[ CAS No. 1885-13-8 ] {[proInfo.proName]}

Name: 1885-13-8|4-Methoxyphthalic acid|97%
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3d Animation Molecule Structure of 1885-13-8

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Quality Control of [ 1885-13-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1885-13-8 ]

Product Details of [ 1885-13-8 ]

CAS No. :	1885-13-8	MDL No. :	MFCD00094739
Formula :	C₉H₈O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JKZSIEDAEHZAHQ-UHFFFAOYSA-N
M.W :	196.16	Pubchem ID :	74665
Synonyms :

Calculated chemistry of [ 1885-13-8 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.11
Num. rotatable bonds :	3
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	46.85
TPSA :	83.83 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) :	-6.67 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.9
Log Po/w (XLOGP3) :	1.17
Log Po/w (WLOGP) :	1.09
Log Po/w (MLOGP) :	0.95
Log Po/w (SILICOS-IT) :	0.65
Consensus Log Po/w :	0.95

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-1.91
Solubility :	2.4 mg/ml ; 0.0122 mol/l
Class :	Very soluble
Log S (Ali) :	-2.53
Solubility :	0.585 mg/ml ; 0.00298 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.28
Solubility :	10.4 mg/ml ; 0.0528 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.59

Safety of [ 1885-13-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1885-13-8 ]

* 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 [ 1885-13-8 ]
Downstream synthetic route of [ 1885-13-8 ]

[ 1885-13-8 ] Synthesis Path-Upstream 1~3

1
[ 1885-13-8 ]
[ 50727-04-3 ]

Reference： [1] Journal of Organic Chemistry, 1983, vol. 48, # 18, p. 2981 - 2989
[2] Chemische Berichte, 1988, vol. 121, p. 243 - 252
[3] Patent: WO2003/99786, 2003, A2, . Location in patent: Page 38
[4] Journal of the American Chemical Society, 2014, vol. 136, # 17, p. 6239 - 6242
[5] Chemistry - A European Journal, 2016, vol. 22, # 34, p. 11997 - 12001

2
[ 1885-13-8 ]
[ 28281-76-7 ]

Yield	Reaction Conditions	Operation in experiment
99%	With acetic anhydride In tetrahydrofuran for 4 h; Heating / reflux	Acetic anhydride (40 ml) was added to a mixture of 4-methoxyphthalic acid (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99percent) as an off white solid. ¹H NMR (DMSO-d₆) 8.02 (1 H, d), 7.59 (1 H, d), 7.49 (1 H, dd), 3.97 (3H, s). MS: [M+H]⁺ 179.
99%	With acetic anhydride In tetrahydrofuran for 4 h; Heating / reflux	Acetic anhydride (40 ml) was added to a mixture of 4-methoxyphthalic acid (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. <n="227"/>Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99percent) as an off white solid. ¹H NMR (DMSOd₆) 8.02 (1 H₁ d), 7.59 (1 H, d), 7.49 (1H, dd), 3.97 (3H₁ s). MS: [M+H]⁺ 179.
99%	With acetic anhydride In tetrahydrofuran for 4 h; Heating / reflux	Acetic anhydride (40 ml) was added to a mixture of 4-methoxyphthalic acid (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99percent) as an off white solid. ¹H NMR (DMSO-d₆) 8.02 (1 H, d), 7.59 (1 H, d), 7.49 (1 H, dd), 3.97 (3H, s). MS: [M+H]⁺ 179.

99%	With acetic anhydride In tetrahydrofuran for 4 h; Heating / reflux	Acetic anhydride (40 ml) was added to a mixture of 4-methoxyphthalic acid (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99percent) as an off white solid. ¹H NMR (DMSO-d₆) 8.02 (1 H, d), 7.59 (1 H, d), 7.49 (1 H₁ dd), 3.97 (3H, s). MS: [M+H]⁺ 179.
99%	With acetic anhydride In tetrahydrofuran for 4 h; Reflux	Acetic anhydride (40 ml) was added to a mixture of 4-methoxyphthalic acid (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99percent) as an off white solid. ¹H NMR (DMSO-d₆) 8.02 (1H, d), 7.59 (1H, d), 7.49 (1H, dd), 3.97 (3H, s). MS: [M+H]⁺179.
78%	With 1,4-diaza-bicyclo[2.2.2]octane; thionyl chloride In dichloromethane at 0 - 20℃; for 0.833333 h;	1 ,4-Diazabicyclic[2,2,2]octane (336 mg, 3 mmol) was dissolved in anhydrous dichloromethane (3 ml_) and then stirred for five minutes while slowly adding distilled thionyl chloride (0.2 ml_, 3 mmol) at O⁰C. And then,4-methoxyphthalic acid (200 mg, 1 mmol) was slowly added dropwise at room temperature for 50 minutes. 10percent sodium bicarbonate was added to neutralize the reaction solution and the resultant was extracted with dichloromethane.Organic layers were dried with anhydrous sodium sulfate and filtered, and the filtrate was distilled under reduced pressure, separated and then purified by a column chromatography on silica gel (hexane/ethyl acetate=3:1), to obtain139 mg of the desired compound (yield 78percent).¹H NMR (300 MHz, CDCI₃) δ 7.92 (d, J=5.6 Hz, 1 H) 7.43 (d, J=2.9, 1 H),7.36 (dd, J=11.2, 3.0 Hz, 1 H), 3.99 (s, 1 H). 1³C NMR (75 Hz, CDCI₃) δ 166.17, 163.00, 162.43, 134.14, 127.28,123.22, 123.98, 108.89, 56.44.
58%	With 1,4-diaza-bicyclo[2.2.2]octane; thionyl chloride In dichloromethane at 20℃; for 2 h;	To a mixture of 4-methoxy-phthalic acid (1.8 g, 9.18 mmol), thionyl chloride (1.4 mL, 19.79 mmol) in CH₂C1₂ (15 mL) is added DABCO (1.1 g, 9.81 mmol). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with CH₂C1₂ (100 mL), washed with H₂0 (75 mL x2), dried with Na₂S0₄ and filtered. The filtrate is concentrated under reduced pressure to afford 5-methoxy-isobenzofuran-l,3- dione (950 mg, 58percent).

