 ml) was prepared. A 500 mL flask was charged with isopropanol (20 ml) and <strong>[636-61-3]D-malic acid</strong> salt of product (200 mg, 1.0 wt%) as seed. The resulting suspension was warmed to 35 C. <strong>[636-61-3]D-Malic acid</strong> and primary amine solutions were added simultaneously to the suspension in the 500 mL flask. The slurry was allowed to stir to room temperature, filtered and the cake was washed with 1:2 isopropanol: tert-butyl methyl ether (90 mL) followed by tert-butyl methyl ether (90 mL). After drying under N2, 28.35 g of white crystals of the product were obtained (80% isolated yield from alkoxyketone, 99.95:0.05 dr, 99.8 LCAP by HPLC).

Reference： [1]Patent: WO2012/24100,2012,A2 .Location in patent: Page/Page column 85-86
[2]Organic Letters,2014,vol. 16,p. 2716 - 2719

34
[ 636-61-3 ]
[ 136236-51-6 ]
[ 1377248-97-9 ]

Yield	Reaction Conditions	Operation in experiment
84%	In isopropyl alcohol;Heating; Cooling with ice;	500 mg (2.920 mmoles) of <strong>[136236-51-6]rasagiline</strong> base and 391.5 (2.920 mmoles) of (Z))-malic acid are dissolved in 5.0 ml of hot isopropyl-alcohol. The warm solution is slowly cooled and thereafter placed in an icecold water bath. The precipitated crystals are filtered and washed with cold isopropyl-alcohol; The off-white crude salt thus obtained (830 mg) is recrystallized from 1 1 ml of hot isopropyl-alcohol, filtered in the cold, washed with cooled isopropyl-alcohol and finally dried on the air. Yield : 745 mg (84 %), white crystals.Melting point: 126-129 CElementary analysis for the Formula: Ci6Hi9N0 (305,33): CAlculated [%] C: 62.94 H: 6.27 N: 4.59 O: 26.20 Found [%] C: 62.62 H: 6.40 N: 4.47IR (ICBr): 3222, 2965, 2588, 2454, 1708, 1631, 1561 , 1412, 1311, 1276, 1216, 1183, 1091 cm"1.1H-NMR (DMSO- 6, 400 MHz) delta 8.41 (bs, 4H), 7.41 (d, 1H, J = 7.1 Hz), 7.26 (t, 1H, J = 7.0 Hz), 7.23 (d, 1H, J = 7.2 Hz), 7.20 (t, 1H, J = 7.0 Hz), 4.44 (dd, 1H, J = 6.8, 5.8 Hz), 4.13 (t, 1H, J = 6.6 Hz), 3.58 (d, 2H, J = 2.5 Hz), 3.28 (t, 1H, J = 2.5 Hz), 2.98 (m, 1H), 2.80 (m, 1H), 2.57 (dd, lH, J = 15.6, 6.6 Hz), 2.39 (dd, 1H, J = 15.6, 6.5 Hz), 2.33 (m, 1H), 1.90 (m, 1H) ppm.HPLC purity: >99.8%[a] 22D = +14,l (c=l; EtOH)

Reference： [1]Patent: WO2012/66366,2012,A1 .Location in patent: Page/Page column 36-37

35
[ 636-61-3 ]
[ 84057-84-1 ]
2C₉H₇Cl₂N₅*C₄H₆O₅ [ No CAS ]

Reference： [1]CrystEngComm,2012,vol. 14,p. 7898 - 7906

36
[ 636-61-3 ]
[ 328-42-7 ]

Yield	Reaction Conditions	Operation in experiment
	With recombinant D-lactate dehydrogenase from Lactobacillus jensenii 269-3; nicotinamide adenine dinucleotide In aq. phosphate buffer at 25℃; Enzymatic reaction;	Substrate specificity of d-LDHs General procedure: Substrate specificities of d-LDHs were examined using 50 mM sodium phosphatebuffer (pH 8.0) containing 10 mM various substrates (sodium pyruvate,2-ketobutyric acid, oxaloacetic acid, sodium phenylpyruvate) for reduction reactionand 10 mM various substrates (sodium d-lactate, (R)-2-hydroxybutyric acid,d-(+)-malic acid, d-(+)-3-phenyllactic acid) for oxidation reaction.

Reference： [1]Jun, Chanha; Sa, Young Seung; Gu, Sol-A; Joo, Jeong Chan; Kim, Seil; Kim, Kyung-Jin; Kim, Yong Hwan [Process Biochemistry, 2013, vol. 48, # 1, p. 109 - 117]

37
[ 328-42-7 ]
[ 636-61-3 ]

Yield	Reaction Conditions	Operation in experiment
	With recombinant D-lactate dehydrogenase from Lactobacillus jensenii 27-2 CHN; NADH In aq. phosphate buffer at 25℃; Enzymatic reaction;	Substrate specificity of d-LDHs General procedure: Substrate specificities of d-LDHs were examined using 50 mM sodium phosphatebuffer (pH 8.0) containing 10 mM various substrates (sodium pyruvate,2-ketobutyric acid, oxaloacetic acid, sodium phenylpyruvate) for reduction reactionand 10 mM various substrates (sodium d-lactate, (R)-2-hydroxybutyric acid,d-(+)-malic acid, d-(+)-3-phenyllactic acid) for oxidation reaction.

