[ CAS No. 610-35-5 ] {[proInfo.proName]}

Name: 610-35-5|4-Hydroxyphthalic acid|98%
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Quality Control of [ 610-35-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 610-35-5 ]

CAS No. :	610-35-5	MDL No. :	MFCD00013984
Formula :	C₈H₆O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MWRVRCAFWBBXTL-UHFFFAOYSA-N
M.W :	182.13	Pubchem ID :	11881
Synonyms :

Calculated chemistry of [ 610-35-5 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	3.0
Molar Refractivity :	42.38
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) :	-6.68 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.32
Log Po/w (XLOGP3) :	1.03
Log Po/w (WLOGP) :	0.79
Log Po/w (MLOGP) :	0.63
Log Po/w (SILICOS-IT) :	0.15
Consensus Log Po/w :	0.58

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.83
Solubility :	2.71 mg/ml ; 0.0149 mol/l
Class :	Very soluble
Log S (Ali) :	-2.61
Solubility :	0.446 mg/ml ; 0.00245 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-0.57
Solubility :	49.0 mg/ml ; 0.269 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.31

Safety of [ 610-35-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 610-35-5 ]

* 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 [ 610-35-5 ]
Downstream synthetic route of [ 610-35-5 ]

[ 610-35-5 ] Synthesis Path-Upstream 1~9

1
[ 610-35-5 ]
[ 50727-04-3 ]

Reference： [1] Chemische Berichte, 1988, vol. 121, p. 243 - 252
[2] Journal of Organic Chemistry, 1983, vol. 48, # 18, p. 2981 - 2989
[3] Journal of the American Chemical Society, 2014, vol. 136, # 17, p. 6239 - 6242
[4] Chemistry - A European Journal, 2016, vol. 22, # 34, p. 11997 - 12001

2
[ 610-35-5 ]
[ 50727-06-5 ]

Yield	Reaction Conditions	Operation in experiment
72%	With ammonium carbonate; hydrogenchloride; sodium hydroxide In conc. AcOH	Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120° C. for 45 min., then the clear, bright yellow mixture was heated at 160° C. for 2 h. The resulting mixture was maintained at 160° C. and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This mixture was cooled to 0° C. and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72percent): ¹H NMR (DMSO-d₆) δ7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H).
72%	With ammonium carbonate; hydrogenchloride; sodium hydroxide In conc. AcOH	Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120° C. for 45 min., then the clear, bright yellow mixture was heated at 160° C. for 2 h. The resulting mixture was maintained at 160° C. and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This mixture was cooled to 0° C. and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72percent): ¹H NMR (DMSO-d₆) δ 7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H).
72%	With ammonium carbonate; hydrogenchloride; sodium hydroxide In conc. AcOH	Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120° C. for 45 min., then the clear, bright yellow mixture was heated at 160° C. for 2 h. The resulting mixture was maintained at 160° C. and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This mixture was cooled to 0° C. and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72percent): ¹H NMR (DMSO-d₆) δ 7.00-7.03 (m, 2H), 7.56 (d, J=9.3Hz, 1H).

72%	With ammonium carbonate In hydrogenchloride; sodium hydroxide; conc. AcOH	Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120° C. for 45 min., then the clear, bright yellow mixture was heated at 160° C. for 2 h. The resulting mixture was maintained at 160° C. and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a IN NaOH solution. This mixture was cooled to 0° C. and slowly acidified to pH 5 using a IN HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72percent): ¹H NMR (DMSO-d₆) δ7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H).
72%	at 120 - 160℃; for 2.75 h;	Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120° C. for 45 min., then the clear, bright yellow mixture was heated at 160° C. for 2 h. The resulting mixture was maintained at 160° C. and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This mixture was cooled to 0° C. and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72percent): ¹H NMR (DMSO-d₆) δ 7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H).
71%	at 120 - 160℃; for 2.75 h;	e) 5-Hydroxy-isoindole-1,3-dione; [0156] A mixture of 4-hydroxyphthalic acid (5.0 g, 27.0 mmol), acetic acid (25 mL), and ammonium carbonate (5.3 g, 55 mmol) was heated at 120[deg.] C. for 45 min followed by heating at 160[deg.] C. for 2 h. After cooling to room temperature, the reaction mixture was half-evaporated and then the reaction mixture was basified to pH 10 with 1 N NaOH followed by acidification to pH 5 at 0[deg.] C. with concentrated HCl. The resulting precipitate was filtered off, washed with water, dried at 60[deg.] C. under high vacuum over night, to afford the title compound (3.2 g, 71percent) as an off-white crystalline solid. MS: m/e=162.1 (M-H<+>).

Reference： [1] Patent: US2003/144278, 2003, A1,
[2] Patent: US2003/181442, 2003, A1,
[3] Patent: US2001/11135, 2001, A1,
[4] Patent: US2002/165394, 2002, A1,
[5] Patent: US2003/207872, 2003, A1, . Location in patent: Page/Page column 9
[6] Patent: US2003/195208, 2003, A1, . Location in patent: Page/Page column 9
[7] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 7, p. 2060 - 2062
[8] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 4, p. 529 - 535
[9] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1798 - 1806

3
[ 610-35-5 ]
[ 50727-06-5 ]

Yield	Reaction Conditions	Operation in experiment
72%	With ammonium carbonate; hydrogenchloride; sodium hydroxide In conc. AcOH	Step 1. Synthesis of5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120° C. for 45 min., then the clear, bright yellow mixture was heated at 160° C. for 2 h. The resulting mixture was maintained at 160° C. and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This mixture was cooled to 0° C. and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72percent): ¹H NMR (DMSO-d₆) δ 7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H).

Reference： [1] Patent: US2002/65296, 2002, A1,

4
[ 610-35-5 ]
[ 27550-59-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	at 210℃; Green chemistry	(3) 12.3 g (67.5 mmol) of 4-hydroxyphthalic acid was placed in a sublimation tube and sublimed at 210 ° C to give 10.8 g of 4-hydroxyphthalic anhydride as a pale yellow solid in 97percent yield.
74.9%	at 220℃;	4-Hydroxyphthalic acid (1 g, 5.49 mmol) was sublimated at 220° C. under vacuum (about 10 mbar). The obtained white solid 5-hydroxyisobenzofuran-1,3-dione (675 mg, 4.11 mmol, 74.9percent yield, MS/ESI⁺164.9 [MH]⁺) was collected, stored under vacuum and used as such in the next step.
74.9%	at 220℃;	Example 45 (S)-3,5-Dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) phenyl)-2-(2-(1 ,3-dioxo-5-(pyridin-3-ylmethoxy)isoindolin-2-yl)acetoxy)ethyl) pyridine 1 -oxide 2,2,2-trifluoroacetic acid salt (Compound 248) Scheme 45 Step 1 : Preparation of 5-hydroxyisobenzofuran-1 ,3-dione (244): 4-Hydroxyphthalic acid (1 g, 5.49 mmol) was sublimated at 220°C under vacuum (about 10 mbar). The obtained white solid 5-hydroxyisobenzofuran-1 ,3- dione (675 mg, 4.1 1 mmol, 74.9percent yield, MS/ESI⁺ 164.9 [MH] ⁺) was collected, stored under vacuum and used as such in the next step.