Reference： [1] Patent: WO2008/44029, 2008, A1, . Location in patent: Page/Page column 204
[2] Patent: WO2008/44041, 2008, A1, . Location in patent: Page/Page column 225-226
[3] Patent: WO2008/44045, 2008, A1, . Location in patent: Page/Page column 277-278
[4] Patent: WO2008/44054, 2008, A2, . Location in patent: Page/Page column 122
[5] Patent: US2010/152184, 2010, A1, . Location in patent: Page/Page column 72; 73
[6] Journal of Medicinal Chemistry, 2010, vol. 53, # 16, p. 5956 - 5969
[7] RSC Advances, 2016, vol. 6, # 52, p. 46170 - 46185
[8] Journal of Natural Products, 2018, vol. 81, # 6, p. 1460 - 1467
[9] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5701 - 5704
[10] Patent: WO2009/54653, 2009, A2, . Location in patent: Page/Page column 25
[11] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 5, p. 1628 - 1631
[12] Patent: WO2011/68821, 2011, A1, . Location in patent: Page/Page column 108
[13] Chemische Berichte, 1883, vol. 16, p. 1964
[14] Journal of the Chemical Society, 1909, vol. 95, p. 1883
[15] Helvetica Chimica Acta, 1931, vol. 14, p. 513
[16] Chemische Berichte, 1938, vol. 71, p. 907,910
[17] Chemische Berichte, 1988, vol. 121, p. 243 - 252
[18] Journal of the American Chemical Society, 2014, vol. 136, # 17, p. 6239 - 6242
[19] Chemistry - A European Journal, 2016, vol. 22, # 34, p. 11997 - 12001
[20] Molecules, 2017, vol. 22, # 2,

3
[ 1885-13-8 ]
[ 22246-66-8 ]

Reference： [1] Chemische Berichte, 1988, vol. 121, p. 243 - 252

[ 1885-13-8 ] Synthesis Path-Downstream 1~88

2
[ 4685-47-6 ]
[ 1885-13-8 ]

Reference： [1]Chemische Berichte,1900,vol. 33,p. 742
Chemische Berichte,1901,vol. 34,p. 1259
[2]Tetrahedron,2000,vol. 56,p. 7797 - 7803
[3]Chemical and Pharmaceutical Bulletin,2011,vol. 59,p. 96 - 99

3
[ 5111-69-3 ]
[ 1885-13-8 ]

Reference： [1]Chemische Berichte,1900,vol. 33,p. 742
Chemische Berichte,1901,vol. 34,p. 1259

4
[ 1885-13-8 ]
[ 28281-76-7 ]

Yield	Reaction Conditions	Operation in experiment
99%	With acetic anhydride; In tetrahydrofuran; for 4h;Heating / reflux;	Acetic anhydride (40 ml) was added to a mixture of <strong>[1885-13-8]4-methoxyphthalic acid</strong> (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99%) as an off white solid. 1H NMR (DMSO-d6) 8.02 (1 H, d), 7.59 (1 H, d), 7.49 (1 H, dd), 3.97 (3H, s). MS: [M+H]+ 179.
99%	With acetic anhydride; In tetrahydrofuran; for 4h;Heating / reflux;	Acetic anhydride (40 ml) was added to a mixture of <strong>[1885-13-8]4-methoxyphthalic acid</strong> (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. <n="227"/>Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99%) as an off white solid. 1H NMR (DMSOd6) 8.02 (1 H1 d), 7.59 (1 H, d), 7.49 (1H, dd), 3.97 (3H1 s). MS: [M+H]+ 179.
99%	With acetic anhydride; In tetrahydrofuran; for 4h;Heating / reflux;	Acetic anhydride (40 ml) was added to a mixture of <strong>[1885-13-8]4-methoxyphthalic acid</strong> (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99%) as an off white solid. 1H NMR (DMSO-d6) 8.02 (1 H, d), 7.59 (1 H, d), 7.49 (1 H, dd), 3.97 (3H, s). MS: [M+H]+ 179.

99%	With acetic anhydride; In tetrahydrofuran; for 4h;Heating / reflux;	Acetic anhydride (40 ml) was added to a mixture of <strong>[1885-13-8]4-methoxyphthalic acid</strong> (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99%) as an off white solid. 1H NMR (DMSO-d6) 8.02 (1 H, d), 7.59 (1 H, d), 7.49 (1 H1 dd), 3.97 (3H, s). MS: [M+H]+ 179.
99%	With acetic anhydride; In tetrahydrofuran; for 4h;Reflux;	Acetic anhydride (40 ml) was added to a mixture of <strong>[1885-13-8]4-methoxyphthalic acid</strong> (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99%) as an off white solid. 1H NMR (DMSO-d6) 8.02 (1H, d), 7.59 (1H, d), 7.49 (1H, dd), 3.97 (3H, s). MS: [M+H]+ 179.
98%	In acetic anhydride; for 18h;Reflux;	Step 4: Preparation of 5-methoxyisobenzofuran-1,3-dione The compound prepared in step 3 above (0.23 g, 1.2 mmol) was dissolved in 4 ml of acetic anhydride. The prepared solution was heated under reflux for 18 hours. The temperature of the solution was cooled down to room temperature, followed by concentration by rotary evaporation. The obtained residue was purified by flash column chromatography. As a result, a target compound was obtained (0.21 g, 98%). 1H NMR (DMSO-d6, 500 MHz) delta 7.99 (d, J=8.4 Hz, 1H), 7.58 (d, J=2.3 Hz, 1H), 7.48 (dd, J=8.5, 2.3 Hz, 1H), 3.97 (s, 3H). 13C NMR (DMSO-d6, 125 MHz) delta 165.7, 163.1, 162.7, 134.0, 127.2, 122.9, 122.7, 109.3, 56.7.
78%	With 1,4-diaza-bicyclo[2.2.2]octane; thionyl chloride; In dichloromethane; at 0 - 20℃; for 0.833333h;	1 ,4-Diazabicyclic[2,2,2]octane (336 mg, 3 mmol) was dissolved in anhydrous dichloromethane (3 ml_) and then stirred for five minutes while slowly adding distilled thionyl chloride (0.2 ml_, 3 mmol) at O0C. And then,<strong>[1885-13-8]4-methoxyphthalic acid</strong> (200 mg, 1 mmol) was slowly added dropwise at room temperature for 50 minutes. 10% sodium bicarbonate was added to neutralize the reaction solution and the resultant was extracted with dichloromethane.Organic layers were dried with anhydrous sodium sulfate and filtered, and the filtrate was distilled under reduced pressure, separated and then purified by a column chromatography on silica gel (hexane/ethyl acetate=3:1), to obtain139 mg of the desired compound (yield 78%).1H NMR (300 MHz, CDCI3) delta 7.92 (d, J=5.6 Hz, 1 H) 7.43 (d, J=2.9, 1 H),7.36 (dd, J=11.2, 3.0 Hz, 1 H), 3.99 (s, 1 H). 13C NMR (75 Hz, CDCI3) delta 166.17, 163.00, 162.43, 134.14, 127.28,123.22, 123.98, 108.89, 56.44.
58%	With 1,4-diaza-bicyclo[2.2.2]octane; thionyl chloride; In dichloromethane; at 20℃; for 2h;	To a mixture of <strong>[1885-13-8]4-methoxy-phthalic acid</strong> (1.8 g, 9.18 mmol), thionyl chloride (1.4 mL, 19.79 mmol) in CH2C12 (15 mL) is added DABCO (1.1 g, 9.81 mmol). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with CH2C12 (100 mL), washed with H20 (75 mL x2), dried with Na2S04 and filtered. The filtrate is concentrated under reduced pressure to afford 5-methoxy-isobenzofuran-l,3- dione (950 mg, 58%).
	With acetic anhydride; In tetrahydrofuran; for 4h;Reflux;	The solution of <strong>[1885-13-8]4-methoxyphthalic acid</strong> (16 mmol) and Ac2O (0.4 mL) in 2 mL THF was refluxedfor 4 h. Once completed, the solvent was evaporated and the intermediate 4-methyl phthalic anhydridewas afforded. Then it was mixed with aniline (0.16 mL) in 5 mL acetic acid under reflux to afford thefinal product quantitively [27].