Reference： [1]Jun, Chanha; Sa, Young Seung; Gu, Sol-A; Joo, Jeong Chan; Kim, Seil; Kim, Kyung-Jin; Kim, Yong Hwan [Process Biochemistry, 2013, vol. 48, # 1, p. 109 - 117]

38
[ 636-61-3 ]
[ 29840-65-1 ]
ethyl 7-[(3R)-hydroxy-2,5-dioxopyrrolidin-1-yl]heptanoate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 9488 - 9493

39
[ 636-61-3 ]
[ 100-46-9 ]
[ 165657-63-6 ]

Yield	Reaction Conditions	Operation in experiment
64.8%	In 5,5-dimethyl-1,3-cyclohexadiene; at 20℃; for 10h;Heating; Cooling with ice;	<strong>[636-61-3]D-malic acid</strong> (10.0 g, 74.6 mmol) and benzylamine (9.59 g, 89.5 mmol) were dispersed in 250 mL of xylene and heated to separate water for 8 hours. After cooling to room temperature, the mixture was cooled and stirred under an ice bath for 2 hours, filtered, and the filter cake was washed with petroleum ether to obtain a cake. Column chromatography (petroleum ether / ethyl acetate, 1/2) to give a white solid powder was 9.91g to give Compound 4. Yield: 64.8%.

Reference： [1]Patent: CN109651359,2019,A .Location in patent: Paragraph 0217; 0218; 0219; 0256; 0257; 0258
[2]Bioorganic Chemistry,2014,vol. 54,p. 81 - 88

40
[ 636-61-3 ]
[ 1443623-92-4 ]
[ 1919868-77-1 ]

Yield	Reaction Conditions	Operation in experiment
> 96% ee	Stage #1: 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole With bis(1,5-cyclooctadiene)diiridium(I) dichloride; diphenylsilane; (R)-2-(2-(diphenylphosphino)phenyl)-4-isopropyl-4,5-dihydrooxazole In tert-butyl methyl ether at 5 - 20℃; Stage #2: D-Malic acid In ethanol at 65℃;	B.C; B.D Step C-Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine: Step D-Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine(R)-2-hydroxy-succinate: Step C-Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine: Chloro-l,5-cyclooctadiene iridium dimer (0.2 mol %) and (R)-2-(2-(diphenylphosphino)phenyl)-4- isopropyl-4,5-dihydrooxazole (0.4 mol %) were suspended in 5 volumes of MTBE (based on 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole) at room temperature. The mixture was stirred for 1 hour and most of the solids dissolved with the solution turning dark red. The catalyst formation was monitored using an HPLC/PDA detector. The reaction was cooled to less than 5° Celsius and 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole (1.0 eq.) was added using a 0.5 volumes of MTBE rinse. Diphenylsilane (1.5 eq.) was added over about 20 minutes while maintaining a reaction temperature below 10° Celsius. The reaction was stirred for 30 minutes below 10° Celsius and then allowed to warm to room temperature. The reaction was stirred overnight at room temperature. The completion of the reaction was confirmed by HPLC and then cooled to less than 5° Celsius. The reaction was quenched with 5 volumes of 2M aqueous HC1 maintaining temperature below 20° Celsius. After 10 minutes the ice/water bath was removed and the reaction temperature was allowed to increase to room temperature while stirring for 2 hours. The mixture was transferred to a separatory funnel with 3 volumes of MTBE. The aqueous layer was washed with 3.5 volumes of MTBE followed by addition of 5 volumes of MTBE to the aqueous layer while adjusting the pH to about 14 by adding 0.75 volumes of aqueous 50% NaOH. The organic layer was washed with 5 volumes of aqueous saturated NaCl, then concentrated to an oil, and diluted with 3 volumes of MTBE. The solution was filtered through a polypropylene filter cloth and rinsed with 1 volume of MTBE. The filtrate was concentrated to an oil of (R)-2-(2,5-difluorophenyl)-pyrrolidine with a 95% to 100% theoretical yield and with 75-85% ee. Step D-Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine(R)-2-hydroxy-succinate: (R)-2-(2,5-difluorophenyl)-pyrrolidine (1.0 eq.) was transferred to a round bottom flask charged with 15 volumes (corrected for potency) of EtOH (200 prf). D-malic acid (1.05 eq.) was added and the mixture was heated to 65° Celsius. The solids all dissolved at about 64° Celsius. The solution was allowed to cool to RT. At about 55° Celsius the solution was seeded with (R)-2-(2,5- difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate (about 50 mg, >97% ee) and stirred at room temperature overnight. The suspension was then filtered through a polypropylene filter cloth and washed with 2x1 volumes of EtOEl (200 prf). The solids were dried under vacuum at 55° Celsius, yielding (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxysuccinate with a 75% to 90% theoretical yield and with >96% ee.