74%	at 200℃; for 1 h;	2^nd Stage: 4-hydroxyphthalic anhydride 4-hydroxyphthalic acid (23.80 g, 0.131 mol) was heated for 1 h in an oil bath preheated to 200° C. After cooling the brownish solid was recrystallized from ethyl acetate/n-hexane (1:1). 15.82 g (96.4 mmol; 74percent yield) of a white solid was obtained. ¹H-NMR (DMSO-d₆, 400 MHz): δ=7.25 (d, 1H; J=2.0 Hz), 7.28 (dd, 1H; J=2.0 Hz, 8.5 Hz), 7.89 (d, 2H, J=8.0 Hz), 11.44 (br s, 1H). ¹³C-NMR (DMSO-d₆, 100 MHz): δ=111.0, 120.7, 123.0, 127.6, 133.9, 162.7, 163.2, 164.8.
74%	at 200℃; for 1 h;	2^nd Stage: 4-hydroxyphthalic anhydride 4-hydroxyphthalic acid (23.80 g, 0.131 mol) was heated for 1 h in an oil bath preheated to 200° C. After cooling the brownish solid was recrystallized from ethyl acetate/n-hexane (1:1). 15.82 g (96.4 mmol; 74percent yield) of a white solid was obtained. ¹H-NMR (DMSO-d₆, 400 MHz): δ=7.25 (d, 1H; J=2.0 Hz), 7.28 (dd, 1H; J=2.0 Hz, 8.5 Hz), 7.89 (d, 2H, J=8.0 Hz), 11.44 (br s, 1H). ¹³C-NMR (DMSO-d₆, 100 MHz): δ=111.0, 120.7, 123.0, 127.6, 133.9, 162.7, 163.2, 164.8.

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 20, p. 4427 - 4431
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 1, p. 342 - 353
[3] Patent: CN104910113, 2017, B, . Location in patent: Page/Page column 0041; 0044-0046
[4] European Journal of Medicinal Chemistry, 1987, vol. 22, p. 229 - 238
[5] Patent: US2013/102576, 2013, A1, . Location in patent: Paragraph 0607
[6] Patent: WO2013/57013, 2013, A2, . Location in patent: Page/Page column 193
[7] Patent: US2013/90404, 2013, A1, . Location in patent: Paragraph 0075; 0076; 0077; 0078
[8] Patent: US9393181, 2016, B2, . Location in patent: Page/Page column 9
[9] Monatshefte fuer Chemie, 1902, vol. 23, p. 401
[10] Journal of the Chemical Society, 1907, vol. 91, p. 103
[11] Chemische Berichte, 1877, vol. 10, p. 1079
[12] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1798 - 1806
[13] Journal of the Chemical Society. Perkin Transactions 2, 1998, # 5, p. 1249 - 1256
[14] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 1, p. 283 - 287
[15] Patent: EP1681283, 2006, A1, . Location in patent: Page/Page column 4-5
[16] Synthesis, 2008, # 21, p. 3415 - 3422
[17] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 14, p. 5323 - 5338
[18] RSC Advances, 2015, vol. 5, # 96, p. 79207 - 79215
[19] Marine Drugs, 2016, vol. 14, # 6,

5
[ 610-35-5 ]
[ 28281-76-7 ]

Reference： [1] Journal of the Chemical Society. Perkin Transactions 2, 1998, # 5, p. 1249 - 1256
[2] Chemische Berichte, 1988, vol. 121, p. 243 - 252
[3] Journal of the American Chemical Society, 2014, vol. 136, # 17, p. 6239 - 6242
[4] Chemistry - A European Journal, 2016, vol. 22, # 34, p. 11997 - 12001

6
[ 67-56-1 ]
[ 610-35-5 ]
[ 22479-95-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	at 80℃; for 4 h;	[00176] Preparation of dimethyl 4-hydroxyphthalate (‘1-2. To a solution of 4- hydroxyphthalic acid (20 g, 110 mmol) in CH3OH (100 mL) was added SOC12 (20 mL), The resulting solution was stirred at 80 °C for 4 hrs, The volatile was removed in vacuo to yield compound C1-2 as a white solid (23 g, yield: 99percent), which was used directly in the next step without further purification. ‘H NMR (CDCI3, 400 MHz) : 7.77(d, J = 8.8 Hz, lH), 7.03 (d, J 2 Hz, lH), 6.95 (dd, J 8.4 and 2.0 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H); MS (ESI): ,n/z 21 l(M÷l).
92%	at 0℃; for 20 h;	A solution of 4-hydroxyphthalic acid 1 (25.0 g, 137 mmol) in MeOH (700 mL) was charged with SOCl₂ (30.0 mL, 412 mmol) at 0° C. and stirred at room temperature for 20 h. The solvent was removed and the residue was partitioned between saturated aqueous NaHCO₃ solution (100 mL) and CH₂Cl₂ (250 mL). The CH₂Cl₂ layer was separated and the aqueous layer was extracted with CH₂Cl₂ (2*250 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated to afford compound 2 (26.5 g, 92percent) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J=8.5 Hz, 1H), 7.00 (d, J=2.6 Hz, 1H), 6.91 (dd, J=8.5, 2.6 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H).
90%	Heating / reflux	A solution of 5 g (27.6 mmol) of 4-aminophthalic acid in 50 ml of 1M sulphuric acid is cooled to 0° C. and a solution of 2.27 g of sodium nitrite in 6 ml of water is then slowly added. After 15 minutes at 0° C., 15 ml of concentrated sulphuric acid are added and the mixture is heated at 100° C., with vigorous stirring, for 1 hour. At room temperature, the reaction medium is extracted with ethyl acetate and washed with water. After decantation, the organic phase is dried over magnesium sulphate and concentrated. The residue is purified on a silica column (dichloromethane 80-methanol 20). It is then dissolved in 100 ml of methanol and refluxed with 2 ml of acetic acid. After the disappearance of the diacid, the methanol is evaporated and the product is taken up in ethyl acetate and washed with water. [00350] M=5.2 g. Y=90percent. ¹H NMR (DMSO): 3.64 (3H, s), 3.67 (3H, s), 6.79-6.86 (2H, m), 7.56-7.60 (1H, d, J=8.4 Hz), 10.51 (1H, OH, s).