Reference： [1]Patent: WO2008/44029,2008,A1 .Location in patent: Page/Page column 204
[2]Patent: WO2008/44041,2008,A1 .Location in patent: Page/Page column 225-226
[3]Patent: WO2008/44045,2008,A1 .Location in patent: Page/Page column 277-278
[4]Patent: WO2008/44054,2008,A2 .Location in patent: Page/Page column 122
[5]Patent: US2010/152184,2010,A1 .Location in patent: Page/Page column 72; 73
[6]Journal of Medicinal Chemistry,2010,vol. 53,p. 5956 - 5969
[7]RSC Advances,2016,vol. 6,p. 46170 - 46185
[8]Journal of Natural Products,2018,vol. 81,p. 1460 - 1467
[9]Patent: US2019/345126,2019,A1 .Location in patent: Paragraph 0192; 0199-0200
[10]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 5701 - 5704
[11]Patent: WO2009/54653,2009,A2 .Location in patent: Page/Page column 25
[12]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1628 - 1631
[13]Patent: WO2011/68821,2011,A1 .Location in patent: Page/Page column 108
[14]Chemische Berichte,1883,vol. 16,p. 1964
[15]Helvetica Chimica Acta,1931,vol. 14,p. 513
[16]Chemische Berichte,1938,vol. 71,p. 907,910
[17]Chemische Berichte,1988,vol. 121,p. 243 - 252
[18]Journal of the American Chemical Society,2014,vol. 136,p. 6239 - 6242
[19]Chemistry - A European Journal,2016,vol. 22,p. 11997 - 12001
[20]Molecules,2017,vol. 22

5
[ 1885-13-8 ]
[ 610-35-5 ]

Reference： [1]Chemische Berichte,1879,vol. 12,p. 818,821
[2]Chemische Berichte,1879,vol. 12,p. 818,821

6
[ 1885-13-8 ]
[ 98589-66-3 ]
[ 408339-12-8 ]

Reference： [1]Journal of the Chemical Society,1914,vol. 105,p. 163

7
[ 1885-13-8 ]
[ 201287-73-2 ]
[ 856806-20-7 ]

Reference： [1]Journal of the Chemical Society,1939,p. 1159
Journal of the Chemical Society,1948,p. 265

8
[ 57-62-5 ]
[ 1885-13-8 ]

Reference： [1]Journal of the American Chemical Society,1952,vol. 74,p. 3710

9
[ 22895-19-8 ]
[ 1885-13-8 ]

Yield	Reaction Conditions	Operation in experiment
99%		A solution of dimethyl 4-methoxyphthalate (36.75 g, 0.16 mol) in methanol (100 ml) was treated with a solution of potassium hydroxide (28.0 g, 0.5 mol) in water (50 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the methanol was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 5M hydrochloric acid. The solid material was filtered off, washed with water and sucked dry under reduced pressure overnight to afford 4-methoxyphthalic acid (31.8 g, 99%) as an off white solid. 1H NMR (DMSOd6) 12.90 (2H, br s), 7.74 (1H, d), 7.12-7.05 (2H1 m), 3.84 (3H, s). MS: [M+H]+ 197.
99%		A solution of dimethyl 4-methoxyphthalate (36.75 g, 0.16 mol) in methanol (100 ml) was treated with a solution of potassium hydroxide (28.0 g, 0.5 mol) in water (50 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the methanol was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 5M hydrochloric acid. The solid material was filtered off, washed with water and sucked dry under reduced pressure overnight to afford 4-methoxyphthalic acid (31.8 g, 99%) as an off white solid. 1H NMR (DMSO-d6) 12.90 (2H, br s), 7.74 (1H, d), 7.12-7.05 (2H, m), 3.84 (3H, s). MS: [M+H]+ 197.
99%		A solution of dimethyl 4-methoxyphthalate (36.75 g, 0.16 mol) in methanol (100 ml) was treated with a solution of potassium hydroxide (28.0 g, 0.5 mol) in water (50 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the methanol was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 5M hydrochloric acid. The solid material was filtered off, washed with water and sucked dry under reduced pressure overnight to afford 4-methoxyphthalic acid (31.8 g, 99%) as an off white solid. 1H NMR (DMSOd6) 12.90 (2H, br s), 7.74 (1H1 d), 7.12-7.05 (2H, m), 3.84 (3H, s). MS: [M+H]+ 197.

