[ CAS No. 95233-18-4 ] {[proInfo.proName]}

Name: 95233-18-4|2-(trans-4-(4-Chlorophenyl)cyclohexyl)-3-hydroxynaphthalene-1,4-dione|99%
Brand: Ambeed
SKU: A242112
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Quality Control of [ 95233-18-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 95233-18-4 ]

Product Details of [ 95233-18-4 ]

CAS No. :	95233-18-4	MDL No. :	MFCD00889188
Formula :	C₂₂H₁₉ClO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BSJMWHQBCZFXBR-UHFFFAOYSA-N
M.W :	366.84	Pubchem ID :	74989
Synonyms :	Atavaquone;BW 566C;Wellvone;Mepron;hydroxynaphthoquinone 566C80;GlaxoSmithKline brand of atovaquone;Glaxo Wellcome brand of atovaquone;compound 566;atovaquone GlaxoSmithKline brand;566C80 hydroxynaphthoquinone;566C80;566C;BW 556C-80

Calculated chemistry of [ 95233-18-4 ]

Physicochemical Properties

Num. heavy atoms :	26
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.27
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	102.04
TPSA :	54.37 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-4.5 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.54
Log Po/w (XLOGP3) :	5.68
Log Po/w (WLOGP) :	5.51
Log Po/w (MLOGP) :	3.28
Log Po/w (SILICOS-IT) :	5.19
Consensus Log Po/w :	4.64

Druglikeness

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

Water Solubility

Log S (ESOL) :	-5.9
Solubility :	0.000459 mg/ml ; 0.00000125 mol/l
Class :	Moderately soluble
Log S (Ali) :	-6.59
Solubility :	0.0000949 mg/ml ; 0.000000259 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-6.97
Solubility :	0.0000397 mg/ml ; 0.000000108 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	1.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	3.97

Safety of [ 95233-18-4 ]

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

Application In Synthesis of [ 95233-18-4 ]

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

Upstream synthesis route of [ 95233-18-4 ]
Downstream synthetic route of [ 95233-18-4 ]

[ 95233-18-4 ] Synthesis Path-Upstream 1~12

1
[ 137732-39-9 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	at 15 - 16℃; for 0.333333 h;	Cis-2-[4-(4-chlorophenyl)cyclohexyl]-3 -hydroxy- 1,4-naphthoquinone (1 g, 2.7 mmol) was stirred in 8 ml concentrated H₂SO₄ at 15-16°C for 20 minutes. The reaction mixture was slowly poured into 30 g ice and further stirred for 20 minutes. The obtained solid was filtered and washed with water until the pH of the filtrate becomes in the range of 4 to 5. The resulting solid is dried at 50-55°C for 6 hours to yield 0.85 g of trans-2-[4-(4- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone (85percent yield, 95.5 percent purity).

Reference： [1] Patent: WO2010/1378, 2010, A1, . Location in patent: Page/Page column 11
[2] Patent: WO2012/153162, 2012, A1, . Location in patent: Page/Page column 32-33

2
[ 1409957-21-6 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
74%	at 20℃; for 5 h; Green chemistry	To 1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione (13.5g, 1.6 mmol) taken in a reactor was added cone. H₂SO₄ (135 mL) and stirred for 5 h at RT. Water (2 L) was added to the reaction mass and extracted with DCM (3*200 mL). Solvent was evaporated under reduced pressure to give crude product which was further re-crystallized from acetonitrile to obtain pure compound as a yellow solid (10 g, 74percent yield). FTIR (KBr): 3375, 2958, 2924, 2853, 1659, 1646, 1625, 1594, 1490, 1369, 1344, 1277, 1248, 1216, 1089, 998, 822, 727, 656, 530 cm^-1. ¹Ή NMR (CDCl3, 400 MHz): δ 1.58 (q, 2H), 1.75 (d, 2H), 1.96 (d, 2H), 2.16-2.20 (m, 2H), 2.63 (t, 1H), 3.16 (t, 1H), 7.18 (d, 2H), 7.28 (d, 2H), 7.48 (s, 1H), 7.68 (t, 1H), 7.76 (t,lH), 8.07 (d, 1H), 8.13 (d, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ 29.18, 34.34, 34.46, 34.64, 43.22, 126, 127, 127.25, 128.43, 129.19, 129.31, 131.45, 132.86, 133.12, 135.02, 146.05, 152.98, 181.80, 184.56; MS (EI): C₂₂H₁₉C10₃: 366.1023; [M+Na]⁺: 388.95, [M-H]^': 365.30; DSC peak at 220.44 °C (10°C/min) DSC: peak at 221.2 °C PXRD [20] (Cu K„i = 1.54060 A, K_a2 = 1.54443 A, K_p = 1.39225 A; 40 mA, 45 kV): 7.30, 9.70, 10.79, 1 1.1 1, 1 1.83, 15.43, 16.16, 16.89, 17.39, 22.93, 24.62, 24.68, 25.35, 26.18, 26.84, 28.52, 28.70, 29.52, 30.68, 34.23, 36.84.

Reference： [1] Patent: WO2013/14486, 2013, A1, . Location in patent: Page/Page column 27; 28

3
[ 94015-53-9 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	at 5℃; for 0.75 h; Resolution of racemate	Example 5 Preparation of the Atovaquone by Epimerization of the Cis/Trans Atovaquone with Concentrated Sulfuric Acid at +5° C.8 g (21.8 mmoles) of CIS/TRANS atovaquone in a ratio of 58/42 are added portionwise in 15 minutes to 80 ml of sulfuric acid 96percent at +5° C. At the end of the addition it is left under agitation at 5° C. for 30 minutes and the temperature is then brought to 20-25° C. The reaction mixture is poured slowly onto 230 ml of water pre-cooled to 5° C. without exceeding the internal temperature of 25° C. 340 ml of methyl ethyl ketone are added and the mixture is heated to 70° C. The acid aqueous phase is separated and the organic phase is washed with a solution of 8 g of sodium chloride in 80 ml of water, maintaining the temperature at 60° C. The organic phase is concentrated to approximately 1/6 of the initial volume by distillation of the solvent at atmospheric pressure. It is gradually cooled to 0-5° C. and maintained cold for 1 hour. The solid is filtered and washed with 10 ml of water. The damp product is dried at 45° C. at reduced pressure for 6-8 hours, providing 6.5 g of atovaquone (yield 81percent) with HPLC purity >99percent (CIS isomer=0.45percent).

Reference： [1] Patent: US2010/137644, 2010, A1, . Location in patent: Page/Page column 3-4
[2] Patent: WO2010/1378, 2010, A1, . Location in patent: Page/Page column 11
[3] Patent: US2010/152302, 2010, A1, . Location in patent: Page/Page column 5-6
[4] Patent: WO2012/153162, 2012, A1,
[5] Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625
[6] Journal of the American Chemical Society, 2017, vol. 139, # 35, p. 12251 - 12258

4
[ 129719-64-8 ]
[ 95233-18-4 ]

Reference： [1] Tetrahedron Letters, 1998, vol. 39, # 42, p. 7629 - 7632

5
[ 94015-53-9 ]
[ 137732-39-9 ]
[ 95233-18-4 ]

Reference： [1] Patent: WO2012/153162, 2012, A1, . Location in patent: Page/Page column 33

6
[ 83-72-7 ]
[ 137732-39-9 ]
[ 95233-18-4 ]

Reference： [1] Journal of the American Chemical Society, 2017, vol. 139, # 35, p. 12251 - 12258

7
[ 95233-37-7 ]
[ 95233-18-4 ]

Reference： [1] Tetrahedron Letters, 1998, vol. 39, # 42, p. 7629 - 7632

8
[ 95233-37-7 ]
[ 95233-18-4 ]

Reference： [1] Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625
[2] Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625
[3] Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625

9
[ 130-15-4 ]
[ 95233-18-4 ]

Reference： [1] Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625
[2] Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625

10
[ 1100053-58-4 ]
[ 95233-18-4 ]

Reference： [1] Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625
[2] Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625

11
[ 1010-60-2 ]
[ 95233-18-4 ]

Reference： [1] Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625

12
[ 1100053-59-5 ]
[ 95233-18-4 ]

Reference： [1] Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625

[ 95233-18-4 ] Synthesis Path-Downstream 1~50

1
[ 129719-64-8 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium hydroxide In methanol Heating;

Reference： [1]Williams, David R.; Clark, Michael P. [Tetrahedron Letters, 1998, vol. 39, # 42, p. 7629 - 7632]

2
[ 1010-60-2 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 14 percent / (NH₄)2S₂O₈ / CH₂Cl₂; acetonitrile; H₂O / Heating 2: 94 percent / KOH / methanol / Heating

Reference： [1]Williams, David R.; Clark, Michael P. [Tetrahedron Letters, 1998, vol. 39, # 42, p. 7629 - 7632]

3
[ 95233-37-7 ]
[ 95233-18-4 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 7629 - 7632

4
[ 814-49-3 ]
[ 95233-18-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium carbonate In butanone; Petroleum ether	1 3-[ trans -4-(4-Chlorophenyl)cyclohexyl]-1,4-dioxo-2-naphthyldiethylphosphate Example 1 3-[ trans -4-(4-Chlorophenyl)cyclohexyl]-1,4-dioxo-2-naphthyldiethylphosphate 2-[ trans -4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone (4.2g), diethylchlorophosphate (4.2g) and sodium carbonate (1.6g) were mixed in 40ml of methylethylketone and refluxed for 1.5 hours. The yellow mixture was diluted with methylethylketone, washed with 80ml of 20% conc. hydrochloric acid and then with water. The methylethylketone solution (yellow) was dried (MgSO4) and the solvent removed to give a yellow solid which was washed with ca.250ml 60-80°C petroleum ether (boiling) to give the title compound (3.52g). m.p. 163-164°C. 1H nmr (CDCl3) δ 1.42 (6H, t of d, 2 x CH3), 1.5-2.3 (8H, m, 4 x CH2), 2.68 (1H, t of t, C H (CH2)2), 3.18 (1H, t of t C H (CH2)2), 4.40 (4H, m, 2 x CH 2CH3), 7.20 (4H, m, aromatic), 7.71 (2H, m, aromatic), 8.08 (2H, m, aromatic).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - EP537947, 1993, A1