Reference： [1]Current Patent Assignee: PFIZER INC - US2016/137654, 2016, A1 Location in patent: Paragraph 0246-0247

41
[ 636-61-3 ]
[ 120786-18-7 ]
(-)-huperzine A D-(+)-malic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	In water; acetone; at 20℃; for 1h;	Example 4 ; The preparation of (-)-huperzine A-D-(+)-malic acid salt 1 g of (+-)-huperzine A was suspended in acetone-water with a ratio of 1:1 (v:v). 0.45 g of D-(+)-malic acid was added at 20 C. After stirring for 1 h, the resulting salt was filtered to obtain a solid which was then recrystallized from anhydrous ethanol to give 1 g of (-)-huperzine A-D-(+)-malic acid salt.

Reference： [1]Patent: US2016/159745,2016,A1 .Location in patent: Paragraph 0133; 0134

42
[ 636-61-3 ]
[ 482-20-2 ]
C₂₄H₂₇NO₄*C₄H₆O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	In methanol; dichloromethane; at 20℃; for 8h;	Single-port in 250mL flask 1.0mmol malic acid were added 50mLCH 2 Cl 2 and 50mLCH 3 OH, room temperature Slowly dropped 1.0mmol tylophorine of 50mLCH 2 Cl 2 solution, dripping was completed, stirring was continued reaction 8h, filtered to give the corresponding Tylophorine acid salt derivatives. Wherein the product obtained when using L- malic acid is NK007-1, the use of D- malic acid, The product obtained was NK007-2.

Reference： [1]Patent: CN105461716,2016,A .Location in patent: Paragraph 0037; 0044; 0045

43
[ 636-61-3 ]
[ 116-11-0 ]
[ 73991-95-4 ]

Yield	Reaction Conditions	Operation in experiment
50%	With pyridinium p-toluenesulfonate; In acetone; at 35℃; for 16h;	Preparation of (R)-2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid A solution of (R)-malic acid (4.50 g, 33.6 mmol), 2-methoxyprop-1-ene (9.68 g, 134 mmol) and pyridinium p-toluenesulfonate (844 mg, 3.36 mmol) in acetone (50 mL) was stirred at 35 C. for 16 h. After this time, water (200 mL) was added, and the aqueous solution was extracted with ethyl acetate (2*200 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/heptane to provide (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (2.92 g, 50%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) delta 4.72 (dd, J=6.6, 3.9 Hz, 1H), 3.01 (dd, J=17.4, 3.9 Hz, 1H), 2.86 (dd, J=17.4, 6.6 Hz, 1H), 1.63 (s, 3H), 1.58 (s, 3H), CO2H proton not observed.

Reference： [1]Patent: US2016/326182,2016,A1 .Location in patent: Paragraph 0506; 0507

44
[ 636-61-3 ]
[ 1218935-59-1 ]
(R)-(+)-2-(2,5-difluorophenyl)pyrrolidine (R)-2-hydroxysuccinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65 g	In ethanol; at 60 - 70℃;	Taking 41 g of the compound product of the above formula 00, adding 15 volumes of ethanol 600 ml and 0.85 equivalents of malic acid 25 g,Heat to 60-70 C, cool to room temperature, suction filtration, remove the liquid, filter cake directly collected, add 280ml ethanol, heated to dissolve, cooled to room temperature, suction filtration, filter cake washed with 50ml ethanol twice The solid was collected and dried to give 65 g of compound (L) as a white solid. The yield of the above two steps (de-BOC and resolution of the compound of formula (M): 91.7% ee% 98.1%.

Reference： [1]Patent: CN108101820,2018,A .Location in patent: Paragraph 0061

45
[ 636-61-3 ]
[ 1218935-59-1 ]
(R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In ethanol; at 20 - 65℃;Inert atmosphere;	10414] <strong>[1218935-59-1](R)-2-(2,5-difluorophenyl)pyrrolidine</strong> (1.0 eq.) was transferred to a round bottom flask charged with 15 volumes (corrected for potency) of EtOH (200 pro. D-malic acid (1.05 eq.) was added and the mixture was heated to 65Celsius. The solids all dissolved at about 64 Celsius. Thesolution was allowed to cool to RT. At about 55 Celsius the solution was seeded with (R)-2-(2,5-difluorophenyl)pyrro- lidine (R)-2-hydroxy-succinate (about 50 mg, >97% cc) and stirred at room temperature overnight. The suspension was then filtered through a polypropylene filter cloth and washed with 2x1 volumes of EtOH (200 pro. The solids were dried under vacuum at 55 Celsius, yielding (R)-2-(2,5-difluoro- phenyl)pyrrolidine (R)-2-hydroxy-succinate with a 75% to 90% theoretical yield and with >96% cc.