99%		A solution of dimethyl 4-methoxyphthalate (36.75 g, 0.16 mol) in methanol (100 ml) was treated with a solution of potassium hydroxide (28.0 g, 0.5 mol) in water (50 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the methanol was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 5M hydrochloric acid. The solid material was filtered off, washed with water and sucked dry under reduced pressure overnight to afford 4-methoxyphthalic acid (31.8 g, 99%) as an off white solid. 1H NMR (DMSOd6) 12.90 (2H, br s), 7.74 (1 H, d), 7.12-7.05 (2H, m), 3.84 (3H, s). MS: [M+H]+ 197.
99%	With water; potassium hydroxide; In methanol; for 4h;Reflux;	A solution of dimethyl 4-methoxyphthalate (36.75 g, 0.16 mol) in methanol (100 ml) was treated with a solution of potassium hydroxide (28.0 g, 0.5 mol) in water (50 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the methanol was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 5M hydrochloric acid. The solid material was filtered off, washed with water and sucked dry under reduced pressure overnight to afford 4-methoxyphthalic acid (31.8 g, 99%) as an off white solid. 1H NMR (DMSO-d6) 12.90 (2H, br s), 7.74 (1H, d), 7.12-7.05 (2H, m), 3.84 (3H, s). MS: [M+H]+ 197.
	With sodium hydroxide; In water; for 1h;Heating / reflux;	A solution of dimethyl 4-methoxyphthalate (20 g, 89 [MMOL)] was heated at reflux in 10% aqueous sodium hydroxide (85 mL) for 1 hour. The mixture was cooled to room temperature then acidified to pH 1 using concentrated hydrochloric acid. The precipitate that formed was filtered off, washed with water and dried under vacuum to afford the title compound D22 (13.61 g). MH-195.'H NMR [8] (DMSO-d6) 3.83 (3H, s), 7.05-7. 10 (3H, m), 7.72 [(1H,] d).
		Example 3 5-(5-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid; To a solution of 4-hydroxyphthalic acid (0.25 g, 1.37 mmol) in anhydrous N,N-dimethylformamide (3 ml) under nitrogen was added sodium hydride (0.22 g, 5.48 mmol). The solution was stirred for 5 minutes and then methyl iodide (0.68 ml) was added and continued stirring for 3 hours. Several drops of water were added to quench the reaction and the mixture was concentrated in vacuo. The crude material was partitioned between ethyl acetate (40 ml) and water (10 ml). The layers were separated and the organic layer washed with brine (2×10 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The resulting oil was dissolved in methanol (8 ml) and 1N sodium hydroxide (4 ml) was added. The reaction was stirred at ambient temperature for 24 h., after which LC-MS indicated only partial hydrolysis. The material was reconstituted in methanol (5 ml) and treated with of sodium hydroxide (0.12 g, 3.0 mmol) dissolved in water (1 ml). The reaction mixture was stirred for 48 h., at which time a precipitate had formed. The mixture was acidified with 6N hydrochloric acid until pH=1, causing the solution to become homogeneous. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate (30 ml) and 0.5N hydrochloric acid (10 ml). The layers were separated and the organic layer concentrated in vacuo to give 100 mg (51%) of 4-methoxy-phthalic acid as a solid.1H NMR (300 MHz, CD3OD) delta 7.83 (d; J=8, 1H), 7.10-7.06 (m, 2H), 3.87 (s, 3H).LC-MS: Rt=1.45 min, [M+H]+=197.1A solution of 4-methoxy-phthalic acid (0.10 g, 0.51 mmol), 1-hydroxy-benzotriazole (0.15 g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.22 g, 1.1 mmol), and triethylamine (0.35 ml, 2.5 mmol) was prepared in distilled acetonitrile (4 ml) under nitrogen. 2-Amino-5-aminomethyl-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.11 g, 0.39 mmol) was added in small portions and the reaction was stirred at ambient temperature for 18 h., and then concentrated in vacuo. The crude mixture was diluted in ethyl acetate (30 ml) and washed with 1% hydrochloric acid (5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a 10% mixture of ethyl acetate/dichloromethane as eluant. Pure fractions were collected and the solvent evaporated in vacuo to give 54 mg (31%) of 2-amino-5-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester.1H NMR (300 MHz, CDCl3) delta 7.76 (d, J=8, 1H), 7.32 (s, 1H), 7.14 (d, J=8, 1H), 4.62-4.48 (m, 2H), 4.00-3.72 (m, 3H), 3.91 (s, 3H), 2.86 (d, J=17, 1H), 2.55 (dd, J=17, 10, 1H), 1.49 (s, 9H).To a solution of the above 2-amino-5-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester (54 mg, 0.12 mmol) in distilled dichloromethane (3 ml) under nitrogen was added midazol-1-yl-oxo-acetic acid tert-butyl ester (0.25 g, 0.36 mmol) and triethylamine (50 mul, 0.36 mmol). The reaction was stirred for 4 h., concentrated in vacuo and the residue reconstituted in ethyl acetate (20 ml). The organic layer was washed with 1% hydrochloric acid (2×5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic phase was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a 5% mixture of ethyl acetate/dichloromethane as eluant. Pure fractions were collected and the solvent evaporated in vacuo to give 56 mg (81%) of 2-(tert-butoxyoxalyl-amino)-5-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester.1H NMR (300 MHz, CDCl3) delta 12.48 (s, 1H), 7.75 (d, J=8, 1H), 7.32 (d, J=2, 1H), 7.15 (dd, J=8, 2, 1H), 4.78 (d, J=15, 1H), 4.65 (d, J=15, 1H), 4.03-3.75 (m, 3H), 3.91 (s, 3H), 2.95 (d, J=17, 1H), 2.66 (dd, J=17, 9, 1H), 1.58 (s, 9H), 1.54 (s, 9H).APCI-MS: [M+H]+=574The above 2-(tert-butoxyoxalyl-amino)-5-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester (55 mg, 0.096 mmol) was dissolved in a solution of 50% trifluoroacetic acid/dichloromethane (4 ml). The reaction was stirred at ambient temperature for 7 h., concentrated in vacuo and evaporated in vacuo from dichloromethane (3×10 ml). The resulting precipitate was washed with dichloromethane and dried in vacuo to give 17 mg (40%) of the title compound as a solid.1H NMR (300 MHz, DMSO-d6) delta 12.32 (s, 1H), 7.81 (d, J=8, 1H), 7.40 (d, J=2, 1H), 7.31 (dd, J=8, 2, 1H), 4.75 (d, J=15, 1H), 4.56 (d, J=15, 1H), 3.92 (s, 3H), 3.91-3.69 (m, 3H), 2.98 (d, J=17, 1H), 2.57 (dd, J=17, 9, 1H).AP...
	With water; sodium hydroxide; In acetone; at 20℃;	The 3 ml of acetone containing the compound prepared in step 2 (0.31 g, 1.4 mmol) dissolved therein was treated with 2 ml of water containing NaOH (0.34 g, 8.4 mmol) dissolved therein, followed by stirring at room temperature for overnight. After evaporating acetone, the reaction mixture was acidized with 6 M HCl to adjust to pH 2, followed by extraction with ethyl acetate. The combined organic layer was dried over MgSO4, and the solvent was eliminated under reduced pressure. As a result, a crude target compound was obtained (0.27 g, 97%). 1H NMR (DMSO-d6, 500 MHz) delta 12.94 (s, 2H), 7.74 (d, J=8.5 Hz, 1H), 7.07 (dd, J=8.5, 2.7 Hz, 1H), 7.05 (d, J=2.5 Hz, 1H), 3.83 (s, 3H). 13C NMR (DMSO-d6, 125 MHz) delta 169.3, 167.4, 161.4, 137.1, 131.3, 122.7, 115.1, 113.0, 55.7.