5
[ 94015-53-9 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sulfuric acid at 5℃; for 0.75h; Resolution of racemate;	5 Example 5 Preparation of the Atovaquone by Epimerization of the Cis/Trans Atovaquone with Concentrated Sulfuric Acid at +5° C.8 g (21.8 mmoles) of CIS/TRANS atovaquone in a ratio of 58/42 are added portionwise in 15 minutes to 80 ml of sulfuric acid 96% at +5° C. At the end of the addition it is left under agitation at 5° C. for 30 minutes and the temperature is then brought to 20-25° C. The reaction mixture is poured slowly onto 230 ml of water pre-cooled to 5° C. without exceeding the internal temperature of 25° C. 340 ml of methyl ethyl ketone are added and the mixture is heated to 70° C. The acid aqueous phase is separated and the organic phase is washed with a solution of 8 g of sodium chloride in 80 ml of water, maintaining the temperature at 60° C. The organic phase is concentrated to approximately 1/6 of the initial volume by distillation of the solvent at atmospheric pressure. It is gradually cooled to 0-5° C. and maintained cold for 1 hour. The solid is filtered and washed with 10 ml of water. The damp product is dried at 45° C. at reduced pressure for 6-8 hours, providing 6.5 g of atovaquone (yield 81%) with HPLC purity >99% (CIS isomer=0.45%).
	With sulfuric acid at 15 - 16℃;	3 The procedure of example 1 was repeated for a mixture of cis and trans-2-[4-(4- chlorophenyl)cyclohexyl]-3 -hydroxy- 1,4-naphthoquinone (48:41.5 ratio cis/trans) to obtain 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone (95% yield, 4:85.5 ratio cis/trans)
	Stage #1: atovaquone With potassium hydroxide In methanol; water for 2.5h; Reflux; Stage #2: With hydrogenchloride In methanol; water at 0℃; Reflux;	5 Example 5 2-[4-(4-Chlorophenyl)cyclohexy-3-chloro-1,4-naphthoquinone (20 gm) is added to methanol (400 ml) at 25-30° C., the contents are heated to reflux and then potassium hydroxide solution (20 gm) in water (200 ml) is slowly added for 30 minutes at reflux. The reaction mass is stirred for 2 hours at reflux, to the resulting mass added hydrochloric acid (72 ml) slowly for 15 to 20 minutes at reflux and then cooled to 25-30° C. The resulting mass is further cooled to 0° C. and then stirred for 1 hour at 0-5° C. The solid is filtered, washed with water and the material then dried at 50-60° C. to give 18.2 gm of crude atovaquone [HPLC purity: 98%; Content of cis impurity: 0.04% (at 0.61 RRT)]. The crude atovaquone is further recrystallized from acetonitrile as per the process described in example 1 to give 16.5 gm of pure atovaquone (HPLC purity: 99.92%; Content of cis impurity: Not detected).

	Multi-step reaction with 2 steps 1: sulfuric acid / 2 h / 20 °C / Resolution of racemate 2: titanium tetrachloride / dichloromethane / 24 h / 40 °C
64.5 g	With sulfuric acid at 28 - 30℃;
	With sulfuric acid at 20℃;

Reference： [1]Current Patent Assignee: P&R SPA - US2010/137644, 2010, A1 Location in patent: Page/Page column 3-4
[2]Current Patent Assignee: SK CAPITAL PARTNERS LP - WO2010/1378, 2010, A1 Location in patent: Page/Page column 11
[3]Current Patent Assignee: HETERO DRUGS LIMITED - US2010/152302, 2010, A1 Location in patent: Page/Page column 5-6
[4]Current Patent Assignee: LUPIN LIMITED - WO2012/153162, 2012, A1
[5]Dike, Suneel Y.; Singh, Dharmendra; Thankachen, Byju N.; Sharma, Brajesh; Mathur, Pramil K.; Kore, Swapnil; Kumar, Ashok [Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625]
[6]Gutiérrez-Bonet, Álvaro; Remeur, Camille; Matsui, Jennifer K.; Molander, Gary A. [Journal of the American Chemical Society, 2017, vol. 139, # 35, p. 12251 - 12258]

6
[ 137732-39-9 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sulfuric acid at 15 - 16℃; for 0.333333h;	1 Cis-2-[4-(4-chlorophenyl)cyclohexyl]-3 -hydroxy- 1,4-naphthoquinone (1 g, 2.7 mmol) was stirred in 8 ml concentrated H2SO4 at 15-16°C for 20 minutes. The reaction mixture was slowly poured into 30 g ice and further stirred for 20 minutes. The obtained solid was filtered and washed with water until the pH of the filtrate becomes in the range of 4 to 5. The resulting solid is dried at 50-55°C for 6 hours to yield 0.85 g of trans-2-[4-(4- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone (85% yield, 95.5 % purity).
	With titanium tetrachloride In dichloromethane at 40℃; for 24h;	12 Cis isomer of Atovaquone (0.5 g) was dissolved in dichloromethane (20 mL) and T1CI4 (0.5 mL)was added to it at RT. Resulting reaction mixture was heated to 40 °C and stirred for 24 h. Reaction was monitored for conversion of cis isomer of Atovaquone to trans isomer at different intervals. After 24 h, HPLC analysis showed the cis to trans ratio as 50:50.HPLC Retention time for cis isomer: 19.33 minHPLC Retention time for trans isomer: 22.66 min

Reference： [1]Current Patent Assignee: SK CAPITAL PARTNERS LP - WO2010/1378, 2010, A1 Location in patent: Page/Page column 11
[2]Current Patent Assignee: LUPIN LIMITED - WO2012/153162, 2012, A1 Location in patent: Page/Page column 32-33

7
[ CAS Unavailable ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
76%	With sulfuric acid at 15℃; for 0.75h;	4 Example 4 Preparation of the Atovaquone by Epimerization and Deprotection of the CIS/TRANS Acetyl-Atovaquone with Concentrated Sulfuric Acid at +15° C.8 g (19.6 mmoles) of CIS/TRANS acetyl-atovaquone are added portionwise in 15 minutes to 80 ml of sulfuric acid 96% at +15° C. At the end of the addition it is left under agitation at 15° C. for 30 minutes and the temperature is then brought to 20-25° C. The reaction mixture is poured slowly onto 230 ml of water pre-cooled to 5° C. without exceeding the internal temperature of 25° C. 160 ml of toluene are added and the mixture is heated to 70° C. The acid aqueous phase is separated and the organic phase is washed with a solution of 8 g of sodium chloride in 40 ml of water, maintaining the temperature at 60° C. The organic phase is concentrated to approximately 1/3 of the initial volume by distillation of the solvent at atmospheric pressure. It is gradually cooled to 0-5° C. and maintained cool for 1 hour. The solid is filtered and washed with 10 ml of cold toluene. The damp product is dried at 45° C. at reduced pressure for 6-8 hours, providing 6.08 g of atovaquone (yield 76%) with HPLC purity >99%.

Reference： [1]Current Patent Assignee: P&R SPA - US2010/137644, 2010, A1 Location in patent: Page/Page column 3

8
[ 94015-53-9 ]
[ 137732-39-9 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid at 20℃; for 2h; Resolution of racemate;	13 Cis/trans Atovaquone (0.5 g) was added in sulphuric acid (10 mL) at RT and stirred for 2 h, after which the reaction mixture was poured in ice water and product was extracted with dichloromethane, which was analyzed on HPLC as per resolution method given in US pharmacopoeia.HPLC Retention time for cis isomer: 19.33 minHPLC Retention time for trans isomer: 22.66 min

Reference： [1]Current Patent Assignee: LUPIN LIMITED - WO2012/153162, 2012, A1 Location in patent: Page/Page column 33

9
[ 1409957-21-6 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
74%	With sulfuric acid at 20℃; for 5h; Green chemistry;	19 Example 19: Synthesis of Atovaquone [I] To 1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione (13.5g, 1.6 mmol) taken in a reactor was added cone. H2SO4 (135 mL) and stirred for 5 h at RT. Water (2 L) was added to the reaction mass and extracted with DCM (3*200 mL). Solvent was evaporated under reduced pressure to give crude product which was further re-crystallized from acetonitrile to obtain pure compound as a yellow solid (10 g, 74% yield). FTIR (KBr): 3375, 2958, 2924, 2853, 1659, 1646, 1625, 1594, 1490, 1369, 1344, 1277, 1248, 1216, 1089, 998, 822, 727, 656, 530 cm-1. 1Ή NMR (CDCl3, 400 MHz): δ 1.58 (q, 2H), 1.75 (d, 2H), 1.96 (d, 2H), 2.16-2.20 (m, 2H), 2.63 (t, 1H), 3.16 (t, 1H), 7.18 (d, 2H), 7.28 (d, 2H), 7.48 (s, 1H), 7.68 (t, 1H), 7.76 (t,lH), 8.07 (d, 1H), 8.13 (d, 1H); 13C NMR (CDCl3, 100 MHz): δ 29.18, 34.34, 34.46, 34.64, 43.22, 126, 127, 127.25, 128.43, 129.19, 129.31, 131.45, 132.86, 133.12, 135.02, 146.05, 152.98, 181.80, 184.56; MS (EI): C22H19C103: 366.1023; [M+Na]+: 388.95, [M-H]': 365.30; DSC peak at 220.44 °C (10°C/min) DSC: peak at 221.2 °C PXRD [20] (Cu K„i = 1.54060 A, Ka2 = 1.54443 A, Kp = 1.39225 A; 40 mA, 45 kV): 7.30, 9.70, 10.79, 1 1.1 1, 1 1.83, 15.43, 16.16, 16.89, 17.39, 22.93, 24.62, 24.68, 25.35, 26.18, 26.84, 28.52, 28.70, 29.52, 30.68, 34.23, 36.84.