Reference： [1]Patent: US2017/281632,2017,A1 .Location in patent: Paragraph 0414

46
[ 636-61-3 ]
tenofovir disoproxil [ No CAS ]
tenofovir disoproxil D-malic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.6%	In di-isopropyl ether; isopropyl alcohol; at 15 - 50℃;	At 40 ~ 50 C, Tenofovir disoproxil 50g (96.3mmol) and <strong>[636-61-3]D-malic acid</strong> 12.9g(96.2mmol), was dissolved in 250mL of isopropanol, dissolved completely, the control of the internal temperature 40 ~ 50 C was added isopropyl ether 250mL, after the addition was stirred and cooled to 15 ~ 20 C, stirring was continued to crystallize ; Suction filtration; the filter cake was dried under reduced pressure at 30 ~ 40 C, to give diethyl docetaxel D-mannitol 48.2g, yield 76.6%.

Reference： [1]Patent: CN103626803,2017,B .Location in patent: Paragraph 0313-0315

47
[ 636-61-3 ]
[ 441785-25-7 ]
C₄H₆O₅*2C₁₀H₁₄N₅O₄P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.51%	In methanol; at 15 - 45℃;	Besifovir 5.0 g (9.48 mmol) and oxalic acid 0.85 g (9.44 mmol) were dissolved in 200 mL of isopropanol at 40-45 C., and the mixture was dissolved and cooled to 15-20 C., Continue stirring crystallization; suction filtration; cake was dried under reduced pressure at 30 ~ 35 C, oxalic acid baisofavir (1: 1). Yield 95.2% HPLC purity 99.6%.

Reference： [1]Patent: CN106977548,2017,A .Location in patent: Paragraph 0066; 0072

48
[ 67-56-1 ]
[ 636-61-3 ]
[ 50446-44-1 ]
[ 7732-18-5 ]
[ 142-71-2 ]
catena-[tetraaquamethanoldi-R-malatemonohydro{4,4',4"-benzene-1,3,5-triyltris(benzoate)}tetracopper(II)] tetrahydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	at 100℃;	General procedure: Compound 1 was synthesized by the reaction of copper(II) acetate (0.048 g, 0.24 mmol), S-malic acid (S-H3mal) (0.016 g,0.12 mmol), and 4,4,4?-benzene-1,3,5-triyltris(benzoic acid) (H3btb) (0.032 g, 0.072 mmol) in a 1 : 1 methanol-water mixture (2.0 mL). The reaction was performed in a sealed glass tube on heating to 100 C overnight. The heating was accompanied by the formation of blue plate-like crystals and a white amorphous precipitate. The amorphous precipitate was separated by decantation. The crystals were washed with methanol and dried in air. Compound 2 was prepared under conditions similar to those used in the synthesis of compound 1, but starting from R-malic acid instead of S-malic acid.

Reference： [1]Russian Chemical Bulletin,2018,vol. 67,p. 36 - 44
Izv. Akad. Nauk, Ser. Khim.,2018,vol. 67,p. 36 - 44,9

49
[ 636-61-3 ]
[ 2867-59-6 ]
(S)-3-amino-1-butanol L-malate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40.3%	In ethanol; at 30 - 40℃;	75 g of D-malic acid (0.56 mol) in 250 ml of anhydrous ethanol, stirred at room temperature, the system was dissolved, then added dropwiseA 50 g mixture of 3-amino-1-butanol (0.56 mol) in racemic mixture was added dropwise and warmed to 30-40C. The system was dissolved and 0.5 g of (S)-3-amino-1-butanol was added. D Malate salt as a seed crystal, and stirring during heat preservation, the solid precipitated after half an hour, continue to stir for 2 to 3 hours, slowly to room temperature, and continue to cool to 5 to 10 C for half an hour, suction filtration, to obtain an optical purity of 90.8 %ee.The D-malate salt of (S)-3-amino-1-butanol.The resulting (S)-3-amino-1-butanol D-malate with an optical purity of 90.8% ee was suspended in 200 ml of anhydrous ethanol, warmed to reflux, and the system was dissolved, slowly cooled, and the cooling process was solid. Gradually precipitated, cooled to room temperature, stirred for 1~2 hours, continued cooling to 5~10C, and kept stirring for 0.5 hour. Filtered to obtain an optical purity of 98.7%e.The D-malate salt of (S)-3-amino-1-butanol.The above-mentioned recrystallized D-malate salt of (S)-3-amino-1-butanol having an optical purity of 98.7% ee was suspended in 150 ml of anhydrous ethanol, and the temperature was raised to reflux. After the system was dissolved, the temperature was slowly lowered. The solids gradually precipitated, dropped to room temperature, incubated for 1 to 1.5 hours while stirring, and continued to cool down to 5 to 10C for half an hour, filtered by suction, and vacuum dried at 50C to a constant weight to give an optical purity of 99.4% ee.(S). D-malate salt of 3-amino-1-butanol.The above-mentioned recrystallized D-malate salt of (S)-3-amino-1-butanol having an optical purity of 99.4%ee was suspended in 120 ml of absolute ethanol, and the temperature was raised to reflux. After the system was dissolved, the temperature was gradually lowered. Solids gradually precipitated, dropped to room temperature, incubated for 1 to 1.5 hours while stirring, and continued to cool to 5 to 10C for half an hour, filtered, and vacuum dried at 50C to constant weight.50.4 g of D-malate salt with an optical purity of 99.9% ee.(S)-3-amino-1-butanol are obtained,Yield 40.3%.