Reference： [1]Patent: WO2008/44029,2008,A1 .Location in patent: Page/Page column 203
[2]Patent: WO2008/44041,2008,A1 .Location in patent: Page/Page column 225
[3]Patent: WO2008/44045,2008,A1 .Location in patent: Page/Page column 277-278
[4]Patent: WO2008/44054,2008,A2 .Location in patent: Page/Page column 122
[5]Patent: US2010/152184,2010,A1 .Location in patent: Page/Page column 72
[6]Journal of Medicinal Chemistry,2010,vol. 53,p. 5956 - 5969
[7]RSC Advances,2016,vol. 6,p. 46170 - 46185
[8]Journal of the Chemical Society,1907,vol. 91,p. 103
[9]Journal of Organic Chemistry,1983,vol. 48,p. 2981 - 2989
[10]Patent: WO2003/99786,2003,A2 .Location in patent: Page 38
[11]Patent: US7115624,2006,B1 .Location in patent: Page/Page column 56-57
[12]Journal of the American Chemical Society,2014,vol. 136,p. 6239 - 6242
[13]Patent: US2019/345126,2019,A1 .Location in patent: Paragraph 0192; 0197-0198

10
[ 6245-57-4 ]
[ 1885-13-8 ]

Reference： [1]Chemische Berichte,1879,vol. 12,p. 818,821

11
[ 3168-59-0 ]
[ 1885-13-8 ]

Reference： [1]Chemische Berichte,1883,vol. 16,p. 1964
[2]Journal of Organic Chemistry,1960,vol. 25,p. 334 - 343

12
[ 22811-86-5 ]
[ 1885-13-8 ]

Reference： [1]Journal of the Indian Chemical Society,1969,vol. 46,p. 351 - 357

13
[ 1730-48-9 ]
[ 1885-13-8 ]
[ 1078-19-9 ]

Reference： [1]Tetrahedron,1985,vol. 41,p. 4107 - 4118

14
[ 1885-13-8 ]
[ 50727-04-3 ]

Yield	Reaction Conditions	Operation in experiment
	With urea; In ethylene glycol; at 180℃; for 3h;	A mixture of D22 (13.61 g, 69 [MMOL)] and urea (8.3 g, 139 [MMOL)] were heated together in ethylene glycol (150 mL) at [180C] for 3 hours. The mixture was cooled to room temperature and the precipitate that formed filtered off, washed with water then dried to afford the title compound D23 (6.78 g). MH-176.'H NMR 8 (DMSO-d6) 3.92 (3H, s), 7.27- 7.38 (2H, m), 7.71-7. 76 [(1H,] d).

Reference： [1]Journal of Organic Chemistry,1983,vol. 48,p. 2981 - 2989
[2]Chemische Berichte,1988,vol. 121,p. 243 - 252
[3]Patent: WO2003/99786,2003,A2 .Location in patent: Page 38
[4]Journal of the American Chemical Society,2014,vol. 136,p. 6239 - 6242
[5]Chemistry - A European Journal,2016,vol. 22,p. 11997 - 12001

15
[ 610-35-5 ]
[ 77-78-1 ]
[ 1885-13-8 ]

Reference： [1]Chemische Berichte,1988,vol. 121,p. 243 - 252

16
[ 1078-19-9 ]
[ 1885-13-8 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1982,vol. 324,p. 550 - 556

17
[ 82894-69-7 ]
[ 1885-13-8 ]

Reference： [1]Journal of Chemical Research, Miniprint,1982,p. 1710 - 1725

18
7-methoxy-1,4-diphenylisoquinoline [ No CAS ]
[ 1885-13-8 ]

Reference： [1]Journal of Chemical Research, Miniprint,1982,p. 1710 - 1725

19
[ 1885-13-8 ]
[ 36132-95-3 ]

Reference： [1]Journal of the American Chemical Society,1994,vol. 116,p. 10593 - 10600
[2]Journal of Organic Chemistry,2014,vol. 79,p. 8143 - 8155
[3]Angewandte Chemie - International Edition,2017,vol. 56,p. 8196 - 8200
Angew. Chem.,2017,vol. 129,p. 8308 - 8312,5

20
[ 1596-15-2 ]
[ 1885-13-8 ]

Reference： [1]Journal of Organic Chemistry USSR (English Translation),1967,vol. 3,p. 861 - 864
Zhurnal Organicheskoi Khimii,1967,vol. 3,p. 896 - 899

21
[ 91061-91-5 ]
[ 762-21-0 ]
[ 1885-13-8 ]

Reference： [1]Monatshefte fur Chemie,1964,vol. 95,p. 649 - 670

22
[ 1885-13-8 ]
[ 36132-96-4 ]

Reference： [1]Journal of the American Chemical Society,1994,vol. 116,p. 10593 - 10600

23
[ 1885-13-8 ]
[ 36132-97-5 ]

Reference： [1]Journal of the American Chemical Society,1994,vol. 116,p. 10593 - 10600

24
[ 1885-13-8 ]
[ 159683-65-5 ]

Reference： [1]Journal of the American Chemical Society,1994,vol. 116,p. 10593 - 10600

25
[ 1885-13-8 ]
[ 159683-68-8 ]

Reference： [1]Journal of the American Chemical Society,1994,vol. 116,p. 10593 - 10600

26
[ 85-44-9 ]
NaCl [ No CAS ]
[ 1885-13-8 ]

Reference： [1]Chemische Berichte,1988,vol. 121,p. 243 - 252

27
[ 134-08-7 ]
[ 1885-13-8 ]

Reference： [1]Chemische Berichte,1988,vol. 121,p. 243 - 252

28
[ 1885-13-8 ]
[ 22246-66-8 ]

Reference： [1]Chemische Berichte,1988,vol. 121,p. 243 - 252

29
[ 610-35-5 ]
[ 1885-13-8 ]

Reference： [1]Journal of Organic Chemistry,1983,vol. 48,p. 2981 - 2989
[2]Journal of the Chemical Society,1907,vol. 91,p. 103
[3]Journal of the American Chemical Society,2014,vol. 136,p. 6239 - 6242
[4]Chemistry - A European Journal,2016,vol. 22,p. 11997 - 12001
[5]Patent: US2019/345126,2019,A1

30
[ 1885-13-8 ]
[ 86611-64-5 ]

Reference： [1]Journal of Organic Chemistry,1983,vol. 48,p. 2981 - 2989

31
[ 1885-13-8 ]
[ 86611-72-5 ]

Reference： [1]Journal of Organic Chemistry,1983,vol. 48,p. 2981 - 2989

32
[ 1885-13-8 ]
[ 86611-68-9 ]

Reference： [1]Journal of Organic Chemistry,1983,vol. 48,p. 2981 - 2989

33
[ 22479-95-4 ]
[ 1885-13-8 ]