87%	With hydrogenchloride In isopropyl alcohol at 0℃; for 24 h; Reflux	A solution of 4-hydroxyphthalic acid 16 (25.0 g, 137 mmol) in MeOH (500 mL) was charged with 6 N HCl in z^'-PrOH (46.0 mL, 274 mmol) at 0 °C and refluxed for 24 h. The solvent was removed and the residue was partitioned between saturated aqueous NaHCC solution (100 mL) and EtOAc (250 mL). The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (2 χ 250 mL). The combined organic extracts were washed with brine, dried over Na₂S0₄, and concentrated to afford compound 17 (25.0 g, 87percent) as a brown color solid: NMR (400 MHz, (Χ,) δ 7.72 id, ./ 8.5 Hz, 1 H), 7.00 (d, J = 2.6 Hz, H I ), 6.91 (dd, J = 8.5, 2.6 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H).
55%	at 10 - 70℃;	4-hydroxyphthalic acid (50g, 274.5mmol) was dissolved in methanol (800mL) and cooled to 10°C. Sulfuric acid (134g, 1.37mol) was slowly added dropwise with stirring. After the addition was complete the reaction temperature was raised to 70°C overnight. Cooling to room temperature, it was concentrated in vacuo. It was extracted with ethyl acetate (700mL) and washed with water (500mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the product (32g, 55percent yield).

Reference： [1] Patent: WO2014/18866, 2014, A1, . Location in patent: Paragraph 00175; 00176
[2] ChemMedChem, 2010, vol. 5, # 2, p. 213 - 231
[3] Chemistry of Materials, 2014, vol. 26, # 14, p. 4151 - 4162
[4] Patent: US2015/56305, 2015, A1, . Location in patent: Paragraph 0270; 0271; 0387; 0388
[5] Chemical Science, 2018, vol. 9, # 24, p. 5312 - 5321
[6] Patent: US6689922, 2004, B1, . Location in patent: Page column 20
[7] Patent: WO2016/176423, 2016, A1, . Location in patent: Page/Page column 74
[8] Toxicology Letters, 2000, vol. 118, # 1-2, p. 1 - 8
[9] Journal of Fluorine Chemistry, 2003, vol. 119, # 2, p. 141 - 149
[10] Patent: CN105524045, 2016, A, . Location in patent: Paragraph 0221; 0222; 0223
[11] Justus Liebigs Annalen der Chemie, 1886, vol. 233, p. 226[12] Journal of the Chemical Society, 1886, vol. 49, p. 518
[13] Monatshefte fuer Chemie, 1902, vol. 23, p. 401
[14] Journal of the Chemical Society, 1907, vol. 91, p. 103
[15] Journal of Organic Chemistry, 1983, vol. 48, # 18, p. 2981 - 2989
[16] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 22, p. 4125 - 4128
[17] Patent: WO2007/20046, 2007, A1, . Location in patent: Page/Page column 97-98
[18] Patent: US6706725, 2004, B1, . Location in patent: Page column 11
[19] Journal of the American Chemical Society, 2014, vol. 136, # 17, p. 6239 - 6242
[20] Chemistry - A European Journal, 2016, vol. 22, # 34, p. 11997 - 12001
[21] European Journal of Medicinal Chemistry, 2017, vol. 137, p. 76 - 87

7
[ 610-35-5 ]
[ 18107-18-1 ]
[ 22479-95-4 ]

Yield	Reaction Conditions	Operation in experiment
13%	at 20℃; for 15 h;	To a solution of 4-hydroxyphthalic acid (1.04 g, 5.71 mmol) in MeOH (11.4 mL) was slowly added TMSCHN₂(6.28 mL, 12.56 mmol). The reaction mixture was stirred at RT for 15 h, then was concentrated in vacuo. The residue was partitioned between EtOAc and H₂O. The organic phase was washed with brine, dried (MgSO₄), and concentrated in vacuo. The crude residue was chromatographed (SiO₂; continuous gradient from 0percent EtOAc/Hexane to 100percent EtOAc/Hexane) to provide Part A compound (150 mg, 13percent) as a solid.

Reference： [1] Patent: US2008/21052, 2008, A1, . Location in patent: Page/Page column 31

8
[ 610-35-5 ]
[ 22479-95-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride In methanol	Example 9 4-Hydroxyphthalic acid dimethyl ester Thionyl chloride (30 ml, 0.413 mmol) is added dropvise at -10° C. to a solution of 4-hydroxyphthalic acid (15 g, 82.4 mmol) in methanol (150 ml). The resulting mixture is heated at reflux temperature for 3 hours, cooled to room temperature and evaporated to dryness in vacuo to give 4-hydroxyphthalic acid dimethyl ester (yield: 17.1 g(99percent)) as white crystals. ¹H-NMR (CDCl₃) in ppm: δ 3.86 (3H,s), 3.92 (3H,s), 6.92 (1H,d,d.), 7.0 (1H,d), 7.76 (1H,d). In a similar way the following compounds were prepared: 3-Hydroxyphthalic acid dimethyl ester from 3-hydroxyphthalic acid. ¹H-NMR (CDCl₃) in ppm: δ 3.88 (3H,s); 3.92 (3H,s); 6.97 (1H,d.d.); 7.08 (1H,d.d.); 7.47 (1H,d.d.).