Reference： [1]Patent: CN107793320,2018,A .Location in patent: Paragraph 0079; 0080; 0081; 0082; 0086; 0087-0091

50
[ 636-61-3 ]
[ 29122-68-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	at 20℃;	2.1 2.1 Process for the preparation of atenolol hydrochloride crystals Atenolol (1 g, 3.75 mmol) was mixed with equimolar proportion of D-(+)-malic acid (0.503 g, 3.75 mmol). A dense liquid material that was formed upon mixing was kept in a clean & dried petridish. Sodium chloride crystals in equimolar quantity were added and the material was kept aside for observation.

Reference： [1]Kandula, Rama Kumar; Vepuri, Suresh B.; Devarajegowda; Raja [Journal of Molecular Structure, 2018, vol. 1169, p. 39 - 45]

51
[ 141-86-6 ]
[ 636-61-3 ]
[ 1931-44-8 ]

Reference： [1]Chemistry - A European Journal,2019,vol. 25,p. 785 - 795

52
[ 636-61-3 ]
4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile [ No CAS ]
(x)C₄H₆O₅*C₂₈H₂₇N₉O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.2%	In ethanol; dichloromethane; at 25℃; for 20h;	General procedure: Four salts (HCl, HBr, L- and <strong>[636-61-3]D-malic acid</strong> salts) and the freebase of the compound of formula I were scaled up to 2 grams (Table 18). The four salts were analyzed and characterized by PLM, DSC, TGA, DVS, XRPD, FTIR, and 1H NMR (Figs. 16A-16F, 17A-17D, and 18A- 18H). (1240) [00698] Table 18. Scale-up of HCl, HBr, L-Malic and D-Malic salts (1241) (1242) (1243) [00699] Chlorine and bromine analysis verified the formation of the corresponding mono-HX salts. The L- and D- malic acid salts were provided in 75-78% yield; the HCl salt was prepared in 90% yield.

Reference： [1]Patent: WO2019/75108,2019,A1 .Location in patent: Paragraph 00697-00699

53
[ 636-61-3 ]
[ 700-63-0 ]
C₈H₁₀N₂O*C₄H₆O₅ [ No CAS ]

Reference： [1]Crystal Growth and Design,2019,vol. 19,p. 3652 - 3659

54
[ 636-61-3 ]
[ 700-63-0 ]
2C₈H₁₀N₂O*C₄H₆O₅ [ No CAS ]

Reference： [1]Crystal Growth and Design,2019,vol. 19,p. 3652 - 3659

55
[ 636-61-3 ]
[ 886503-15-7 ]
[ 1919868-77-1 ]

Yield	Reaction Conditions	Operation in experiment
77%	In ethanol at 20 - 65℃; for 48h;
34.33%	In ethanol	1-4 Take 64g of the racemic compound 2-(2,5-difluorophenyl)-1-pyrrolidine from the above product, add 95% ethanol (640ml), D-malic acid (47g, 1eq) was added for resolution and crystallization, the resulting product was crystallized with 95% ethanol, and the resulting product was (2R)-2-(2,5-Difluorophenyl)-1-pyrrolidine D-malate, the yield is 34.33%, Detecting the salt by chiral HPLC showed that ((2R)-2-(2,5-difluorophenyl)-1-pyrrolidine: (2S)-2-(2,5-difluorophenyl)-1 -Pyrrolidine = 99.01:0.99).
34.1%	In ethanol for 0.333333h; Reflux;

30.9%

In ethanol at 0 - 5℃; for 1h;

1-4 Add 74.37g of compound IV, 43.55g of D-malic acid and 315.0ml of absolute ethanol into a 500mL four-necked flask. After adding, heat and stir. After dissolving and clarifying, slowly cool down. After cooling to 0-5°C, no solid precipitated. After adding seed crystals, a large amount of white solid precipitated. After stirring for 1 hour at this temperature, the filter cake was obtained by suction filtration. The filter cake was vacuum dried to obtain 59.2 g of crude product 1.Add crude product 1 and 600.0ml absolute ethanol to a 1000ml four-necked flask, heat and stir until it is clear. After holding for 0.5h, turn off the heating and slowly cool down and crystallize. After a large amount of crystals are precipitated, the cooling bath is slowly cooled to 0-5°C and kept for 1 hour. Suction filtration, vacuum drying to obtain a solid, 39.86g of pureproduct V is obtainedrepeatedly in this way. The yield was 30.9% (relative to compound IV), the purity was 99.96%, and the ee value was 99.11%.