Reference： [1]Journal of Organic Chemistry,1983,vol. 48,p. 2981 - 2989
[2]Journal of the American Chemical Society,2014,vol. 136,p. 6239 - 6242
[3]Patent: US2019/345126,2019,A1

34
[ 95-65-8 ]
[ 1885-13-8 ]

Reference： [1]Chemische Berichte,1900,vol. 33,p. 742
Chemische Berichte,1901,vol. 34,p. 1259

35
[ 1885-13-8 ]
4-methoxy-3-nitro-phthalic acid-anhydride [ No CAS ]

Reference： [1]Journal of the Chemical Society,1914,vol. 105,p. 163

36
[ 1885-13-8 ]
[ 856806-20-7 ]

Reference： [1]Journal of the Chemical Society,1914,vol. 105,p. 163

37
[ 73502-03-1 ]
[ 1885-13-8 ]

Reference： [1]Chemische Berichte,1883,vol. 16,p. 1964

38
[ 586-38-9 ]
[ 1885-13-8 ]

Reference： [1]Journal of the Chemical Society,1929,p. 199

39
[ 591-31-1 ]
[ 1885-13-8 ]

Reference： [1]Journal of the Chemical Society,1929,p. 199

40
[ 5336-62-9 ]
[ 1885-13-8 ]

Reference： [1]Journal of Organic Chemistry,1960,vol. 25,p. 334 - 343

41
[ 108481-83-0 ]
[ 1885-13-8 ]

Reference： [1]Journal of Organic Chemistry,1960,vol. 25,p. 334 - 343

42
[ 2746-25-0 ]
aqueous NaOH-solution [ No CAS ]
[ 1885-13-8 ]

Reference： [1]Journal of Organic Chemistry,1960,vol. 25,p. 334 - 343

43
[ 105-13-5 ]
[ 1885-13-8 ]

Reference： [1]Journal of Organic Chemistry,1960,vol. 25,p. 334 - 343

44
[ 673-22-3 ]
[ 1885-13-8 ]

Reference： [1]Monatshefte fur Chemie,1964,vol. 95,p. 649 - 670

45
[ 7577-76-6 ]
[ 1885-13-8 ]

Reference： [1]Monatshefte fur Chemie,1964,vol. 95,p. 649 - 670

46
[ 20734-74-1 ]
[ 1885-13-8 ]

Reference： [1]Monatshefte fur Chemie,1964,vol. 95,p. 649 - 670

47
[ 95-01-2 ]
air [ No CAS ]
[ 1885-13-8 ]

Reference： [1]Monatshefte fur Chemie,1964,vol. 95,p. 649 - 670

48
[ 243968-20-9 ]
[ 1885-13-8 ]
[ 330192-19-3 ]

Yield	Reaction Conditions	Operation in experiment
31%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 20℃; for 18h;	A solution of <strong>[1885-13-8]4-methoxy-phthalic acid</strong> (0.10 g, 0.51 mmol), 1-hydroxy-benzotriazoie (0.15 g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.22 g, 1.1 mmol), and triethylamine (0.35 ml, 2.5 mmol) was prepared in distilled acetonitrile (4 ml) under nitrogen. 2-Amino-5-aminomethyl-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acidtert-butyl ester (0.11 g, 0.39 mmol) was added in small portions and the reaction was stirred at ambient temperature for 18 hours and then concentrated invacuo. The crude mixture was diluted in ethyl acetate (30 ml) and washed with 1% hydrochloric acid (5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic layer was dried (Na2SO4), filtered, and the solvent evaporated invacuo. The crude material was purified by silica gel chromatography using a 10 % mixture of ethyl acetate/dichloromethane as eluent. Pure fractions were collected and the solvent evaporated invacuo to give 54 mg (31 %) of 2-amino-5-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester.1H-NMR (300 MHz, CDCl3) delta 7.76 (d, 1H, J = 8 Hz), 7.32 (s, 1H), 7.14 (d, 1H, J = 8 Hz), 4.62-4.48 (m, 2H), 4.00-3.72 (m, 3H), 3.91 (s, 3H), 2.86 (d, 1H, J = 17 Hz), 2.55 (dd, 1H, J = 17 Hz and J = 10 Hz), 1.49 (s, 9H).
31%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 20℃; for 18h;	A solution of <strong>[1885-13-8]4-methoxy-phthalic acid</strong> (0.10 g, 0.51 mmol), 1-hydroxy-benzotriazole (0.15 g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.22 g, 1.1 mmol), and triethylamine (0.35 ml, 2.5 mmol) was prepared in distilled acetonitrile (4 ml) under nitrogen. 2-Amino-5-aminomethyl-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.11 g, 0.39 mmol) was added in small portions and the reaction was stirred at ambient temperature for 18 hours and then concentrated in vacuo. The crude mixture was diluted in ethyl acetate (30 ml) and washed with 1% hydrochloric acid (5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a 10% mixture of ethyl acetate/dichloromethane as eluent. Pure fractions were collected and the solvent evaporated in vacuo to give 54 mg (31%) of 2-amino-5-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester.1H-NMR (300 MHz, CDCl3) delta 7.76 (d, 1H, J=8 Hz), 7.32 (s, 1H), 7.14 (d, 1H, J=8 Hz), 4.62-4.48 (m, 2H), 4.00-3.72 (m, 3H), 3.91 (s, 3H), 2.86 (d, 1H, J=17 Hz), 2.55 (dd, 1H, J=17 Hz and J=10 Hz), 1.49 (s, 9H).
31%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 20℃; for 18h;	Example 3 5-(5-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid; To a solution of 4-hydroxyphthalic acid (0.25 g, 1.37 mmol) in anhydrous N,N-dimethylformamide (3 ml) under nitrogen was added sodium hydride (0.22 g, 5.48 mmol). The solution was stirred for 5 minutes and then methyl iodide (0.68 ml) was added and continued stirring for 3 hours. Several drops of water were added to quench the reaction and the mixture was concentrated in vacuo. The crude material was partitioned between ethyl acetate (40 ml) and water (10 ml). The layers were separated and the organic layer washed with brine (2×10 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The resulting oil was dissolved in methanol (8 ml) and 1N sodium hydroxide (4 ml) was added. The reaction was stirred at ambient temperature for 24 h., after which LC-MS indicated only partial hydrolysis. The material was reconstituted in methanol (5 ml) and treated with of sodium hydroxide (0.12 g, 3.0 mmol) dissolved in water (1 ml). The reaction mixture was stirred for 48 h., at which time a precipitate had formed. The mixture was acidified with 6N hydrochloric acid until pH=1, causing the solution to become homogeneous. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate (30 ml) and 0.5N hydrochloric acid (10 ml). The layers were separated and the organic layer concentrated in vacuo to give 100 mg (51%) of <strong>[1885-13-8]4-methoxy-phthalic acid</strong> as a solid.1H NMR (300 MHz, CD3OD) delta 7.83 (d; J=8, 1H), 7.10-7.06 (m, 2H), 3.87 (s, 3H).LC-MS: Rt=1.45 min, [M+H]+=197.1A solution of <strong>[1885-13-8]4-methoxy-phthalic acid</strong> (0.10 g, 0.51 mmol), 1-hydroxy-benzotriazole (0.15 g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.22 g, 1.1 mmol), and triethylamine (0.35 ml, 2.5 mmol) was prepared in distilled acetonitrile (4 ml) under nitrogen. 2-Amino-5-aminomethyl-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.11 g, 0.39 mmol) was added in small portions and the reaction was stirred at ambient temperature for 18 h., and then concentrated in vacuo. The crude mixture was diluted in ethyl acetate (30 ml) and washed with 1% hydrochloric acid (5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a 10% mixture of ethyl acetate/dichloromethane as eluant. Pure fractions were collected and the solvent evaporated in vacuo to give 54 mg (31%) of 2-amino-5-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester.1H NMR (300 MHz, CDCl3) delta 7.76 (d, J=8, 1H), 7.32 (s, 1H), 7.14 (d, J=8, 1H), 4.62-4.48 (m, 2H), 4.00-3.72 (m, 3H), 3.91 (s, 3H), 2.86 (d, J=17, 1H), 2.55 (dd, J=17, 10, 1H), 1.49 (s, 9H).To a solution of the above 2-amino-5-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester (54 mg, 0.12 mmol) in distilled dichloromethane (3 ml) under nitrogen was added midazol-1-yl-oxo-acetic acid tert-butyl ester (0.25 g, 0.36 mmol) and triethylamine (50 mul, 0.36 mmol). The reaction was stirred for 4 h., concentrated in vacuo and the residue reconstituted in ethyl acetate (20 ml). The organic layer was washed with 1% hydrochloric acid (2×5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic phase was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a 5% mixture of ethyl acetate/dichloromethane as eluant. Pure fractions were collected and the solvent evaporated in vacuo to give 56 mg (81%) of 2-(tert-butoxyoxalyl-amino)-5-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester.1H NMR (300 MHz, CDCl3) delta 12.48 (s, 1H), 7.75 (d, J=8, 1H), 7.32 (d, J=2, 1H), 7.15 (dd, J=8, 2, 1H), 4.78 (d, J=15, 1H), 4.65 (d, J=15, 1H), 4.03-3.75 (m, 3H), 3.91 (s, 3H), 2.95 (d, J=17, 1H), 2.66 (dd, J=17, 9, 1H), 1.58 (s, 9H), 1.54 (s, 9H).APCI-MS: [M+H]+=574The above 2-(tert-butoxyoxalyl-amino)-5-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno-[2,3-c]pyran-3-carboxylic acid tert-butyl ester (55 mg, 0.096 mmol) was dissolved in a solution of 50% trifluoroacetic acid/dichloromethane (4 ml). The reaction was stirred at ambient temperature for 7 h., concentrated in vacuo and evaporated in vacuo from dichloromethane (3×10 ml). The resulting precipitate was washed with dichloromethane and dried in vacuo to give 17 mg (40%) of the title compound as a solid.1H NMR (300 MHz, DMSO-d6) delta 12.32 (s, 1H), 7.81 (d, J=8, 1H), 7.40 (d, J=2, 1H), 7.31 (dd, J=8, 2, 1H), 4.75 (d, J=15, 1H), 4.56 (d, J=15, 1H), 3.92 (s, 3H), 3.91-3.69 (m, 3H), 2.98 (d, J=17, 1H), 2.57 (dd, J=17, 9, 1H).AP...