Reference： [1]Current Patent Assignee: LUPIN LIMITED - WO2013/14486, 2013, A1 Location in patent: Page/Page column 27; 28

10
[ 80841-78-7 ]
[ 95233-18-4 ]
[ 1445850-06-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In acetonitrile; at 60 - 65℃;	Charged Atovaquone (1 equivalent, obtained by the process described in example 1 of the U.S. Patent No. 4,981,874), Acetonitrile (20V), K2C03 (2.5 equivalent) to the reactor fitted with a guard tube. Added 5-methyl- 4-chloromethyldioxalone(2.5eq) drop wise to the mass at room temperature. The mass was further heated to 60-65C for 16-18 hrs. Reaction was monitored by TLC. After the completion of the reaction, distilled of the solvent completely under vacuum. To the mass added water (10V) and Ethyl acetate (5V) and stirred the mass at room temperature for hr. Filtered the heterogeneous mass under suction. Bed washed with IV of Ethyl acetate. Suction dried the mass for 2 hrs. Dried the mass in Vacuum tray dryer (VTD) at 65-70C for 4hrs. Yield: 90 % Purity: 98.7%

Reference： [1]Patent: WO2013/93937,2013,A2 .Location in patent: Page/Page column 12

11
[ 153977-22-1 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium hydroxide In methanol; water at 65 - 68℃; for 1.08333h; Reflux; Large scale;
18.1 g	With water; potassium hydroxide In methanol for 6.5h; Reflux;	1 Process for the preparation of Atovaquone 2-[4-(4-Chlorophenyl)cyclohexyl-3-chloro-l ,4-naphthoquinone (20 gm) was added to methanol (400 ml) at 25-30°C, the contents were heated to reflux and then potassium hydroxide solution (20 gm) in water (200 ml) was slowly added for 30 minutes at reflux. The reaction mass was stirred for 6 hours at reflux, to the resulting mass added hydrochloric acid (72 ml) slowly for 15 to 20 minutes at reflux and then cooled to 25-30°C. The resulting mass was further cooled to 0°C and then stirred for 1 hour at 0-5°C. The solid was filtered, washed with water and then dried at 50 - 60°C to give 18.1 gm of atovaquone

Reference： [1]Dike, Suneel Y.; Singh, Dharmendra; Thankachen, Byju N.; Sharma, Brajesh; Mathur, Pramil K.; Kore, Swapnil; Kumar, Ashok [Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625]
[2]Current Patent Assignee: ALKEM LAB - WO2013/93937, 2013, A2 Location in patent: Page/Page column 11; 12

12
[ 1010-60-2 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: silver nitrate; ammonium peroxydisulfate / acetonitrile; water / 4 h / Reflux 2: potassium hydroxide / water; methanol / 1.08 h / 65 - 68 °C / Reflux; Large scale

13
[ 49708-81-8 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: silver nitrate; ammonium peroxydisulfate / acetonitrile; water / 4 h / Reflux 2: potassium hydroxide / water; methanol / 1.08 h / 65 - 68 °C / Reflux; Large scale
	Multi-step reaction with 3 steps 1: silver nitrate; ammonium peroxydisulfate / acetonitrile; water / 1.5 h / Reflux; Large scale 2: acetic acid; chlorine / 20 °C / Large scale 3: potassium hydroxide / water; methanol / 1.08 h / 65 - 68 °C / Reflux; Large scale
	Multi-step reaction with 4 steps 1: silver nitrate; ammonium peroxydisulfate / acetonitrile; water / 1.5 h / Reflux; Large scale 2: acetic acid; chlorine / 20 °C / Large scale 3: sodium acetate / 1 h / Reflux; Large scale 4: potassium hydroxide / water; methanol / 1.08 h / 65 - 68 °C / Reflux; Large scale

Multi-step reaction with 3 steps 1: C₁₁H₁₄F₃N₂O₂S⁽¹⁺⁾*CF₃O₃S^(1-); 4-piperidinylpyridine; pinacolborane / dichloromethane / 10 min / 25 °C / Schlenk technique; Inert atmosphere 2: ammonium acetate; acetic acid / 1.5 h / 60 °C 3: sodium methylate / methanol / 18 h / 20 °C

Reference： [1]Dike, Suneel Y.; Singh, Dharmendra; Thankachen, Byju N.; Sharma, Brajesh; Mathur, Pramil K.; Kore, Swapnil; Kumar, Ashok [Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625]
[2]Dike, Suneel Y.; Singh, Dharmendra; Thankachen, Byju N.; Sharma, Brajesh; Mathur, Pramil K.; Kore, Swapnil; Kumar, Ashok [Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625]
[3]Dike, Suneel Y.; Singh, Dharmendra; Thankachen, Byju N.; Sharma, Brajesh; Mathur, Pramil K.; Kore, Swapnil; Kumar, Ashok [Organic Process Research and Development, 2014, vol. 18, # 5, p. 618 - 625]
[4]Chen, Du; Xu, Liangxuan; Yu, Yi; Mo, Qinliang; Qi, Xiaotian; Liu, Chao [Angewandte Chemie - International Edition, 2023, vol. 62, # 2][Angew. Chem., 2023, vol. 135, # 2]

14
[ 130-15-4 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: silver nitrate; ammonium peroxydisulfate / acetonitrile; water / 1.5 h / Reflux; Large scale 2: acetic acid; chlorine / 20 °C / Large scale 3: potassium hydroxide / water; methanol / 1.08 h / 65 - 68 °C / Reflux; Large scale
	Multi-step reaction with 4 steps 1: silver nitrate; ammonium peroxydisulfate / acetonitrile; water / 1.5 h / Reflux; Large scale 2: acetic acid; chlorine / 20 °C / Large scale 3: sodium acetate / 1 h / Reflux; Large scale 4: potassium hydroxide / water; methanol / 1.08 h / 65 - 68 °C / Reflux; Large scale

15
[ 1100053-58-4 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: acetic acid; chlorine / 20 °C / Large scale 2: potassium hydroxide / water; methanol / 1.08 h / 65 - 68 °C / Reflux; Large scale
	Multi-step reaction with 3 steps 1: acetic acid; chlorine / 20 °C / Large scale 2: sodium acetate / 1 h / Reflux; Large scale 3: potassium hydroxide / water; methanol / 1.08 h / 65 - 68 °C / Reflux; Large scale

16
[ 1100053-59-5 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium acetate / 1 h / Reflux; Large scale 2: potassium hydroxide / water; methanol / 1.08 h / 65 - 68 °C / Reflux; Large scale

17
[ 83-72-7 ]
[ 2125962-96-9 ]
[ 137732-39-9 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
24 % de	With sodium persulfate; trifluoroacetic acid In water; acetonitrile at 20℃; Inert atmosphere; Overall yield = 54 %; Overall yield = 73.7 mg;

Reference： [1]Gutiérrez-Bonet, Álvaro; Remeur, Camille; Matsui, Jennifer K.; Molander, Gary A. [Journal of the American Chemical Society, 2017, vol. 139, # 35, p. 12251 - 12258]

18
[ 75-36-5 ]
[ 95233-18-4 ]
[ 129700-44-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile at 80℃; for 10h;	3 General procedure: To a suspension of trans-2-[4-(4-chlorophenyl)cyclohexyl] -3-hydroxy- 1 ,4-naphthalenedione (1 equiv) and K2C03 (2 equiv) in anhydrous CH3CN (0.1 M) was added the appropriate acid chloride (3.5 equiv). The reaction mixture stirred for 10 hours at 80 CC. Upon completion, the reaction was cooled to ambient temperature and quenched with water, extracted with EtOAc, and washed with brine. The organic layers were combined, dried under Na2SO4, filtered, and concentrated under reduced pressure. The crude material was submitted to silica gel column chromatography to afford the desired products (eluent hexanes -* hexanes:EtOAc = 19:1) as yellow solids.

Reference： [1]Current Patent Assignee: SCRIPPS RESEARCH - WO2017/222996, 2017, A1 Location in patent: Paragraph 00222

19
[ 153977-22-1 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-1,4-naphthoquinone With water; potassium hydroxide In methanol Reflux; Stage #2: With hydrogenchloride; water In methanol Cooling with ice;	1.II Stage II. 2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l> 4-naphthoquinone (Atovaquone) (6) ; Product from stage I (1.5gm) is taken in methanol and under stirring, potassium hydroxide (1.52 gm) dissolved in water (15 ml) is added over a period of 15 - 20 minutes, dropwise. The mixture is then refluxed approximately for 6 - 7 hrs. During this period the mixture became dark red. The mixture is then cooled in ice and concentrated hydrochloric acid (5.4 ml) is added dropwise to get yellow solid, which is filtered and washed thoroughly with water. The product after crystallization from methanol-acetic acid afforded the title compound as trans isomer (750 mg).Melting point, IR, NMR matched with the product obtained from monochloro naphthoquinone.

Reference： [1]Current Patent Assignee: ALKEM LABORATORIES - WO2009/122432, 2009, A2 Location in patent: Page/Page column 25

20
[ 2417796-61-1 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 2-[trans-4-(4-chlorophenyl)cyclohexyl]-2,3-dihydronaphthalene-1,4-dione With hydrogen bromide; dihydrogen peroxide In 1,2-dichloro-ethane at 30 - 40℃; for 6h; Stage #2: With sodium hydroxide In water; 1,2-dichloro-ethane at 50 - 65℃; for 7h;	3-5; 2 Example 4: Preparation of Atovaquone (I) In a 500 ml four-necked flask equipped with a stirring, thermometer, reflux condenser, and constant pressure dropping funnel,Add 220 grams of 1,2-dichloroethane,17.6 g (0.05 mol) of 2-trans- [4- (4-chlorophenyl)] cyclohexyl-2,3-dihydro-1,4-naphthalenedione (IV) prepared in Example 2,22.5 g (0.11 mole) of 40 wt% hydrobromic acid,Add 13.5 g (0.12 mol) of 30 wt% hydrogen peroxide dropwise at 30-35 ° C.After about 2 hours,After that, the reaction was stirred at 35-40 ° C for 4 hours.Cool to 20-25 ° C, add 60.0 g (0.15 mole) of 10 wt% aqueous sodium hydroxide solution,Stir the reaction at 50-55 ° C for 3 hours, and then stir the reaction at 60-65 ° C for 4 hours.Cool to 20-25 , pH value of 30wt% hydrochloric acid acidification system is 6.0-7.0,The layers were separated and the aqueous layer was extracted 3 times with 1,2-dichloroethane.30 g each time, combine the organic phases,1,2-dichloroethane was recovered by distillation, and 0.3 g of activated carbon was added to the residue.40 grams of isopropanol, stirred at 75-80 ° C for 1 hour,Filter while hot, the filtrate is cooled, recrystallized, filtered, dried,16.5 g of atovaquone (I) are obtained,The yield was 90.0% (based on the compound of formula IV) and the liquid purity was 99.7%.