Reference： [1]Lundrigan, Travis; Welsh, Erin N.; Hynes, Toren; Tien, Chieh-Hung; Adams, Matt R.; Roy, Kayelani R.; Robertson, Katherine N.; Speed, Alexander W. H. [Journal of the American Chemical Society, 2019, vol. 141, # 36, p. 14083 - 14088]
[2]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN112457231, 2021, A Location in patent: Paragraph 0068; 0070-0071; 0073-0074; 0076-0077; 0079
[3]Lv, Xunlei; Chen, Liang; Pan, Jing; Meng, Xue; Bi, Siju; Liu, Weiyuan; Zhou, Ting; Lin, Kuaile; Ye, Deyong; Zhou, Weicheng [Chirality, 2021, vol. 33, # 12, p. 931 - 937]
[4]Current Patent Assignee: JIANGSU PHARMSYN PHARMACEUTICAL TECH - CN111302997, 2020, A Location in patent: Paragraph 0053; 0057; 0059-0060; 0061; 0063; 0065-0066

56
[ 503612-47-3 ]
[ 636-61-3 ]
[ 2434624-50-5 ]

Yield	Reaction Conditions	Operation in experiment
48.6 g	In methanol; 2,2,2-trifluoroethanol at 30 - 35℃; for 19h;	2 Example 2: Preparation of apixaban / D-malic acid eutectic form II At room temperature, 13.2g of D-malic acid, 60g of apixaban, 350ml of trifluoroethanol, and 170ml of methanol were added to the reaction flask. After stirring for 1 hour to dissolve, remove allThe obtained solution was kept at 30 35 , stirring was continued for 18 hours, and then the cooling rate was controlled at 10-15 / hour, and the crystallization solution was cooled to 0 5 for 6 hours.There are a lot of crystals,The resulting crystals were filtered and washed with a small amount of methanol, and then vacuum dried at 55 ° C for 24 hours48.6 g of apixaban / D-malic acid co-crystal was obtained.After testing, the resulting eutectic is Apixaban / D-malic acid eutectic Form II.The X-ray powder diffraction data of the sample are shown in Figure 4 and Table 2;The TGA pattern is shown in Figure 5; the DSC pattern is shown in Figure 6.

Reference： [1]Current Patent Assignee: ZHEJIANG TIANYU PHARMACEUTICAL - CN110922403, 2020, A Location in patent: Paragraph 0096-0099

57
[ 636-61-3 ]
[ 886503-15-7 ]
[ 1919868-77-1 ]
(S)-2-(2,5-difluorophenyl)pyrrolidine (S)-2-hydroxy-succinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol at 25 - 65℃; Overall yield = 56 percent; Optical yield = 50.5 percent ee;	2 The 2-(2,5-difluorophenyl)-pyrrolidine (5 g, 1 eq) obtained in Example 1 was transferred to a reaction flask containing 15 volumes of ethanol (75 ml). D-malic acid (3.84g, 1.05eq) was added, and the mixture was heated to 65 °C, all solids were dissolved, the solution was cooled to 25 °C, at about 55 °C,The solution was crystallized with (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate (ee>97%) and stirred overnight at room temperature. Filter, wash the solid with ethanol (10 ml), dry the solid in vacuum at 55°C, test solid ee: 50.5%, yield: 56%.

Reference： [1]Current Patent Assignee: SHANGHAI FOSUN PHARMACEUTICAL (GROUP) CO., LTD. - CN111138333, 2020, A Location in patent: Paragraph 0122-0124

58
[ 64-17-5 ]
[ 636-61-3 ]
[ 7554-28-1 ]
(R)-4-ethoxy-2-hydroxy-4-oxobutanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 18.6 mg 2: 12 mg	With hydrogenchloride In water at 20℃; for 0.25h;	Esterification of malic acid General procedure: (R) or (S)-Malic acid (0.9 g or 2 g) and EtOH(10.1 mL)were reacted in the presence of 1 M HCl (679 μL) for15 min at room temperature [11]. The reaction mixture(1.1 g or 2.0 g) was subjected to silica gel flash columnchromatography followed by Sephadex LH-20 gel (GEHealthcare, Uppsala, Sweden; CHCl3/MeOH = 1/1,35 × 500 mm, 100 g). As a result, two stereoisomers ofmonoethyl esters 1 (18.6 mg, 1.8% yield) and 8 (10.2 mg,0.4% yield) along with diethyl esters 9 (12.0 mg, 1.0%yield) and 10 (98.9 mg, 3.5% yield) were isolated. (R)-4-Ethoxy-2-hydroxy-4-oxobutanoic acid (synthetic1). C6H10O5, ESIMS m/z 185 [M+ Na]+;[α]D28 + 12 (c 0.25, MeOH); 1H NMR (in CD3OD): δ1.27 (3 H, t, J = 7.5 Hz, H-2), 2.65 (1 H, dd, J = 16.0,7.5 Hz, H-3), 2.75 (1 H, dd, J = 16.0, 4.5 Hz, H-3), 4.19(2 H, m, H-1), 4.46 (1 H, t, J = 6.0 Hz, H-2).