Reference： [1]Patent: EP1214325,2005,B1 .Location in patent: Page/Page column 28
[2]Patent: US7019026,2006,B1 .Location in patent: Page/Page column 40-41
[3]Patent: US7115624,2006,B1 .Location in patent: Page/Page column 56-57

49
[ 610-35-5 ]
[ 74-88-4 ]
[ 1885-13-8 ]

Yield	Reaction Conditions	Operation in experiment
51%		EXAMPLE 3; 5-(5-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid To a solution of 4-hydroxyphthalic acid (0.25 g, 1.37 mmol) in anhydrous N,N-dimethylformamide (3 ml) under nitrogen was added sodium hydride (0.22 g, 5.48 mmol). The solution was stirred for 5 minutes and then methyl iodide (0.68 ml) was added and continued stirring for 3 hours. Several drops of water were added to quench the reaction and the mixture was concentrated in vacuo . The crude material was partitioned between ethyl acetate (40 ml) and water (10 ml). The layers were separated and the organic layer washed with brine (2 x 10 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo . The resulting oil was dissolved in methanol (8 ml) and 1 N sodium hydroxide (4 ml) was added. The reaction was stirred at ambient temperature for 24 hours, after which LC-MS indicated only partial hydrolysis. The material was reconstituted in methanol (5 ml) and treated with of sodium hydroxide (0.12 g, 3.0 mmol) dissolved in water (1 ml). The reaction mixture was stirred for 48 hours, at which time a precipitate had formed. The mixture was acidified with 6 N hydrochloric acid until pH = 1, causing the solution to become homogeneous. The reaction was concentratedin vacuo and the residue partitioned between ethyl acetate (30 ml) and 0.5N hydrochloric acid (10 ml). The layers were separated and the organic layer concentrated in vacuo to give 100 mg (51 %) of 4-methoxy-phthalic acid as a solid. 1H-NMR (300 MHz, CD3OD) delta 7.83 (d, 1H, J = 8 Hz), 7.10-7.06 (m, 2H), 3.87 (s, 3H). LC-MS: Rt = 1.45 min, m/z: 197 [M+H]+
51%		Example 3 5-(5-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid To a solution of 4-hydroxyphthalic acid (0.25 g, 1.37 mmol) in anhydrous N,N-dimethylformamide (3 ml) under nitrogen was added sodium hydride (0.22 g, 5.48 mmol). The solution was stirred for 5 minutes and then methyl iodide (0.68 ml) was added and continued stirring for 3 hours. Several drops of water were added to quench the reaction and the mixture was concentrated in vacuo. The crude material was partitioned between ethyl acetate (40 ml) and water (10 ml). The layers were separated and the organic layer washed with brine (2*10 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The resulting oil was dissolved in methanol (8 ml) and 1N sodium hydroxide (4 ml) was added. The reaction was stirred at ambient temperature for 24 hours, after which LC-MS indicated only partial hydrolysis. The material was reconstituted in methanol (5 ml) and treated with of sodium hydroxide (0.12 g, 3.0 mmol) dissolved in water (1 ml). The reaction mixture was stirred for 48 hours, at which time a precipitate had formed. The mixture was acidified with 6 N hydrochloric acid until pH=1, causing the solution to become homogeneous. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate (30 ml) and 0.5N hydrochloric acid (10 ml). The layers were separated and the organic layer concentrated in vacuo to give 100 mg (51%) of 4-methoxy-phthalic acid as a solid. 1H-NMR (300 MHz, CD3OD) delta 7.83 (d, 1H, J=8 Hz), 7.10-7.06 (m, 2H), 3.87 (s, 3H). LC-MS: Rt=1.45 min, m/z: 197 [M+H]+