Reference： [1]Current Patent Assignee: XINFA PHARMACEUTICAL CO LTD - CN110734369, 2020, A Location in patent: Paragraph 0064-0072; 0076-0077

21
[ 2417796-62-2 ]
[ 95233-18-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium methylate / tetrahydrofuran / 7 h / 40 - 50 °C 1.2: 3 h / 20 - 70 °C 1.3: 1 h / 30 - 40 °C / pH 1 - 2 2.1: hydrogen bromide; dihydrogen peroxide / 1,2-dichloro-ethane / 6 h / 30 - 40 °C 2.2: 7 h / 50 - 65 °C

Reference： [1]Current Patent Assignee: XINFA PHARMACEUTICAL CO LTD - CN110734369, 2020, A

22
[ CAS Unavailable ]
[ 95233-18-4 ]
[ 2755862-61-2 ]

Yield	Reaction Conditions	Operation in experiment
0.158 g	With pyridine In dichloromethane at 20℃;	5-Chloro-2-(2,4-dichlorophenoxy)phenyl-3-[4-(4-chlorophenyl)cyclohexyl]-1,4-dioxo-1,4-dihydronaphthalen-2-yl octanedioate (4) To compound3(0.1 g, 0.22 mmol) was added thionyl chloride (0.081 mL, 1.1 mmol) and the mixture was stirred at 50°C for 3 h. Excess SOCl2was removed by repetitive evaporation. Dry dichloromethane (1.5 mL), pyridine (0.036 mL, 0.45 mmol) and atovaquone (82 mg, 0.22 mmol) were then added and the mixture was stirred at room temperature for 1 day. The excess solvent was removedin vacuoand the obtained crude was purifiedviasilica gelcolumn chromatography (100% dichloromethane) to afford4as a yellow solid (0.158 g, 89% yield).1H NMR (CDCl3, 400 MHz) δ 8.15-8.05 (m, 2H), 7.79-7.68 (m, 2H), 7.45 (d,4J= 2.5 Hz, 1H), 7.29-7.24 (m, 2H), 7.20-7.13 (m, 5H), 6.86-6.83 (m, 2H), 3.07 (m, 1H), 2.70 (t,3J= 7.4 Hz, 2H), 2.59 (m, 1H), 2.52 (t,3J= 7.3 Hz, 2H), 2.07-1.93 (m, 4H), 1.87-1.77 (m, 4H), 1.72 (p,3J= 8 Hz, 2H), 1.61-1.40 (m, 6H).13C NMR (CDCl3, 100 MHz) δ 184.7 (Cq), 178.4 (Cq), 171.4 (Cq), 171.1 (Cq), 151.2 (Cq), 151.1 (Cq), 146.7 (Cq), 145.6 (Cq), 142.0 (Cq), 141.9 (Cq), 134.2 (CH), 133.8 (CH), 132.5 (Cq), 131.8 (Cq), 130.8 (Cq), 130.5 (CH), 129.5 (Cq), 129.5 (Cq), 128.6 (2 CH), 128.3 (CH), 128.2 (2 CH), 127.1 (CH), 127.1 (CH), 126.6 (CH), 125.8 (Cq), 124.6 (CH), 120.5 (CH), 120.3 (CH), 43.4 (CH), 36.1 (CH), 34.4 (2 CH2), 34.0 (CH2), 33.9 (CH2), 30.1 (2 CH2), 28.8 (CH2), 28.2 (CH2), 24.7 (CH2), 24.7 (CH2). HR-MS (DCI/CH4) m/z calculated for C42H36Cl4O7(M+)792.1215, found 792.1212; for C44H41O7Cl4(M + C2H5+) 821.1606, found 821.1594. IRν(cm-1)1760, 1754, 1681, 1661 (CO).

Reference： [1]Ouji, Manel; Nguyen, Michel; Mustière, Romain; Jimenez, Tony; Augereau, Jean-Michel; Benoit-Vical, Françoise; Deraeve, Céline [Bioorganic and Medicinal Chemistry Letters, 2021, vol. 39]

23
[ CAS Unavailable ]
[ 95233-18-4 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
1: 40 mg 2: 20 mg	With pyridine In dichloromethane at 20℃;	[2,8-Bis(trifluoromethyl)quinolin-4-yl](piperidin-2-yl)methyl-3-[4-(4-chlorophenyl)cyclohexyl]-1,4-dioxo-1,4-dihydronaphthalen-2-yl butanedioate (12) To acid10(120 mg, 0.207 mmol) was added dropwise SOCl2(76 µL, 1.03 mmol) and the mixture was stirred under argon at 50°C for 3 h. Excess of SOCl2was removed by repetitive evaporation with dry dichloromethane (3 x 2 mL)in vacuo. The obtained residue was dissolved in dry dichloromethane (3 mL) and atovaquone (76 mg, 0.207 mmol) and dry pyridine (33 µL, 0.415 mmol) were added. The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum and the products were purified by column chromatography on silica gel first with hexane-ethyl acetate 7:3 to afford12-Boc(40 mg, 21% yield) as a yellow solid, then elution with dichloromethane-methanol (95:5) give12(hydrochloride salt, 20 mg, 11% yield) as a yellow solid after washing with EtO2.Additional12was obtained by deprotecting12-Bocunder acidic conditions: To a solution of12-Boc(20 mg, 0,021 mmol) in MeOH (1 mL) was added a 1 mL of 3M hydrogen chloride solution in MeOH. The mixture was stirred at room temperature for 6 h. Evaporation of the solvent under reduced pressure, followed by a washing step of the product with Et2O afforded12as a yellow solid (hydrochloride salt, 17.9 mg, 96 % yield)12-Boc:1H NMR (CDCl3,400 MHz) : δ 8.67 (s, 1H), 8.18-8.09 (m, 2H), 8.07-8.01 (m, 1H), 7.88 (s, 1H), 7.81-7.72 (m, 2H), 7.67 (t,3J= 7.9 Hz, 1H), 7.27 (d,3J= 8.4 Hz, 2H), 7.11 (d,3J= 8.4 Hz, 2H), 6.82 (d,3J= 8.3 Hz, 1H), 4.80 (bs, 1H), 4.00 (bs, 1H), 3.17-2.85 (m, 6H), 2.56 (t,3J= 12.5 Hz, 1H), 2.04-1.61 (m, 10H), 1.55-1.38 (m, 4H), 1.13 (s, 9H).13C NMR (CDCl3, 100 MHz): δ 184.3 (Cq), 178.1 (Cq), 170.9 (Cq), 169.6 (Cq), 150.9 (Cq), 147.5 (q,2J(C,F) = 35 Hz, Cq-CF3), 146.2 (Cq), 145.6 (Cq), 143.9 (Cq), 142.2 (Cq), 134.2 (CH), 133.8 (CH), 132.3 (Cq), 131.5 (Cq), 130.5 (Cq), 129.5 (CH), 128.9 (CH), 128.4 (CH), 128.1 (CH), 127.4 (CH), 127.1 (Cq), 126.9 (CH), 126.4 (CH), 123.4 (q,1J(C,F) = 275 Hz, CF3), 121.0 (q,1J(C,F) = 277 Hz, CF3), 116.0 (CH), 80.16 (Cq), 71.5 (CH), 53.1 (CH), 43.0 (CH2), 40.5 (CH), 35.9 (CH), 34.1 (CH2), 34.0 (CH2), 29.8 (CH2), 29.7 (CH2), 29.0 (CH2), 28.6 (CH2), 27.8 (CH3), 24.5 (CH2), 24.0 (CH2), 19.2 (CH2). LR-MS (DCI/CH4) calculated for C48H46ClF6N2O8(M+H+) 927.2847, found: 927.2895. IRn(cm-1) 1770, 1747, 1675 (CO).12.HCl:1H NMR (DMSO, 400 MHz): δ 10.00 (bs, 1H), 8.98 (d,3J= 8.7 Hz, 1H), 8.90 (bs, 1H), 8.28 (d,3J= 7.3 Hz, 1H), 8.06 (dd,3J= 7.1, 1.9 Hz, 1H), 7.98-7.82 (m, 5H), 7.29 (d,3J= 8.4 Hz, 2H), 7.06-6.94 (m, 3H), 3.68 (t,3J= 10.3 Hz, 1H), 3.43-3.36 (m, 1H), 3.22-2.92 (m, 5H), 2.78 (t,3J= 12.2 Hz, 1H), 2.39-2.26 (m, 1H), 1.87-0.99 (m, 14H).13C NMR (DMSO, 100MHz): δ 184.3 (Cq), 178.3 (Cq), 171.9 (Cq), 170.6 (Cq), 150.6 (Cq), 147.2 (q,2J(C,F) = 35 Hz, Cq-CF3), 146.1 (Cq), 146.0 (Cq), 143.3 (Cq), 142.1 (Cq), 135.3 (CH), 134.8 (CH), 132.2 (Cq), 130.7 (Cq), 130.4 (CH), 130.3 (Cq), 129.4 (CH), 129.1 (CH), 128.8 (CH), 128.6 (CH), 127.5 (q,2J(C,F) = 29 Hz, Cq-CF3), 127.0 (CH), 126.6 (Cq), 126.3 (CH), 123.7 (q,1J(C,F) = 274 Hz, CF3), 121.2 (q,1J(C,F) = 276 Hz, CF3), 115.6 (CH), 71.2 (CH), 57.5 (CH), 44.9 (CH2), 42.2 (CH), 35.6 (CH), 33.7 (CH2), 33.5 (CH2), 29.4 (CH2), 29.2 (CH2), 28.8 (CH2), 22.4 (CH2), 22.0 (CH2), 21.6 (CH2).19F NMR (376 MHz, DMSO): δ = -58.9 (s), -66.8 (s). HRMS (ESI+) calculated for C43H38ClF6N2O6(M-HCl+H+) 827.2323, found: 827.2327. IRn(cm-1) 1763, 1746, 1671 (CO). MS/MS experiments (collision energies from 15 to 50 eV) showed the complete fragmentation of m/z 827.2 ([M-HCl+H]+) into m/z 361.1 ion, in agreement with the absence of intramolecular rearrangement of the diester12under acidic conditions to12-amidoesteras suggested by Grellepoiset al.3