Reference： [1] Patent: US6590118, 2003, B1,

9
[ 610-35-5 ]
[ 22246-66-8 ]

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

[ 610-35-5 ] Synthesis Path-Downstream 1~88

1
[ 67-56-1 ]
[ 610-35-5 ]
[ 22479-95-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride; at 80℃; for 4h;	[00176] Preparation of dimethyl 4-hydroxyphthalate (?1-2. To a solution of 4- hydroxyphthalic acid (20 g, 110 mmol) in CH3OH (100 mL) was added SOC12 (20 mL), The resulting solution was stirred at 80 C for 4 hrs, The volatile was removed in vacuo to yield compound C1-2 as a white solid (23 g, yield: 99%), which was used directly in the next step without further purification. ?H NMR (CDCI3, 400 MHz) : 7.77(d, J = 8.8 Hz, lH), 7.03 (d, J 2 Hz, lH), 6.95 (dd, J 8.4 and 2.0 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H); MS (ESI): ,n/z 21 l(M÷l).
92%	With thionyl chloride; at 0℃; for 20h;	A solution of 4-hydroxyphthalic acid 1 (25.0 g, 137 mmol) in MeOH (700 mL) was charged with SOCl2 (30.0 mL, 412 mmol) at 0 C. and stirred at room temperature for 20 h. The solvent was removed and the residue was partitioned between saturated aqueous NaHCO3 solution (100 mL) and CH2Cl2 (250 mL). The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (2*250 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to afford compound 2 (26.5 g, 92%) as a colorless oil: 1H NMR (400 MHz, CDCl3) delta 7.72 (d, J=8.5 Hz, 1H), 7.00 (d, J=2.6 Hz, 1H), 6.91 (dd, J=8.5, 2.6 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H).
90%	With acetic acid;Heating / reflux;	A solution of 5 g (27.6 mmol) of 4-aminophthalic acid in 50 ml of 1M sulphuric acid is cooled to 0 C. and a solution of 2.27 g of sodium nitrite in 6 ml of water is then slowly added. After 15 minutes at 0 C., 15 ml of concentrated sulphuric acid are added and the mixture is heated at 100 C., with vigorous stirring, for 1 hour. At room temperature, the reaction medium is extracted with ethyl acetate and washed with water. After decantation, the organic phase is dried over magnesium sulphate and concentrated. The residue is purified on a silica column (dichloromethane 80-methanol 20). It is then dissolved in 100 ml of methanol and refluxed with 2 ml of acetic acid. After the disappearance of the diacid, the methanol is evaporated and the product is taken up in ethyl acetate and washed with water. [00350] M=5.2 g. Y=90%. 1H NMR (DMSO): 3.64 (3H, s), 3.67 (3H, s), 6.79-6.86 (2H, m), 7.56-7.60 (1H, d, J=8.4 Hz), 10.51 (1H, OH, s).

87%	With hydrogenchloride; In isopropyl alcohol; at 0℃; for 24h;Reflux;	A solution of 4-hydroxyphthalic acid 16 (25.0 g, 137 mmol) in MeOH (500 mL) was charged with 6 N HCl in z'-PrOH (46.0 mL, 274 mmol) at 0 C and refluxed for 24 h. The solvent was removed and the residue was partitioned between saturated aqueous NaHCC solution (100 mL) and EtOAc (250 mL). The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (2 chi 250 mL). The combined organic extracts were washed with brine, dried over Na2S04, and concentrated to afford compound 17 (25.0 g, 87%) as a brown color solid: NMR (400 MHz, (Chi,) delta 7.72 id, ./ 8.5 Hz, 1 H), 7.00 (d, J = 2.6 Hz, H I ), 6.91 (dd, J = 8.5, 2.6 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H).
55%	With sulfuric acid; at 10 - 70℃;	4-hydroxyphthalic acid (50g, 274.5mmol) was dissolved in methanol (800mL) and cooled to 10C. Sulfuric acid (134g, 1.37mol) was slowly added dropwise with stirring. After the addition was complete the reaction temperature was raised to 70C overnight. Cooling to room temperature, it was concentrated in vacuo. It was extracted with ethyl acetate (700mL) and washed with water (500mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the product (32g, 55% yield).
	With sulfuric acid; for 11h;Heating / reflux;	Example 115: 1-(4-lsopropyl-phenyl)-7-prop-2-ynyloxy-isoquinoline-3-carboxylic acid ethyl ester ; EPO <DP n="98"/>A) Preparation of 4-hydroxy-phthaiic acid dimethyl ester; A solution of 50 g (270 mmol) 4-hydroxy-phthalic acid and 7.4 ml concentrated sulfuric acid in 500 ml methanol is heated under reflux for 11 h. The methanol is evaporated and the residue dissolved in dichloromethane. Upon addition of hexane the dimethyl ester precipitates as white crystals. EPO <DP n="99"/>Retention time: 1.60 min, MS: 211 (M+1 )+
	With sulfuric acid;Heating / reflux;	A solution of 5 g (27.6 mmol) of 4-aminophthalic acid in 50 mL of sulphuric acid (1 M) is cooled to 0 C. A solution of 2.27 g of sodium nitrite in 6 mL of water is then added slowly. After 15 minutes at 0 C., 15 mL of concentrated sulphuric acid are added and the mixture is maintained at 100 C. with vigorous stirring for 1 hour. At room temperature, the reaction medium is extracted with ethyl acetate and washed with water. After separation of the phases by settling, the organic phase is dried over magnesium sulphate and concentrated. The residue is purified on a column of silica (80 dichloromethane/20 methanol). It is then dissolved in 100 mL of methanol and refluxed with 2 mL of sulphuric acid. After disappearance of the diacid, the methanol is evaporated off and the product is taken up in ethyl acetate and washed with water. The organic phase is separated out after settling, dried over sodium sulphate and evaporated. [00140] M=5.2 g. Y=90%. 1H NMR (DMSO): 3.64 (3H, s), 3.67 (3H, s), 6.79-6.86 (2H, m), 7.56-7.60 (1H, d, J=8.4 Hz), 10.51 (1H, OH, s).
	With sulfuric acid;Reflux;	General procedure: General procedure for the preparation of 3 or 4-alkoxyphthalic anhydride (7a-7d, 9a-9d) Following a reported procedure [34], we added H2SO4 (0.054 mL, 1.02 mmol) to a stirred solution of 3- or 4-hydroxyphthalic acid (1.09 g, 6.00 mmol) in 12 mL of MeOH and the reaction was stirred at reflux overnight. Solvent was removed under reduced pressure and the solid residue obtained was dissolved in dichloromethane (40 mL) and washed with water (20 x 3 mL). The combined organic layer was dried over anhydr MgSO4, filtered and concentrated under reduced pressure to provide crude dimethyl 4-hydroxyphthalate.
	With sulfuric acid;Reflux;	4-Hydroxyphthalic acid (1.09 g, 6.0 mmol) was dissolved in 12 ml of methanol. H2SO4 (0.054 ml, 1.02 mmol) was added thereto as a catalyst. The reaction mixture was stirred under reflux for overnight. The solvent was eliminated under reduced pressure, and the obtained solid was dissolved in dichloromethane, which was washed with water. 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 (1.20 g, 95%). 1H NMR (DMSO-d6, 500 MHz) delta 10.61 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 6.97 (dd, J=8.4, 2.5 Hz, 1H), 6.95 (d, J=2.3 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H). 13C NMR (DMSO-d6, 125 MHz) delta 168.3, 166.2, 160.8, 135.8, 131.7, 119.8, 117.1, 114.8, 52.5, 52.1.