Reference： [1]Patent: EP1214325,2005,B1 .Location in patent: Page/Page column 27-28
[2]Patent: US7019026,2006,B1 .Location in patent: Page/Page column 40

50
[ 1885-13-8 ]
4-methoxyphthaloyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With phosphorus pentachloride;	EXAMPLE V In a dry 50 ml. round-bottomed reaction flask equipped with magnetic stirrer, oil bath, reflux condenser and nitrogen-inlet tube, there were placed 2.0 g. (0.0102 mole) of <strong>[1885-13-8]4-methoxyphthalic acid</strong> [H. King, Journal of the Chemical Society, p. 1157 (1939)] and 7.2 g. (0.0345 mole) of phosphorus pentachloride. The crude solid mixture was then heated to a gentle reflux for a period of three hours while under a nitrogen atmosphere and finally cooled to room temperature (~25 C.). After removal of the volatile components by concentrating the spent reaction mixture under reduced pressure, there was obtained crude 4-methoxyphthaloyl chloride as the residue in the form of a pale yellow solid.
	With sulfuryl dichloride; In dichloromethane; for 5h;Reflux; Inert atmosphere;	24.2 g of <strong>[1885-13-8]4-methoxyphthalic acid</strong> and 240 ml of dichloromethane were added to the container, and 17.9 ml of sulfuryl chloride was slowly added dropwise. After the dropwise addition, the reaction was refluxed for 5 h under the protection of nitrogen; and concentrated to give compound 12 under reduced pressure.
	With sulfuryl dichloride; In dichloromethane; for 5h;Reflux; Inert atmosphere;	24.2 g of <strong>[1885-13-8]4-methoxyphthalic acid</strong> and 240 ml of dichloromethane were added to the container, and 17.9 ml of sulfuryl chloride was slowly added dropwise. After the dropwise addition, the reaction was refluxed for 5 h under the protection of nitrogen; and concentrated to give compound 12 under reduced pressure.

With thionyl chloride; In dichloromethane; for 5h;Reflux; Inert atmosphere;

Add 24.2g of <strong>[1885-13-8]4-methoxyphthalic acid</strong> and 240ml of dichloromethane to the container.Slowly dropwise add 17.9ml of thionyl chloride. After the dropwise addition,The reaction was refluxed for 5 h under the protection of nitrogen; and concentrated under reduced pressure to obtain compound 12.

Reference： [1]Patent: US4220650,1980,A
[2]Patent: CN110305000,2019,A .Location in patent: Paragraph 0133-0135
[3]Patent: CN110305103,2019,A .Location in patent: Paragraph 0043-0045
[4]Patent: CN110304999,2019,A .Location in patent: Paragraph 0043-0045

51
[ 201230-82-2 ]
[ 586-38-9 ]
[ 1885-13-8 ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 14082 - 14083

52
[ 1885-13-8 ]
[ 108-24-7 ]
C₁₃H₁₂O₇ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4963 - 4966

53
[ 1885-13-8 ]
[ 100-01-6 ]
[ 1089667-07-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With acetic acid; for 12h;Heating / reflux;	1.1 g (6.2 mmol) of anhydrous <strong>[1885-13-8]4-methoxyphthalic acid</strong> compound obtained in Example 1 was dissolved in 10 ml_ of acetic acid, to which 856 mg (6.2 mmol) of 4-nitroaniline was added dropwise, and then the resultant was refluxed for 12 hours. When the reaction was completed, 10% NaHCO3 solution was added for neutralization. The resultant was extracted with ethyl acetate, and the extract was dried with anhydrous sodium sulfate and filtered. The solvent was distilled off under a reduced pressure, and the residue was purified by a column chromatography to obtain 1.7 g (92%) of the desired compound as a pale yellow solid. 1H NMR (300 MHz, DMSOd6) delta 3.97 (s, 3H), 7.41 (dd, J=2.2, 8.4 Hz,1 H), 7.53 (d, =2.1 Hz, 1 H), 7.78 (d, J=9.0 Hz, 2H), 7.94 (d, J=8.3 Hz, 1 H), 8.40 (d, J=9.0 Hz, 2H).

Reference： [1]Patent: WO2009/54653,2009,A2 .Location in patent: Page/Page column 26

54
[ 1885-13-8 ]
[ 1310530-55-2 ]

Reference： [1]Patent: WO2011/68821,2011,A1

55
[ 1885-13-8 ]
4-methoxyphthalic acid 2-methyl ester [ No CAS ]

Reference： [1]Patent: WO2011/68821,2011,A1

56
[ 1885-13-8 ]
[ 1035797-89-7 ]

Reference： [1]Patent: WO2011/68821,2011,A1

57
[ 1885-13-8 ]
[ 1310532-03-6 ]

Reference： [1]Patent: WO2011/68821,2011,A1

58
[ 1885-13-8 ]
[ 1310532-04-7 ]

Reference： [1]Patent: WO2011/68821,2011,A1

59
[ 1885-13-8 ]
[ 1310532-05-8 ]

Reference： [1]Patent: WO2011/68821,2011,A1

60
[ 1885-13-8 ]
dimethyl (2R,4R)-2-(benzyloxy)-4-(5-methoxy-1,3-dioxoisoindolin-2-yl)-2-phenylcyclopentane-1,1-dicarboxylate [ No CAS ]
dimethyl 2-(benzyloxy)-4-(5-methoxy-1,3-dioxoisoindolin-2-yl)-2-phenylcyclopentane-1,1-dicarboxylate [ No CAS ]
[ 1603818-42-3 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 6239 - 6242

61
[ 1885-13-8 ]
[ 1603818-36-5 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 6239 - 6242
[2]Chemistry - A European Journal,2016,vol. 22,p. 11997 - 12001

62
[ 1885-13-8 ]
[ 1603818-34-3 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 6239 - 6242
[2]Chemistry - A European Journal,2016,vol. 22,p. 11997 - 12001

63
[ 1885-13-8 ]
C₁₈H₁₆O₂ [ No CAS ]