24
[ CAS Unavailable ]
[ 95233-18-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
45 mg	With pyridine In dichloromethane at 20℃;	[2,8-Bis(trifluoromethyl)quinolin-4-yl](piperidin-2-yl)methyl-3-[4-(4-chlorophenyl)cyclohexyl]-1,4-dioxo-1,4-dihydronaphthalen-2-yl butanedioate (12) General procedure: To acid10(120 mg, 0.207 mmol) was added dropwise SOCl2(76 µL, 1.03 mmol) and the mixture was stirred under argon at 50°C for 3 h. Excess of SOCl2was removed by repetitive evaporation with dry dichloromethane (3 x 2 mL)in vacuo. The obtained residue was dissolved in dry dichloromethane (3 mL) and atovaquone (76 mg, 0.207 mmol) and dry pyridine (33 µL, 0.415 mmol) were added. The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum and the products were purified by column chromatography on silica gel first with hexane-ethyl acetate 7:3 to afford12-Boc(40 mg, 21% yield) as a yellow solid, then elution with dichloromethane-methanol (95:5) give12(hydrochloride salt, 20 mg, 11% yield) as a yellow solid after washing with EtO2.Additional12was obtained by deprotecting12-Bocunder acidic conditions: To a solution of12-Boc(20 mg, 0,021 mmol) in MeOH (1 mL) was added a 1 mL of 3M hydrogen chloride solution in MeOH. The mixture was stirred at room temperature for 6 h. Evaporation of the solvent under reduced pressure, followed by a washing step of the product with Et2O afforded12as a yellow solid (hydrochloride salt, 17.9 mg, 96 % yield)

25
[ 7333-63-3 ]
[ 95233-18-4 ]
C₄₄H₄₁ClO₃P⁽¹⁺⁾*Br^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 9h;	1 Synthesis of Mito₄-ATO Mito4-ATO was prepared by reacting (4-bromobutyl)-triphenylphosphonium bromide with ATO in the presence of potassium carbonate in DMF (Fig. 1S). Briefly, (4- bromobutyl)-triphenylphosphonium bromide (0.39 g, 0.81 mmol) was added to a mixture of ATO (0.3 g, 0.82 mmol) and potassium carbonate (0.15 g, 0.82 mmol) in DMF. The mixture was stirred at 70°C for 9 h. CH2Cl2 was then added to the mixture followed by the addition of water (20 mL). The organic layer was washed twice with water and dried over Na2SO4. The solvent was removed under reduced pressure. Diethyl ether was added to the mixture to precipitate out the compound that was purified by flash chromatography (CH2Cl2/EtOH, 9:1), yielding the product, Mito4-ATO (0.47 g, 75% yield). The HRMS calculated and found values are C44H41ClO3P+ [M+] 683.2476 and 683.2479.31P NMR (400.13 MHz, CDCl3) δ 24.66.1H NMR (400.13 MHz, CDCl3), δ 8.06-8.03 (1H, m), 7.95-7.93 (1H, m), 7.92-7.85 (6H, m), 7.79-7.72 (3H, m), 7.71-7.63 (8H, m), 7.25-7.21 (2H, m), 7.15-7.12 (2H, m), 4.26 (2H, t, J = 5.6), 4.11-4.02 (2H, m), 3.13-3.03 (1H, m), 2.58-2.48 (1H, m), 2.37-2.28 (2H, m), 2.10-1.98 (4H, m), 1.92-1.88 (2H, m), 1.65 (2H, dd, J = 12.7, 2.7), 1.54-1.39 (2H, m).13C NMR (75 MHz, CDCl3) δ 185.4, 181.7, 157.7, 145.7, 140.0, 134.9, 134.8, 133.8, 133.77, 133.68, 133.2, 132.3, 131.4, 131.3, 130.5, 130.3, 128.3, 128.2, 118.8, 117.9, 72.4, 43.1, 35.5, 34.3, 30.12 (d, 17.6), 30.1, 30.0, 22.2 (d, J = 50.6), 19.1 (d, J = 3.7). NMR spectra and related parameters are included in Fig.8.

Reference： [1]Current Patent Assignee: AIX-MARSEILLE UNIVERSITY; MEDICAL COLLEGE OF WISCONSIN - WO2021/81500, 2021, A1 Location in patent: Paragraph 00104; 00143-00145

26
[ 120677-73-8 ]
[ 95233-18-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 9h;	1 Synthesis of Mito₁₀-ATO Mito10-ATO was prepared by reacting (10-bromodecyl)-triphenylphosphonium bromide with ATO in the presence of potassium carbonate in DMF (Fig. 7). Briefly, (10- bromodecyl)-triphenylphosphonium bromide (1.1 g, 1.9 mmol) was added to a mixture of ATO (0.73 g, 1.9 mmol) and potassium carbonate (0.3 g, 2.1 mmol) in DMF (4 mL). The mixture was stirred at 70°C for 9 h. Methylene chloride (CH2Cl2) was added to the mixture, and then water (20 mL) was added. The organic layer was washed twice with water and dried over anhydrous sodium sulphate. The excess solvent was removed under reduced pressure. Diethyl ether was subsequently added to the mixture to precipitate the compound. Purification by flash chromatography, using a mixture of methylene chloride and ethanol (9:1), yielded the desired compound, Mito10-ATO (1 g, 59% yield). The high-resolution mass spectral (HRMS) calculated for Mito10-ATO C50H53ClO3P+ [M]+ 767.3415, found, 767.3420. 31P NMR (400.13 MHz, CDCl3) δ 24.48. 1H NMR (400.13 MHz, CDCl3 ) δ .08-7.98 (2H, m), 7.90-7.82 (6H, m), 7.81-7.75 (3H, m), 7.73- 7.64 (8H, m), 7.25-7.23 (2H, m), 7.18-7.16 (2H, m), 4.30 (2H, t, J = 6.6), 3.88-3.77 (2H, m), 3.25- 3.15 (1H, m), 2.66-2.55 (1H, m), 2.24-2.11 (2H, m), 2.01-1.92 (2H, m), 1.86-1.77 (2H, m), 1.76- 1.68 (4H, m), 1.60-1.40 (6H, m), 1.38-1.25 (8H, m).13C NMR (75 MHz, CDCl3) δ 185.5, 181.9, 158.0, 146.0, 138.6, 134.9, 134.8, 133.8, 133.72, 133.67, 133.1, 132.4, 131.5, 131.4, 130.5, 130.4, 128.4, 128.2, 126.3, 125.9, 118.9, 118.1, 74.0, 43.3, 35.4, 34.5, 30.4 (d, J = 14.0), 29.9, 29.5, 29.3, 29.2, 25.9, 22.8 (d, J = 49.1), 22.7 (d, J = 4.4). NMR spectra and related parameters are given in Fig.8.

Reference： [1]Current Patent Assignee: AIX-MARSEILLE UNIVERSITY - WO2021/81500, 2021, A1 Location in patent: Paragraph 00104; 00146-00148

27
[ 120677-74-9 ]
[ 95233-18-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
35%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 7h;	1 Synthesis of Mito12-ATO Mito12-ATO was prepared by reacting (12-bromodecyl)-triphenylphosphonium bromide with ATO in the presence of potassium carbonate in DMF (Fig. 1S) as follows: (12- bromododecyl)-triphenylphosphonium bromide (0.6 g, 1.0 mmol) was added to a mixture of ATO (0.45 g, 1.2 mmol) and potassium carbonate (0.17 g, 1.2 mmol) in DMF. The mixture was stirred at 70°C for 7 h. CH2Cl2 was added to the mixture followed by water (20 mL). The organic layer was washed twice with water and dried over Na2SO4. The solvent was removed under reduced pressure. Diethyl ether was then added to precipitate out the compound that was purified by flash chromatography (CH2Cl2/EtOH, 9:1) yielding the product, Mito12-ATO (0.35 g, 35% yield). HRMS calculated for Mito12-ATO C52H57ClO3P+ [M]+ 795.3728, found, 795.3729. 31P NMR (400.13 MHz, CDCl3) δ 24.44. 1H NMR (400.13 MHz, CDCl3), δ 8.07-7.97 (2H, m), 7.87-7.74 (9H, m), 7.72-7.63 (8H, m), 7.24-7.20 (2H, m), 7.18-7.13 (2H, m), 4.30 (2H, t, J = 6.6), 3.82-3.72 (2H, m), 3.25-3.13 (1H, m), 2.65-2.55 (1H, m), 2.23-2.09 (2H, m), 1.99-1.92 (2H, m), 1.84-1.67 (7H, m), 1.63-1.42 (8H, m), 1.37-1.19 (9H, m). 13C NMR (75 MHz, CDCl3) δ 185.5, 181.9, 158.1, 146.0, 138.6, 134.92, 134.89, 133.7, 133.6, 133.1, 132.4, 131.5, 131.4, 130.5, 130.4, 128.4, 128.2, 126.3, 125.9, 118.9, 118.1, 74.1, 43.3, 35.4, 34.5, 30.5, 30.4, 30.3 (d, J = 16.1), 29.9, 29.6, 29.5, 29.3, 29.24, 29.21, 25.9, 22.8 (d, J = 49.2), 22.4 (d, J = 4.4). The NMR spectra and related parameters are given in Fig.8.