Reference： [1]Choi, Jae-Hoon; D’Alessandro-Gabazza, Corina N.; Gabazza, Esteban C.; Harada, Etsuko; Hirai, Hirofumi; Kawagishi, Hirokazu; Malya, Irine Yunhafita; Toda, Masaaki; Wu, Jing; Yasuma, Taro [Bioscience, Biotechnology and Biochemistry, 2020, vol. 84, # 7, p. 1332 - 1338]

59
[ 636-61-3 ]
[ 75-36-5 ]
[ 7554-28-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	In ethanol at 20℃; for 69h;	diethyl (R)-2-hydroxysuccinate (12) To a solution of Acetyl chloride (2.66 mL, 37.3 mmol) in EtOH (150 mL) was added D-malic acid(11) (5.07 g, 37.8 mmol). After stirring for 69 h at room temperature, the mixture was concentrated togive a residue, which was purified by chromatography on silica gel (Hexane/EtOAc) to give ethylester 12 (6.86 g, 95%) as colorless oil:

Reference： [1]Imaizumi, Ryoya; Ogawa, Narihito [Synlett, 2020, vol. 31, # 14, p. 1409 - 1412]

60
[ 636-61-3 ]
[ 118-42-3 ]
C₄H₆O₅*(x)C₁₈H₂₆ClN₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; n-heptane at 20℃; for 48h;	1 General procedure: Base on the solubility test results shown in Table 1, five solvent systems, each a two-solvent mixture, were used in this study. See Table 2 below. Each of twelve chiral organic acids, listed in Table 2, was screened for in-situ precipitation of a (S)-(+)-hydroxychloroquine salt by dissolving the salt-free form of (±)-hydroxychloroquine in each of the five solvent systems to form a solution at a concentration of 40 mg/mL and then adding an equimolar chiral organic acid, in solid form, to 0.5 mL of the solution. The reaction solution was stirred at room temperature for 2 days.

Reference： [1]Current Patent Assignee: GENOVATE BIOTECHNOLOGY CO., LTD. - US2021/323925, 2021, A1 Location in patent: Paragraph 0046-0047

61
[ 636-61-3 ]
[ 1508-65-2 ]
(R)-oxybutynin D-malate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	In water; isopropyl alcohol at 50℃; for 1h;	27.2; 27.3 Step 2: Chiral resolution with D-malic acid Racemic oxybutynin free base (86.1 g) was combined with 2-propanol (400 mL). The mixture was heated to 50 °C, resulting in a solution. Seed crystals of the D-malate salt of R- oxybutynin were added (0.55 g), followed by solid D-malic acid (24.2 g) with a rinse of 30 mL of 2-propanol to produce R-oxybutynin D-malate. The very thin slurry was maintained at 50 °C for 1 hour, then cooled at 0.1 °C/min to 20 °C and held at 20 °C for about 60 hours. An aliquot was taken to estimate yield (-30%) and chiral purity (-93% R, 86% ee) of R- oxybutynin D-malate. To increase yield, the mixture was slowly cooled at 0.1 °C/min to 5 °C and held at 5 °C for 16 hours. A second aliquot indicated a slightly increased yield with comparable chiral purity (-90% R, 80% ee). The mixture was filtered. Slight shelving was observed, and the sides of the reactor were rinsed with MTBE. The combined solids were washed with additional MTBE and air-dried for 1.5 hours. The yield was 41% (49.1 g). Step 3: Recrystallization R-oxybutynin D-malate salt (44 g) was combined with M1BK (220 mL). The mixture was heated to 40 °C for 2 hours, cooled at 0.1 °C/min to 5 °C, and held at 5 °C for about 12 hours. An aliquot of the re-crystallized product indicated 97% R, 3% S (94% ee) with the filtrate indicating a higher amount of the undesired isomer (27% R, 73% S). The product was isolated by vacuum filtration and air-dried for 1 hour. The wet cake product was still very wet (14% loss of MP3K up to 50 °C by TGA). The product was dried in a vacuum oven at 40 °C with nitrogen bleed overnight. The yield of recrystallized product was 93% (40.8 g). Use of MTBE in place of MP3K is also contemplated.

Reference： [1]Current Patent Assignee: APNIMED DELAWARE - WO2021/226020, 2021, A1 Location in patent: Paragraph 0152; 0155-0158