Reference： [1]Patent: WO2014/18866,2014,A1 .Location in patent: Paragraph 00175; 00176
[2]ChemMedChem,2010,vol. 5,p. 213 - 231
[3]Chemistry of Materials,2014,vol. 26,p. 4151 - 4162
[4]Patent: US2015/56305,2015,A1 .Location in patent: Paragraph 0270; 0271; 0387; 0388
[5]Chemical Science,2018,vol. 9,p. 5312 - 5321
[6]Patent: US6689922,2004,B1 .Location in patent: Page column 20
[7]Patent: WO2016/176423,2016,A1 .Location in patent: Page/Page column 74
[8]Toxicology Letters,2000,vol. 118,p. 1 - 8
[9]Journal of Fluorine Chemistry,2003,vol. 119,p. 141 - 149
[10]Patent: CN105524045,2016,A .Location in patent: Paragraph 0221; 0222; 0223
[11]Justus Liebigs Annalen der Chemie,1886,vol. 233,p. 226
Journal of the Chemical Society,1886,vol. 49,p. 518
[12]Monatshefte fur Chemie,1902,vol. 23,p. 401
[13]Journal of Organic Chemistry,1983,vol. 48,p. 2981 - 2989
[14]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 4125 - 4128
[15]Patent: WO2007/20046,2007,A1 .Location in patent: Page/Page column 97-98
[16]Patent: US6706725,2004,B1 .Location in patent: Page column 11
[17]Journal of the American Chemical Society,2014,vol. 136,p. 6239 - 6242
[18]Chemistry - A European Journal,2016,vol. 22,p. 11997 - 12001
[19]European Journal of Medicinal Chemistry,2017,vol. 137,p. 76 - 87
[20]Patent: US2019/345126,2019,A1 .Location in patent: Paragraph 0192-0194; 0205-0207; 0219-0221; 0232-0235

2
[ 89-20-3 ]
[ 610-35-5 ]

Reference： [1]Doklady Akademii Nauk SSSR, <NS> 1933 118,
Chemisches Zentralblatt,1935,vol. 106,p. 1617

3
[ 610-35-5 ]
[ 55104-35-3 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1886,vol. 233,p. 226
Journal of the Chemical Society,1886,vol. 49,p. 518

4
[ 610-35-5 ]
[ 27550-59-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	at 210℃;Green chemistry;	(3) 12.3 g (67.5 mmol) of 4-hydroxyphthalic acid was placed in a sublimation tube and sublimed at 210 C to give 10.8 g of 4-hydroxyphthalic anhydride as a pale yellow solid in 97% yield.
74.9%	at 220℃; under 7.50075 Torr;	4-Hydroxyphthalic acid (1 g, 5.49 mmol) was sublimated at 220 C. under vacuum (about 10 mbar). The obtained white solid 5-hydroxyisobenzofuran-1,3-dione (675 mg, 4.11 mmol, 74.9% yield, MS/ESI+ 164.9 [MH]+) was collected, stored under vacuum and used as such in the next step.
74.9%	at 220℃; under 7.50075 Torr;	Example 45 (S)-3,5-Dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) phenyl)-2-(2-(1 ,3-dioxo-5-(pyridin-3-ylmethoxy)isoindolin-2-yl)acetoxy)ethyl) pyridine 1 -oxide 2,2,2-trifluoroacetic acid salt (Compound 248) Scheme 45 Step 1 : Preparation of 5-hydroxyisobenzofuran-1 ,3-dione (244): 4-Hydroxyphthalic acid (1 g, 5.49 mmol) was sublimated at 220C under vacuum (about 10 mbar). The obtained white solid 5-hydroxyisobenzofuran-1 ,3- dione (675 mg, 4.1 1 mmol, 74.9% yield, MS/ESI+ 164.9 [MH] +) was collected, stored under vacuum and used as such in the next step.

74%	at 200℃; for 1h;	2nd Stage: 4-hydroxyphthalic anhydride 4-hydroxyphthalic acid (23.80 g, 0.131 mol) was heated for 1 h in an oil bath preheated to 200 C. After cooling the brownish solid was recrystallized from ethyl acetate/n-hexane (1:1). 15.82 g (96.4 mmol; 74% yield) of a white solid was obtained. 1H-NMR (DMSO-d6, 400 MHz): delta=7.25 (d, 1H; J=2.0 Hz), 7.28 (dd, 1H; J=2.0 Hz, 8.5 Hz), 7.89 (d, 2H, J=8.0 Hz), 11.44 (br s, 1H). 13C-NMR (DMSO-d6, 100 MHz): delta=111.0, 120.7, 123.0, 127.6, 133.9, 162.7, 163.2, 164.8.
74%	at 200℃; for 1h;	2nd Stage: 4-hydroxyphthalic anhydride 4-hydroxyphthalic acid (23.80 g, 0.131 mol) was heated for 1 h in an oil bath preheated to 200 C. After cooling the brownish solid was recrystallized from ethyl acetate/n-hexane (1:1). 15.82 g (96.4 mmol; 74% yield) of a white solid was obtained. 1H-NMR (DMSO-d6, 400 MHz): delta=7.25 (d, 1H; J=2.0 Hz), 7.28 (dd, 1H; J=2.0 Hz, 8.5 Hz), 7.89 (d, 2H, J=8.0 Hz), 11.44 (br s, 1H). 13C-NMR (DMSO-d6, 100 MHz): delta=111.0, 120.7, 123.0, 127.6, 133.9, 162.7, 163.2, 164.8.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4427 - 4431
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 342 - 353
[3]Patent: CN104910113,2017,B .Location in patent: Page/Page column 0041; 0044-0046
[4]New Journal of Chemistry,2019,vol. 43,p. 9152 - 9161
[5]European Journal of Medicinal Chemistry,1987,vol. 22,p. 229 - 238
[6]Patent: US2013/102576,2013,A1 .Location in patent: Paragraph 0607
[7]Patent: WO2013/57013,2013,A2 .Location in patent: Page/Page column 193
[8]Patent: US2013/90404,2013,A1 .Location in patent: Paragraph 0075; 0076; 0077; 0078
[9]Patent: US9393181,2016,B2 .Location in patent: Page/Page column 9
[10]Monatshefte fur Chemie,1902,vol. 23,p. 401
[11]Journal of Medicinal Chemistry,1987,vol. 30,p. 1798 - 1806
[12]Journal of the Chemical Society. Perkin Transactions 2 (2001),1998,p. 1249 - 1256
[13]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 283 - 287
[14]Patent: EP1681283,2006,A1 .Location in patent: Page/Page column 4-5
[15]Synthesis,2008,p. 3415 - 3422
[16]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 5323 - 5338
[17]RSC Advances,2015,vol. 5,p. 79207 - 79215
[18]Marine Drugs,2016,vol. 14