Reference： [1]Current Patent Assignee: AIX-MARSEILLE UNIVERSITY - WO2021/81500, 2021, A1 Location in patent: Paragraph 00104; 00149-00151

28
[ CAS Unavailable ]
[ 95233-18-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
54%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 7h;	1 Synthesis of Mito₁₆-ATO Mito16-ATO was prepared by reacting (16-bromohexadecyl)- triphenylphosphonium bromide with ATO in the presence of potassium carbonate in DMF as follows: (16-bromohexadecyl)-triphenylphosphonium bromide (0.2 g, 0.34 mmol) was added to a mixture of ATO (0.13 g, 0.37 mmol) and potassium carbonate (0.05 g, 0.37 mmol) in DMF (2 mL). The mixture was stirred at 70°C for 7 h. CH2Cl2 was added to the mixture as well as water (20 mL). The organic layer was washed twice with water and dried over Na2SO4. The solvent was removed under reduced pressure. Diethyl ether was the added to the mixture to precipitate out the compound that was purified by flash chromatography (CH2Cl2/EtOH, 9:1), yielding the product, Mito16-ATO (0.16 g, 54% yield). [00154] HRMS calculated for Mito16-ATO C56H65ClO3P+ [M]+ 851.4354, found, 851.4360. 31P NMR (400.13 MHz, CDCl3) δ 23.39.1H NMR (400.13 MHz, CDCl3), δ 8.00-7.93 (2H, m), 7.81-7.59 (17H, m), 7.21-7.16 (2H, m), 7.11-7.09 (2H, m), 4.26 (2H, t, J = 6.7), 3.75-3.63 (2H, m), 3.20-3.08 (1H, m), 2.60-2.48 (1H, m), 2.17-2.03 (2H, m), 1.94-1.85 (2H, m), 1.80-1.73 (2H, m), 1.70-1.63 (2H, m), 1.68-1.38 (8H, m), 1.33-1.06 (20H, m). 13C NMR (75 MHz, CDCl3) δ 185.54, 181.8, 158.0, 146.0, 138.5, 134.94, 134.91, 133.7, 133.6, 133.0, 132.3, 131.3, 131.4, 130.5, 130.4, 128.3, 128.1, 126.2, 125.9, 118.8, 118.0, 74.0, 43.3, 35.5, 34.5, 30.5, 30.4, 30.3, 29.9, 29.6, 29.59, 29.56, 29.52, 29.4, 29.3, 29.2, 29.1, 25.9, 22.8 (d, J = 49.9), 22.6 (d, J = 4.4). The NMR spectra and related parameters are given in Fig.8.

Reference： [1]Current Patent Assignee: AIX-MARSEILLE UNIVERSITY - WO2021/81500, 2021, A1 Location in patent: Paragraph 00104; 00152-00154

29
[ 112-29-8 ]
[ 95233-18-4 ]
[ 1197376-35-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 20h;

Reference： [1]Current Patent Assignee: AIX-MARSEILLE UNIVERSITY - WO2021/81500, 2021, A1 Location in patent: Paragraph 00167; 00176

30
[ 110-53-2 ]
[ 95233-18-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate In N,N-dimethyl-formamide

Reference： [1]Current Patent Assignee: AIX-MARSEILLE UNIVERSITY - WO2021/81500, 2021, A1 Location in patent: Paragraph 0028; 00104; 00140

31
[ 2834-05-1 ]
[ 95233-18-4 ]
[ 2797982-10-4 ]

Yield	Reaction Conditions	Operation in experiment
2.6 mg	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; for 0.166667h; Stage #2: 11-bromoundecanoic acid In lithium hydroxide monohydrate; butanone Reflux;	2 Charged NaHCO3 (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 11-Bromoundecanoic acid (5.42 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25-30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with acetic acid. The colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25- 30°C, final pH was 3-4. The mass was stirred for 20-30 minutes. The Semisolid oily mass was filtered and washed with water (2 x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out. The net weight obtained was 21 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). Column purified product re-crystallized in n- Hexane at -10°C, filtered at -10°C and washed with chilled n-Hexane (-10°C). It was sucked dried and further product was dried on rota evaporator under vacuum at 30-35°C. Pure product was yellow coloured powder with net weight of 2.6 gm and purity 97 % as assessed by HPLC. Example 3: Preparation of 12-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl)oxy)dodecanoic acid. Chemical Formula: C34H41C1O5. Molecular Weight: 565.1470.
2.6 mg	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; for 0.166667h; Stage #2: 11-bromoundecanoic acid In lithium hydroxide monohydrate; butanone at 20 - 75℃;	2 Charged NaHCO3 (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 11-Bromoundecanoic acid (5.42 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25-30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with acetic acid. The colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25- 30°C, final pH was 3-4. The mass was stirred for 20-30 minutes. The Semisolid oily mass was filtered and washed with water (2 x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out. The net weight obtained was 21 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). Column purified product re-crystallized in n- Hexane at -10°C, filtered at -10°C and washed with chilled n-Hexane (-10°C). It was sucked dried and further product was dried on rota evaporator under vacuum at 30-35°C. Pure product was yellow coloured powder with net weight of 2.6 gm and purity 97 % as assessed by HPLC. Example 3: Preparation of 12-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl)oxy)dodecanoic acid. Chemical Formula: C34H41C1O5. Molecular Weight: 565.1470.

Reference： [1]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 29-31
[2]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 29-31

32
[ 73367-80-3 ]
[ 95233-18-4 ]
[ 2797982-11-5 ]

Yield	Reaction Conditions	Operation in experiment
3 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; for 0.166667h; Stage #2: 12-bromododecanoic acid In lithium hydroxide monohydrate; butanone Reflux;	3 Charged NaHCCh (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 12-Bromododecanoic acid (5.7 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25-30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass was adjust to 3-4 with acetic acid. Colour of reaction turned from red brown to yellowish. Thereafter, charged 225 ml water to the reaction mass at 25-30°C, final pH was 3-4. Mass stirred for 20-30 minutes. Semisolid oily mass was filtered and washed with water (2 x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out. The net weight obtained was 21 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). Column purified product re-crystallized in n- Hexane at -10°C. It was then filtered at -10°C and washed with chilled n-Hexane (-10°C). It was suck dried initially and further product was dried on rota evaporator under vacuum at 30-35°C. Pure product was yellow colour powder with net weigh of 3.0 gm and purity 97% as estimated by HPLC
3 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; for 0.166667h; Stage #2: 12-bromododecanoic acid In lithium hydroxide monohydrate; butanone at 20 - 75℃;	3 Charged NaHCCh (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 12-Bromododecanoic acid (5.7 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25-30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass was adjust to 3-4 with acetic acid. Colour of reaction turned from red brown to yellowish. Thereafter, charged 225 ml water to the reaction mass at 25-30°C, final pH was 3-4. Mass stirred for 20-30 minutes. Semisolid oily mass was filtered and washed with water (2 x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out. The net weight obtained was 21 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). Column purified product re-crystallized in n- Hexane at -10°C. It was then filtered at -10°C and washed with chilled n-Hexane (-10°C). It was suck dried initially and further product was dried on rota evaporator under vacuum at 30-35°C. Pure product was yellow colour powder with net weigh of 3.0 gm and purity 97% as estimated by HPLC

Reference： [1]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 31; 32
[2]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 31; 32

33
[ 676-26-6 ]
[ 95233-18-4 ]
[ 2797982-12-6 ]

Yield	Reaction Conditions	Operation in experiment
3.1 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; for 0.166667h; Stage #2: 14-bromotetradecanoic acid In lithium hydroxide monohydrate; butanone Reflux;	4 Charged NaHCOs (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 14-Bromotetradecanoic acid (6.28 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25- 30°C. Colour of reaction mass was red brown slurry. Subsequently, the reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25- 30°C and pH of reaction mass was adjusted to 3-4 with acetic acid. The colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25-30°C, final pH was 3-4. The mass was stirred for 20-30 minutes. The semisolid oily mass was filtered and washed with water (2 x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out and the net weight obtained was 21 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n- Hexane (5:95). Column purified product was re-crystallized in n- Hexane at - 10°C. It was filtered at -10°C and washed with chilled n-Hexane (-10°C). It was sucked dried initially and further dried on rota evaporator under vacuum at 30- 35°C. Pure product was yellow colour powder with net weight of 3.1 g gm and Purity 97 % as assessed by HPLC.
3.1 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; for 0.166667h; Stage #2: 14-bromotetradecanoic acid In lithium hydroxide monohydrate; butanone at 20 - 75℃;	4 Charged NaHCOs (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 14-Bromotetradecanoic acid (6.28 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25- 30°C. Colour of reaction mass was red brown slurry. Subsequently, the reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25- 30°C and pH of reaction mass was adjusted to 3-4 with acetic acid. The colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25-30°C, final pH was 3-4. The mass was stirred for 20-30 minutes. The semisolid oily mass was filtered and washed with water (2 x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out and the net weight obtained was 21 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n- Hexane (5:95). Column purified product was re-crystallized in n- Hexane at - 10°C. It was filtered at -10°C and washed with chilled n-Hexane (-10°C). It was sucked dried initially and further dried on rota evaporator under vacuum at 30- 35°C. Pure product was yellow colour powder with net weight of 3.1 g gm and Purity 97 % as assessed by HPLC.