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Technical Information

• Acids Combine with Acyl Halides to Produce Anhydrides • Acyl Chloride Hydrolysis • Add Hydrogen Cyanide to Aldehydes and Ketones to Produce Alcohols • Alcohol Syntheses from Aldehydes, Ketones and Organometallics • Alcohols are Weakly Basic • Alcohols as Acids • Alcohols Convert Acyl Chlorides into Esters • Alcohols from Haloalkanes by Acetate Substitution-Hydrolysis • Alcohols React with PX3 • Alcoholysis of Anhydrides • Aldehydes and Ketones Form Hemiacetals Reversibly • Aldol Addition • Alkene Hydration • Alkene Hydration • Amide Hydrolysis • Amide Hydrolysis • Anhydride Hydrolysis • Appel Reaction • Arndt-Eistert Homologation • Base-Catalyzed Hydration of α,β -Unsaturated Aldehydes and Ketones • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Carbonation of Organometallics • Carboxylate Salt Formation • Carboxylic Acids React with Alcohols to Form Esters • Chloroalkane Synthesis with SOCI2 • Chromium Reagents for Alcohol Oxidation • Chugaev Reaction • Claisen Condensations Produce β-Dicarbonyl Compounds • Claisen Condensations Produce β-Dicarbonyl Compounds • Convert Esters into Aldehydes Using a Milder Reducing Agent • Convert Haloalkanes into Alcohols by SN2 • Corey-Kim Oxidation • Decarboxylation of 3-Ketoacids Yields Ketones • Decarboxylation of Substituted Propanedioic • Decomposition of Lithium Aluminum Hydride by Protic Solvents • Deprotection of Cbz-Amino Acids • Dess-Martin Oxidation • Esters Are Reduced by LiAlH4 to Give Alcohols • Esters Hydrolyze to Carboxylic Acids and Alcohols • Ether Synthesis by Oxymercuration-Demercuration • Ethers Synthesis from Alcohols with Strong Acids • Formation of an Amide from an Amine and a Carboxylic Acid • Formation of an Amide from an Amine and a Carboxylic Acid • Friedel-Crafts Alkylations Using Alcohols • Geminal Diols and Acetals Can Be Hydrolyzed to Carbonyl Compounds • Grignard Reagents Transform Esters into Alcohols • Grignard Reagents Transform Esters into Alcohols • Haloalcohol Formation from an Alkene Through Electrophilic Addition • Halogen and Alcohols Add to Alkenes by Electrophilic Attack • Halogen and Alcohols Add to Alkenes by Electrophilic Attack • Heat of Combustion • Hemiaminal Formation from Amines and Aldehydes or Ketones • Hemiaminal Formation from Amines and Aldehydes or Ketones • HIO4 Oxidatively Degrades Vicinal Diols to Give Carbonyl Derivatives • Hunsdiecker-Borodin Reaction • Hydration of the Carbonyl Group • Hydride Reductions • Hydride Reductions of Aldehydes and Ketones to Alcohols • Hydride Reductions of Aldehydes and Ketones to Alcohols • Hydroboration-Oxidation • Hydroboration-Oxidation • Hydrolysis of Haloalkanes • Jones Oxidation • Ketones Undergo Mixed Claisen Reactions to Form β-Dicarbonyl Compounds • Martin's Sulfurane Dehydrating Reagent • Mitsunobu Reaction • Moffatt Oxidation • Nitriles Hydrolyze to Carboxylic Acids • Osmium Tetroxide Reacts with Alkenes to Give Vicinal Diols • Osmium TetroxideReacts with Alkenes to Give Vicinal Diols • Oxidation of Alcohols by DMSO • Oxidation of Aldehydes Furnishes Carboxylic Acids • Oxidation of Primary Alcohols Furnishes Carboxylic Acids • Oxymercuration-Demercuration • Passerini Reaction • Peptide Bond Formation with DCC • Periodic Acid Degradation of Sugars • Preparation of Alcohols • Preparation of Alkenes by Dehydration of Alcohols • Preparation of Alkenes by Dehydration of Alcohols • Preparation of Alkoxides with Alkyllithium • Preparation of Amines • Preparation of Carboxylic Acids • Primary Ether Cleavage with Strong Nucleophilic Acids • Reactions of Alcohols • Reactions of Amines • Reactions of Carboxylic Acids • Reactions with Organometallic Reagents • Reduction of an Ester to an Alcohol • Reduction of Carboxylic Acids by LiAlH4 • Reduction of Carboxylic Acids by Lithium Aluminum Hydride • Reduction of Carboxylic Acids by Lithium Aluminum Hydride • Ring Opening of an Oxacyclopropane by Lithium Aluminum Hydride • Ritter Reaction • Schmidt Reaction • Sharpless Olefin Synthesis • Specialized Acylation Reagents-Ketenes • Swern Oxidation • Synthesis of Alcohols from Tertiary Ethers • Synthesis of an Alkyl Sulfonate • The Conversion of Carboxylic Acids into Acyl Halides • The Nucleophilic Opening of Oxacyclopropanes • Thiazolium Salt Catalysis in Aldehyde Coupling • Thiazolium Salts Catalyze Aldehyde Coupling • Thiazolium Salts Catalyze Aldehyde Coupling • Transesterification • Ugi Reaction • Use 1,3-dithiane to Prepare of α-Hydroxyketones • Vicinal Anti Dihydroxylation of Alkenes • Williamson Ether Syntheses

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P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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

[ CAS No. 636-61-3 ] {[proInfo.proName]}

Quality Control of [ 636-61-3 ]

Related Doc. of [ 636-61-3 ]

Product Details of [ 636-61-3 ]

Calculated chemistry of [ 636-61-3 ] Expand+

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 636-61-3 ]

Application In Synthesis of [ 636-61-3 ]

[ 636-61-3 ] Synthesis Path-Upstream 1~2

[ 636-61-3 ] Synthesis Path-Downstream 1~61

Technical Information

Related Functional Groups of [ 636-61-3 ]

Aliphatic Chain Hydrocarbons

Alcohols

Carboxylic Acids

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 636-61-3 ]