5
[ 89-08-7 ]
[ 610-35-5 ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: 4-sulfophthalic acid With sodium hydroxide In water at 180 - 200℃; for 2h; Stage #2: With hydrogenchloride In water Cooling with ice;	1.1 4-hydroxyphthalic Acid 1st Stage: 4-hydroxyphthalic Acid Sodium hydroxide (251.9 g, 6.30 mol) was added in portions to 4-sulphophthalic acid (50% in water, 258.4 g, 0.525 mol) in a steel vessel accompanied by stirring. After the addition of approx. one third NaOH the increasingly more viscous mixture was heated to 180° C. Once the addition had ended the mixture was stirred for a further 2 h at 200° C. During cooling, the residue was dissolved in water (1000 ml). Conc. hydrochloric acid (620 ml, pH=1) was added accompanied by ice cooling. The solution was extracted with ethyl acetate (5*400 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated on the rotary evaporator. The slightly yellow solid was recrystallized from ethyl acetate. 68.64 g (0.377 mol; 72% yield) of a white solid was obtained. 1H-NMR (DMSO-d6, 400 MHz): δ=6.90-6.93 (m, 2H), 7.69 (dd, 1H; J=2.4 Hz, 6.6 Hz), 10.41 (br s, 1H), 12.87 (br s, 2H). 13C-NMR (DMSO-d6, 100 MHz): δ=114.2, 116.2, 120.7, 131.5, 137.3, 160.1, 167.4, 169.5.
72%	With water; sodium hydroxide at 180 - 200℃; for 2h;	1.1 1^stStage: 4-hydroxyphthalic Acid Sodium hydroxide (251.9 g, 6.30 mol) was added in portions to 4-sulphophthalic acid (50% in water, 258.4 g, 0.525 mol) in a steel vessel accompanied by stirring. After the addition of approx. one third NaOH the increasingly more viscous mixture was heated to 180° C. Once the addition had ended the mixture was stirred for a further 2 h at 200° C. During cooling, the residue was dissolved in water (1000 ml). Conc. hydrochloric acid (620 ml, pH=1) was added accompanied by ice cooling. The solution was extracted with ethyl acetate (5*400 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated on the rotary evaporator. The slightly yellow solid was recrystallized from ethyl acetate. 68.64 g (0.377 mol; 72% yield) of a white solid was obtained. 1H-NMR (DMSO-d6, 400 MHz): δ=6.90-6.93 (m, 2H), 7.69 (dd, 1H; J=2.4 Hz, 6.6 Hz), 10.41 (br s, 1H), 12.87 (br s, 2H). 13C-NMR (DMSO-d6, 100 MHz): δ=114.2, 116.2, 120.7, 131.5, 137.3, 160.1, 167.4, 169.5.
71.5%	Stage #1: 4-sulfophthalic acid With sodium hydroxide; water at 200 - 210℃; for 2.5h; Heating / reflux; Stage #2: With hydrogenchloride; water at 0 - 50℃;

23%	With sodium hydroxide In water at 180℃; for 1h;
	With sodium hydroxide at 175℃;

Reference： [1]Current Patent Assignee: IVOCLAR VIVADENT AKTIENGESELLSCHAFT - US2013/90404, 2013, A1 Location in patent: Paragraph 0071; 0072; 0073; 0074
[2]Current Patent Assignee: IVOCLAR VIVADENT AKTIENGESELLSCHAFT - US9393181, 2016, B2 Location in patent: Page/Page column 8-9
[3]Current Patent Assignee: MITSUI CHEMICALS,INC. - EP1681283, 2006, A1 Location in patent: Page/Page column 4
[4]Ortiz-Soto, Maria Elena; Ertl, Julia; Mut, Jürgen; Adelmann, Juliane; Le, Thien Anh; Shan, Junwen; Teßmar, Jörg; Schlosser, Andreas; Engels, Bernd; Seibel, Jürgen [Chemical Science, 2018, vol. 9, # 24, p. 5312 - 5321]
[5]Ree [Justus Liebigs Annalen der Chemie, 1886, vol. 233, p. 226][Journal of the Chemical Society, 1886, vol. 49, p. 518] Graebe [Chemische Berichte, 1885, vol. 18, p. 1127]

6
[ 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

7
[ 610-35-5 ]
[ 50727-06-5 ]

Yield	Reaction Conditions	Operation in experiment
72%	With ammonium carbonate; hydrogenchloride; sodium hydroxide In conc. AcOH	1 Step 1. Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120° C. for 45 min., then the clear, bright yellow mixture was heated at 160° C. for 2 h. The resulting mixture was maintained at 160° C. and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This mixture was cooled to 0° C. and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%): 1H NMR (DMSO-d6) δ7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H).
72%	With ammonium carbonate; hydrogenchloride; sodium hydroxide In conc. AcOH	3.1 Step 1. Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120° C. for 45 min., then the clear, bright yellow mixture was heated at 160° C. for 2 h. The resulting mixture was maintained at 160° C. and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This mixture was cooled to 0° C. and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%): 1H NMR (DMSO-d6) δ 7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H).
72%	With ammonium carbonate; hydrogenchloride; sodium hydroxide In conc. AcOH	1 Step 1. Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120° C. for 45 min., then the clear, bright yellow mixture was heated at 160° C. for 2 h. The resulting mixture was maintained at 160° C. and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This mixture was cooled to 0° C. and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%): 1H NMR (DMSO-d6) δ 7.00-7.03 (m, 2H), 7.56 (d, J=9.3Hz, 1H).