Reference： [1]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 33; 34
[2]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 33; 34

34
[ 56523-59-2 ]
[ 95233-18-4 ]
[ 2797982-13-7 ]

Yield	Reaction Conditions	Operation in experiment
3 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; for 0.166667h; Stage #2: 15-bromo-pentadecanoic acid In lithium hydroxide monohydrate; butanone Reflux;	5 Charged NaHCO3 (34.3 g) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 15 -Bromopentadecanoic acid (6.57 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25- 30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass adjusted to 3-4 with acetic acid. Colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25- 30°C, final pH is 3-4. The mass was stirred for 20-30 minutes. Semisolid oily mass was filtered and washed with water (2 x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out. The net weight obtained was 21 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). Column purified product re-crystallized in n- Hexane at -10°C. It was filtered at -10°C and washed with chilled n-Hexane (-10°C). It was suck dried initially and further the product was dried using rota evaporator under vacuum at 30-35°C. Pure product was yellow coloured powder with net weight of 3.0 g gm and purity at 97% as assessed by HPLC.
3 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; for 0.166667h; Stage #2: 15-bromo-pentadecanoic acid In lithium hydroxide monohydrate; butanone at 20 - 75℃;	5 Charged NaHCO3 (34.3 g) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 15 -Bromopentadecanoic acid (6.57 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25- 30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass adjusted to 3-4 with acetic acid. Colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25- 30°C, final pH is 3-4. The mass was stirred for 20-30 minutes. Semisolid oily mass was filtered and washed with water (2 x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out. The net weight obtained was 21 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). Column purified product re-crystallized in n- Hexane at -10°C. It was filtered at -10°C and washed with chilled n-Hexane (-10°C). It was suck dried initially and further the product was dried using rota evaporator under vacuum at 30-35°C. Pure product was yellow coloured powder with net weight of 3.0 g gm and purity at 97% as assessed by HPLC.

Reference： [1]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 34; 35
[2]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 34; 35

35
[ 2536-35-8 ]
[ 95233-18-4 ]
[ 2797982-14-8 ]

Yield	Reaction Conditions	Operation in experiment
3.2 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; for 0.166667h; Stage #2: 16-bromohexadecanoic acid In lithium hydroxide monohydrate; butanone Reflux;	6 Charged NaHCCh (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone(15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 16-Bromohexadecanoic acid (6.86 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25- 30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with acetic acid. Colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25-30°C, the final pH is 3-4. It was stirred for 20-30 minutes. Semisolid oily mass was filtered and washed with water (2 x 100 ml). Semi solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out. The net weight was 17 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). The column purified product was re-crystallized in n- Hexane at -10°C. It was then filtered at -10°C and washed with chilled n-Hexane (-10°C). It was then suck dried initially and further the product was dried on rota evaporator under vacuum at 30-35°C. The pure product was yellow coloured powder with weight of 3.2 g gm and purity of 97% as estimated by HPLC.
3.2 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; for 0.166667h; Stage #2: 16-bromohexadecanoic acid In lithium hydroxide monohydrate; butanone at 20 - 75℃;	6 Charged NaHCCh (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone(15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 16-Bromohexadecanoic acid (6.86 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25- 30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with acetic acid. Colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25-30°C, the final pH is 3-4. It was stirred for 20-30 minutes. Semisolid oily mass was filtered and washed with water (2 x 100 ml). Semi solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out. The net weight was 17 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). The column purified product was re-crystallized in n- Hexane at -10°C. It was then filtered at -10°C and washed with chilled n-Hexane (-10°C). It was then suck dried initially and further the product was dried on rota evaporator under vacuum at 30-35°C. The pure product was yellow coloured powder with weight of 3.2 g gm and purity of 97% as estimated by HPLC.

Reference： [1]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 36; 37
[2]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 36; 37

36
[ 55099-31-5 ]
[ 95233-18-4 ]
[ 2797982-15-9 ]

Yield	Reaction Conditions	Operation in experiment
3.2 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; Stage #2: ethyl 10-bromo-decanoate In lithium hydroxide monohydrate; butanone at 70 - 75℃;	7 Charged NaHCOs (13.8 gm) and water (25 ml) at 25-30°C. Reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5gm) and MEK (20 ml) were charged to the reaction mass at 25-30°C. Reaction mass was stirred for 15-20 mins at 25-30°C to obtain red brown slurry mass. 10- Bromodecanoic acid ethyl ester (4.19 gm) and MEK (5 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 25-30 minutes at 25-30°C to obtain red brown slurry mass. Reaction mass was refluxed for 35-40 hrs at 70- 75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with 30 ml acetic acid 75 ml water was added and sticky oily mass was stirred for 15-20 minutes at 25- 30°C. The mass was filtered and washed with water and hexane. The solid isolated weighed 2.5 gm (un-reacted atovaquone). The Hexane layer (containing the product) was washed with water (2 x 50 ml). The Hexane layer was concentrated on rota evaporator under vacuum at 35-40°C. Final crude mass weighed 5.2 gm and was taken for column chromatographyusing ethyl acetate: n-Hexane (5:95) as a mobile phase. After column chromatography, 2.1 gm material thus obtained was taken in 4 ml n-Hexane and cooled to -10°C for 2.0 hrs. It was then filtered and washed with chilled n- hexane (-10°C) suck dried initially and further the product was dried on rota evaporator under vacuum at 30-35°C. The final product was yellow coloured powder weighing 1.2 gm and having purity of 98% as determined by HPLC.
3.2 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; Stage #2: ethyl 10-bromo-decanoate In lithium hydroxide monohydrate; butanone at 25 - 75℃;	7 Charged NaHCOs (13.8 gm) and water (25 ml) at 25-30°C. Reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5gm) and MEK (20 ml) were charged to the reaction mass at 25-30°C. Reaction mass was stirred for 15-20 mins at 25-30°C to obtain red brown slurry mass. 10- Bromodecanoic acid ethyl ester (4.19 gm) and MEK (5 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 25-30 minutes at 25-30°C to obtain red brown slurry mass. Reaction mass was refluxed for 35-40 hrs at 70- 75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with 30 ml acetic acid 75 ml water was added and sticky oily mass was stirred for 15-20 minutes at 25- 30°C. The mass was filtered and washed with water and hexane. The solid isolated weighed 2.5 gm (un-reacted atovaquone). The Hexane layer (containing the product) was washed with water (2 x 50 ml). The Hexane layer was concentrated on rota evaporator under vacuum at 35-40°C. Final crude mass weighed 5.2 gm and was taken for column chromatographyusing ethyl acetate: n-Hexane (5:95) as a mobile phase. After column chromatography, 2.1 gm material thus obtained was taken in 4 ml n-Hexane and cooled to -10°C for 2.0 hrs. It was then filtered and washed with chilled n- hexane (-10°C) suck dried initially and further the product was dried on rota evaporator under vacuum at 30-35°C. The final product was yellow coloured powder weighing 1.2 gm and having purity of 98% as determined by HPLC.

Reference： [1]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 37-39
[2]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 38-39

37
[ 6271-23-4 ]
[ 95233-18-4 ]
[ 2797982-16-0 ]

Yield	Reaction Conditions	Operation in experiment
1.4 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; Stage #2: 11-bromoundecanoic acid ethyl ester In lithium hydroxide monohydrate; butanone at 70 - 75℃;	8 Charged NaHCOs (13.8 gm) and water (25 ml) at 25-30°C. Reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20 ml) was charged to the reaction mass at 25-30°C and stirred for 15- 20 mins at 25-30°C to obtain red brown slurry mass. 11-Bromoundecanoic acid ethyl ester (4.4 gm) and MEK (5 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 25-30 minutes at 25-30°C to obtain red brown slurry mass. Reaction mass was refluxed for 35-40 hrs at 70-75°C. Reaction completion was monitored with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass adjusted to 3-4 with 30 ml acetic acid. 75 ml water was added and sticky oily mass was stirred for 15-20 minutes at 25-30°C. It was then filtered and washed with water and hexane. The isolated solid weighed 2.5 gm (un-reacted atovaquone). The Hexane layer (containing the product) was washed with water (2 x 50 ml). The hexane layer was concentrated on rota evaporator under vacuum at 35-40°C.The final crude mass weighing 5.2 gm was taken for column chromatography using ethyl acetate: n-Hexane (5:95) as mobile phase. After column chromatography 2.1 gm material thus obtained was taken in 4 ml n- Hexane and cooled to -10°C for 2.0 hrs. It was then filtered and washed with chilled n-hexane (-10°C); suck dried initially and subsequently the product was dried on rota evaporator under vacuum at 30-35°C. The product was yellow coloured powder weighing 1.4 gm and purity of 98% as estimated by HPLC.
1.4 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; Stage #2: 11-bromoundecanoic acid ethyl ester In lithium hydroxide monohydrate; butanone at 25 - 75℃;	8 Charged NaHCOs (13.8 gm) and water (25 ml) at 25-30°C. Reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20 ml) was charged to the reaction mass at 25-30°C and stirred for 15- 20 mins at 25-30°C to obtain red brown slurry mass. 11-Bromoundecanoic acid ethyl ester (4.4 gm) and MEK (5 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 25-30 minutes at 25-30°C to obtain red brown slurry mass. Reaction mass was refluxed for 35-40 hrs at 70-75°C. Reaction completion was monitored with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass adjusted to 3-4 with 30 ml acetic acid. 75 ml water was added and sticky oily mass was stirred for 15-20 minutes at 25-30°C. It was then filtered and washed with water and hexane. The isolated solid weighed 2.5 gm (un-reacted atovaquone). The Hexane layer (containing the product) was washed with water (2 x 50 ml). The hexane layer was concentrated on rota evaporator under vacuum at 35-40°C.The final crude mass weighing 5.2 gm was taken for column chromatography using ethyl acetate: n-Hexane (5:95) as mobile phase. After column chromatography 2.1 gm material thus obtained was taken in 4 ml n- Hexane and cooled to -10°C for 2.0 hrs. It was then filtered and washed with chilled n-hexane (-10°C); suck dried initially and subsequently the product was dried on rota evaporator under vacuum at 30-35°C. The product was yellow coloured powder weighing 1.4 gm and purity of 98% as estimated by HPLC.