72%	With ammonium carbonate In hydrogenchloride; sodium hydroxide; conc. AcOH	1 Step 1. Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120° C. for 45 min., then the clear, bright yellow mixture was heated at 160° C. for 2 h. The resulting mixture was maintained at 160° C. and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a IN NaOH solution. This mixture was cooled to 0° C. and slowly acidified to pH 5 using a IN HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%): 1H NMR (DMSO-d6) δ7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H).
72%	With ammonium carbonate; acetic acid at 120 - 160℃; for 2.75h;	A.A3.1 Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120° C. for 45 min., then the clear, bright yellow mixture was heated at 160° C. for 2 h. The resulting mixture was maintained at 160° C. and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This mixture was cooled to 0° C. and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%): 1H NMR (DMSO-d6) δ 7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H).
71%	With ammonium carbonate; acetic acid at 120 - 160℃; for 2.75h;	1.e e) 5-Hydroxy-isoindole-1,3-dione; [0156] A mixture of 4-hydroxyphthalic acid (5.0 g, 27.0 mmol), acetic acid (25 mL), and ammonium carbonate (5.3 g, 55 mmol) was heated at 120[deg.] C. for 45 min followed by heating at 160[deg.] C. for 2 h. After cooling to room temperature, the reaction mixture was half-evaporated and then the reaction mixture was basified to pH 10 with 1 N NaOH followed by acidification to pH 5 at 0[deg.] C. with concentrated HCl. The resulting precipitate was filtered off, washed with water, dried at 60[deg.] C. under high vacuum over night, to afford the title compound (3.2 g, 71%) as an off-white crystalline solid. MS: m/e=162.1 (M-H).
59%	With ammonium hydroxide at 190℃; for 4h;
59%	With ammonium hydroxide at 190℃; for 4h;
	Multi-step reaction with 2 steps 1: 200 °C / 0.6 Torr 2: 86 percent / NH₃ / toluene / Heating

Reference： [1]Current Patent Assignee: BAYER AG - US2003/144278, 2003, A1
[2]Current Patent Assignee: BAYER AG - US2003/181442, 2003, A1
[3]Current Patent Assignee: BAYER AG - US2001/11135, 2001, A1
[4]Current Patent Assignee: BAYER AG - US2002/165394, 2002, A1
[5]Current Patent Assignee: BAYER AG - US2003/207872, 2003, A1 Location in patent: Page/Page column 9
[6]Current Patent Assignee: ROCHE HOLDING AG - US2003/195208, 2003, A1 Location in patent: Page/Page column 9
[7]Kato; Ebiike; Achiwa; Ashizawa; Kurihara; Kobayashi [Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 7, p. 2060 - 2062]
[8]Kato, Yoshiaki; Takemoto, Masumi; Achiwa, Kazuo [Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 4, p. 529 - 535]
[9]Wyrick; Smith; Kemp; Grippo [Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1798 - 1806]

8
[ 610-35-5 ]
[ 109803-51-2 ]

Yield	Reaction Conditions	Operation in experiment
74%	With chlorine; acetic acid Ambient temperature;

Reference： [1]Wyrick; Smith; Kemp; Grippo [Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1798 - 1806]

9
[ 610-35-5 ]
[ 77-78-1 ]
[ 1885-13-8 ]

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

10
[ 610-35-5 ]
[ 108-24-7 ]
[ 27550-63-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	for 14h; Heating / reflux;	Acetic acid 1,3-dioxo-1,3-dihydro-isobenzofuran-5-ylA suspension of 4-hydroxyphthalic acid (158.40 g, 0.8703 mol) and acetic anhydride (725 mL) was heated at reflux for 14 hr (dissolution of the suspension occurred as refluxing began). The reaction mixture was cooled to room temperature and most of the volatile components removed in vacuo. Residual acetic acid and acetic anhydride were coevaporated with toluene (2 x 500 mL). The resulting solid was triturated with heptane, collected, washed with heptane and dried in a vacuum oven at -30 0C for 2.5 hr to give 171.09 g (95%) of Acetic acid 1 ,3-dioxo-1 ,3-dihydro-isobenzofuran-5-yl as a tan solid.
43%	In toluene for 2h; Reflux;
42.5%	In toluene for 2h; Reflux;	4-Acetyloxyphthalic anhydride (2.5) To a solution of 4-hydroxyphthalic acid 2 (5.39 g) in toluene (100 ml) acetic anhydride (25 ml) was added and mixture was refluxed for 2 h. Next day the crystallized product was filtered off. Yield 2.6 g (42.5%).

2.6 g	In toluene for 2h; Reflux;	4-Acetyloxyphthalic anhydride (2.5) This compound was prepared from 4-hydroxy-phthalic acid 2.0 by dehydratation with an excess acetic anhydride in according with procedure published in literature (Synthesis 2008, p.3415) . 2.5 To a solution of 4-hydroxyphthalic acid 2 (5.39 g) in toluene (100 ml) acetic anhydride (25 ml) was added and mixture was refluxed for 2 h. Next day the crystallized product was filtered off. Yield 2.6 g (42.5 %) .
	Reflux; Inert atmosphere;	25.1 Step 1: Synthesis of 1,3-dioxo-1,3-dihydroisobenzofuran-5-yl acetate 4-hydroxyphthalic acid (5 g, 27.5 mmol, 1.0 eq)Mix with acetic anhydride (23 mL) and reflux under nitrogen overnight.The acetic anhydride was concentrated under reduced pressure to give a solid, which was washed with PE.The product was obtained as a light brown solid (4.8 g, yield: 84.8%).It was used in the next reaction without purification

Reference： [1]Current Patent Assignee: PFIZER INC - WO2008/20306, 2008, A2 Location in patent: Page/Page column 22
[2]Location in patent: experimental part Luo, Weiming; Yu, Qian-Sheng; Tweedie, David; Deschamps, Jeffery; Parrish, Damon; Holloway, Harold W.; Li, Yazhou; Brossi, Arnold; Greig, Nigel H. [Synthesis, 2008, # 21, p. 3415 - 3422]
[3]Current Patent Assignee: ILLUMINA INC - US8754244, 2014, B1 Location in patent: Page/Page column 28; 29
[4]Shah, Jamshed H.; Swartz, Glenn M.; Papathanassiu, Adonia E.; Treston, Anthony M.; Fogler, William E.; Madsen, John W.; Green, Shawn J. [Journal of Medicinal Chemistry, 1999, vol. 42, # 16, p. 3014 - 3017]
[5]Current Patent Assignee: ILLUMINA INC - WO2014/135223, 2014, A1 Location in patent: Page/Page column 55-56
[6]Current Patent Assignee: NANJING TRANSTHERA BIOSCIENCES - CN109810041, 2019, A Location in patent: Paragraph 0560; 0564-0566

11
[ 89-20-3 ]
potassium hydroxide [ No CAS ]
[ 610-35-5 ]

Reference： [1]Chemische Berichte,1885,vol. 18,p. 1759

12
[ 71-23-8 ]
[ 610-35-5 ]
Di-n-propyl 4-hydroxyphthalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With sulfuric acid Heating;

Reference： [1]Asai, Daisuke; Tahara, Yoshiko; Nakai, Makoto; Yakabe, Yoshikuni; Takatsuki, Mineo; Nose, Takeru; Shinmyozu, Teruo; Shimohigashi, Yasuyuki [Toxicology Letters, 2000, vol. 118, # 1-2, p. 1 - 8]

13
[ 64-17-5 ]
[ 610-35-5 ]
[ 64139-21-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sulfuric acid Heating;
99%	With sulfuric acid at 20℃; for 24.5h; Reflux;	Diethyl 4-hydroxyphthalate (2.1) To a 0.5 L round bottomed flask containing absolute ethanol (250 ml, 200 g, 4.3 mol) 4-hydroxyphthalic acid 2.0 (15 g, 82.4 mmol) was added in a few portions at room temperature with stirring. This was then followed by an addition of 0.5 ml (0.92 g, 9.4 mmol) of concentrated sulphuric acid. This mixture was stirred at room temperature for half an hour, and then it was further refluxed for 24 hours with a condenser. (0135) About a half of solvent volume was distilled off using a descended condenser and the remaining solvent was removed under a reduced pressure. The viscous oily residue was dissolved in 400 ml DCM. To this solution, 1.5 g anhydrous potassium carbonate was added carefully in small portions. This mixture was kept at room temperature with stirring for about 2 hours, than filtered through 100 g of silica gels. The silica gels were further washed with DCM to elute more absorbed products. The combined organic fractions were dried with anhydrous magnesium sulphate (5 g) overnight. Solids were filtered off, and further washed with DCM. Solvent was evaporated under a reduced pressure. (0136) This ester 2.1 obtained as colourless oily product was used in the next step without further purification. (0137) Yield: 22 g (99%) (0138) 1H NMR: (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.07-6.76 (m, 2H), 4.22 (dq, J=13.4, 7.1 Hz, 4H), 1.25 (td, J=7.1, 3.3 Hz, 6H).
90%	With sulfuric acid Heating;

With sulfuric acid for 24h; Reflux;

Diethyl 4-hydroxyphthalate (2.1) This compound was prepared from 4-hydroxy-phthalic acid2.0 by an esterification with an excess of ethanol(absolute) in the presence of concentrated sulphuric acid . 20 2.1 Preparation :To a 0.5 L round bottomed flask containing absolute ethanol (250 ml, ~ 200 g, ~ 4.3 mol) 4-hydroxyphthalic acid 2.0 (15 g, 82.4 mmol) was added in a few portions at room temperature with stirring. This was then followed by an addition of 0.5 ml (~ 0.92 g, 9.4 mmol) of concentrated sulphuric acid. This mixture was stirred at room temperature for half an hour, and then it was further refluxed for 24 hours with a condenser. About a half of solvent volume was distilled off using a descended condenser and the remaining solvent was removed under a reduced pressure. The viscous oily residue was dissolved in 400 ml DCM. To this solution, 1.5 g anhydrous potassium carbonate was added carefully in small portions. This mixture was kept at room temperature with stirring for about 2 hours, than filtered through ~ 100 g of silica gels. The silica gels were further washed with DCM to elute more absorbed products . The combined organic fractions were dried with anhydrous magnesium sulphate (~ 5 g) overnight. Solids were filtered off, and further washed with DCM. Solvent was evaporated under a reduced pressure. This ester 2.1 obtained as colourless oily product was used in the next step without further purification. Yield: 22 g (~ 99 %) 1H NMR: (400 MHz , DMSO-d6) δ 10.59 (s, 1H) , 7.68 (d, J = 8.5 Hz, 1H) , 7.07 - 6.76 (m, 2H) , 4.22 (dq, J = 13.4, 7.1 Hz, 4H) , 1.25 (td, J = 7.1, 3.3 Hz, 6H).

Reference： [1]Lin, Wenwei; Baron, Oliver; Knochel, Paul [Organic Letters, 2006, vol. 8, # 24, p. 5673 - 5676]
[2]Current Patent Assignee: ILLUMINA INC - US8754244, 2014, B1 Location in patent: Page/Page column 25; 26
[3]Asai, Daisuke; Tahara, Yoshiko; Nakai, Makoto; Yakabe, Yoshikuni; Takatsuki, Mineo; Nose, Takeru; Shinmyozu, Teruo; Shimohigashi, Yasuyuki [Toxicology Letters, 2000, vol. 118, # 1-2, p. 1 - 8]
[4]Current Patent Assignee: ILLUMINA INC - WO2014/135223, 2014, A1 Location in patent: Page/Page column 52-53

14
[ 610-35-5 ]
[ 108-93-0 ]
dicyclohexyl 4-hydroxyphthalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With sulfuric acid Heating;

15
[ 610-35-5 ]
[ 71-36-3 ]
Di-n-butyl 4-hydroxyphthalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With sulfuric acid Heating;

16
[ 610-35-5 ]
[ 100-44-7 ]
[ 5840-66-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium hydroxide at 120℃; for 12h;

Reference： [1]Nakamura, Takanori; Noguchi, Tomomi; Kobayashi, Hisayoshi; Miyachi, Hiroyuki; Hashimoto, Yuichi [Chemical and Pharmaceutical Bulletin, 2006, vol. 54, # 12, p. 1709 - 1714]

17
[ 610-35-5 ]
[ 18107-18-1 ]
[ 22479-95-4 ]

Yield	Reaction Conditions	Operation in experiment
13%	In methanol; at 20℃; for 15h;	To a solution of 4-hydroxyphthalic acid (1.04 g, 5.71 mmol) in MeOH (11.4 mL) was slowly added TMSCHN2 (6.28 mL, 12.56 mmol). The reaction mixture was stirred at RT for 15 h, then was concentrated in vacuo. The residue was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried (MgSO4), and concentrated in vacuo. The crude residue was chromatographed (SiO2; continuous gradient from 0% EtOAc/Hexane to 100% EtOAc/Hexane) to provide Part A compound (150 mg, 13%) as a solid.

Reference： [1]Patent: US2008/21052,2008,A1 .Location in patent: Page/Page column 31

18
[ 610-35-5 ]
[ 107-30-2 ]
[ 933485-58-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate In acetone at 20℃; for 2h;