Reference： [1]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 39; 40
[2]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 39; 40

38
[ 72338-48-8 ]
[ 95233-18-4 ]
[ 2797982-17-1 ]

Yield	Reaction Conditions	Operation in experiment
1.5 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; Stage #2: ethyl 12-bromododecanoate In lithium hydroxide monohydrate; butanone at 70 - 75℃;	9 Charged NaHCOs (13.8 gm) and water (25 ml) at 25-30°C. Reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20 ml) was charged to the reaction mass at 25-30°C and stirred for 15- 20 min at 25-30°C to obtain red brown slurry mass. 12-Bromododecanoic acid ethyl ester (4.6 gm) and MEK (5 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 25-30 minutes at 25-30°C to obtain red brown slurry mass. Reaction mass was refluxed for 35-40 hrs at 70-75°C. Reaction completion was monitored with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with 30 ml acetic acid. 75 ml water was added and sticky oily mass was stirred for 15-20 minutes at 25-30°C. It was then filtered and washed with water and hexane. Isolated solid weighed 2.5 gm (un-reacted atovaquone). The Hexane layer (containing product) was washed with water (2 x 50 ml); concentrated on rota evaporator under vacuum at 35-40°C. The final crude mass weighing 5.2 gm was taken for column chromatography using ethyl acetate: n-Hexane (5:95) as mobile phase. After column chromatography 2.1 gm material thus obtained was taken in 4 ml n-Hexane, cooled to -10°C for 2.0 hrs and then filtered and washed with chilled n- hexane (-10°C) suck dried initially and further product was dried on rota evaporator under vacuum at 30-35°C. The product was yellow coloured powder weighing 1.5 gm and purity 98% as estimated by HPLC.
1.5 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 75℃; Stage #2: ethyl 12-bromododecanoate In lithium hydroxide monohydrate; butanone at 70 - 75℃;	9 Charged NaHCOs (13.8 gm) and water (25 ml) at 25-30°C. Reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20 ml) was charged to the reaction mass at 25-30°C and stirred for 15- 20 min at 25-30°C to obtain red brown slurry mass. 12-Bromododecanoic acid ethyl ester (4.6 gm) and MEK (5 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 25-30 minutes at 25-30°C to obtain red brown slurry mass. Reaction mass was refluxed for 35-40 hrs at 70-75°C. Reaction completion was monitored with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with 30 ml acetic acid. 75 ml water was added and sticky oily mass was stirred for 15-20 minutes at 25-30°C. It was then filtered and washed with water and hexane. Isolated solid weighed 2.5 gm (un-reacted atovaquone). The Hexane layer (containing product) was washed with water (2 x 50 ml); concentrated on rota evaporator under vacuum at 35-40°C. The final crude mass weighing 5.2 gm was taken for column chromatography using ethyl acetate: n-Hexane (5:95) as mobile phase. After column chromatography 2.1 gm material thus obtained was taken in 4 ml n-Hexane, cooled to -10°C for 2.0 hrs and then filtered and washed with chilled n- hexane (-10°C) suck dried initially and further product was dried on rota evaporator under vacuum at 30-35°C. The product was yellow coloured powder weighing 1.5 gm and purity 98% as estimated by HPLC.

Reference： [1]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 41; 42
[2]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 41; 42

39
[ 35295-46-6 ]
[ 95233-18-4 ]
[ 2797982-18-2 ]

Yield	Reaction Conditions	Operation in experiment
1.5 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; Stage #2: 14-Brom-tetradecansaeure-aethylester In lithium hydroxide monohydrate; butanone at 70 - 75℃;	10 harged NaHCCh (13.8 gm) and water (25 ml) at 25-30°C. The reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20 ml) charged to the reaction mass at 25-30°C. The reaction mass was stirred for 15-20 at 25-30°C to obtain red brown slurry mass. 14- Bromotetradecanoic acid ethyl ester (5.03 gm) and MEK (5 ml) charged to the reaction mass at 25-30°C. The reaction mass was stirred for 25-30 minutes at 25- 30°C to obtain red brown slurry mass. The reaction mass was refluxed for 35-40 hrs at 70-75°C. The reaction completion was monitored with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass adjusted to 3-4 with 30 ml acetic acid. 75 ml water added and sticky oily mass was stirred for 15-20 minutes at 25-30°C. It was then filtered and washed with water and hexane. The solid isolated was weighed 2.3 gm (un-reacted atovaquone). The Hexane layer (containing the product) was washed with water (2 x 50 ml). The Hexane layer was concentrated on rota evaporator under vacuum at 35-40°C. The final crude mass weighing 5.4 gm was taken for column chromatography using ethyl acetate: n-Hexane (5:95) as mobile phase. After column chromatography, 2.2 gm material thus obtained was taken in 4 ml n-Hexane, cooled to -10°C for 2.0 hrs and then filtered and washed with chilled n- hexane (-10°C). It was then subjected to suck drying and further the product was dried on rota evaporator under vacuum at 30- 35°C. The product was yellow coloured powder with net weight of 1.5 gm and purity of 98% as estimated by HPLC.
1.5 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; Stage #2: 14-Brom-tetradecansaeure-aethylester In lithium hydroxide monohydrate; butanone at 25 - 75℃;	10 harged NaHCCh (13.8 gm) and water (25 ml) at 25-30°C. The reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20 ml) charged to the reaction mass at 25-30°C. The reaction mass was stirred for 15-20 at 25-30°C to obtain red brown slurry mass. 14- Bromotetradecanoic acid ethyl ester (5.03 gm) and MEK (5 ml) charged to the reaction mass at 25-30°C. The reaction mass was stirred for 25-30 minutes at 25- 30°C to obtain red brown slurry mass. The reaction mass was refluxed for 35-40 hrs at 70-75°C. The reaction completion was monitored with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass adjusted to 3-4 with 30 ml acetic acid. 75 ml water added and sticky oily mass was stirred for 15-20 minutes at 25-30°C. It was then filtered and washed with water and hexane. The solid isolated was weighed 2.3 gm (un-reacted atovaquone). The Hexane layer (containing the product) was washed with water (2 x 50 ml). The Hexane layer was concentrated on rota evaporator under vacuum at 35-40°C. The final crude mass weighing 5.4 gm was taken for column chromatography using ethyl acetate: n-Hexane (5:95) as mobile phase. After column chromatography, 2.2 gm material thus obtained was taken in 4 ml n-Hexane, cooled to -10°C for 2.0 hrs and then filtered and washed with chilled n- hexane (-10°C). It was then subjected to suck drying and further the product was dried on rota evaporator under vacuum at 30- 35°C. The product was yellow coloured powder with net weight of 1.5 gm and purity of 98% as estimated by HPLC.

Reference： [1]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 42; 43
[2]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 42; 43

40
[ 101592-34-1 ]
[ 95233-18-4 ]
[ 2797982-19-3 ]

Yield	Reaction Conditions	Operation in experiment
1.6 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; Stage #2: 15-bromo-ethyl-pentadecanoate In lithium hydroxide monohydrate; butanone at 70 - 75℃;	11 Charged NaHCCh (13.73 gm) and water (25 ml) at 25-30°C. The reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20 ml) charged to the reaction mass at 25-30°C. The reaction mass was stirred for 15-20 at 25-30°C to obtain red brown slurry mass. 15- Bromopentadecanoic acid ethyl ester (5.24 gm) and MEK (5 ml) charged to the reaction mass at 25-30°C. The reaction mass was stirred for 25-30 minutes at 25- 30°C to obtain red brown slurry mass. The reaction mass was refluxed for 35-40 hrs at 70-75°C. The reaction completion was monitor with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with 30 ml acetic acid. 75 ml water was added and sticky oily mass was stirred for 15-20 minutes at 25-30°C. It was then fdtered and washed with water and hexane. The Solid isolated was weighed 2.5 gm (un-reacted atovaquone). The Hexane layer (containing product) was washed with water (2 x 50 ml). The Hexane layer was concentrated on rota evaporator under vacuum at 35-40°C. The final crude mass weighing 5.4 gm was taken for column chromatography using ethyl acetate: n- Hexane (5:95) as mobile phase. After column chromatography, 2.3 gm material thus obtained was taken in 4 ml n-Hexane, cooled to -10°C for 2.0 hrs and then filtered and washed with chilled n- hexane (-10°C). It was then suck dried initially and dried on rota evaporator under vacuum at 30-35°C subsequently. The product was yellow coloured powder with net weight of 1.6 gm and purity of 98% as estimated by HPLC
1.6 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; Stage #2: 15-bromo-ethyl-pentadecanoate In lithium hydroxide monohydrate; butanone at 25 - 75℃;	11 Charged NaHCCh (13.73 gm) and water (25 ml) at 25-30°C. The reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20 ml) charged to the reaction mass at 25-30°C. The reaction mass was stirred for 15-20 at 25-30°C to obtain red brown slurry mass. 15- Bromopentadecanoic acid ethyl ester (5.24 gm) and MEK (5 ml) charged to the reaction mass at 25-30°C. The reaction mass was stirred for 25-30 minutes at 25- 30°C to obtain red brown slurry mass. The reaction mass was refluxed for 35-40 hrs at 70-75°C. The reaction completion was monitor with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with 30 ml acetic acid. 75 ml water was added and sticky oily mass was stirred for 15-20 minutes at 25-30°C. It was then fdtered and washed with water and hexane. The Solid isolated was weighed 2.5 gm (un-reacted atovaquone). The Hexane layer (containing product) was washed with water (2 x 50 ml). The Hexane layer was concentrated on rota evaporator under vacuum at 35-40°C. The final crude mass weighing 5.4 gm was taken for column chromatography using ethyl acetate: n- Hexane (5:95) as mobile phase. After column chromatography, 2.3 gm material thus obtained was taken in 4 ml n-Hexane, cooled to -10°C for 2.0 hrs and then filtered and washed with chilled n- hexane (-10°C). It was then suck dried initially and dried on rota evaporator under vacuum at 30-35°C subsequently. The product was yellow coloured powder with net weight of 1.6 gm and purity of 98% as estimated by HPLC

Reference： [1]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 44; 45
[2]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 44; 45

41
[ 109557-87-1 ]
[ 95233-18-4 ]
[ 2797982-20-6 ]

Yield	Reaction Conditions	Operation in experiment
1.7 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; Stage #2: ethyl 16-bromohexadecanoate In lithium hydroxide monohydrate; butanone at 70 - 75℃;	12 Charged NaHCCh (13.8 gm) and water (25 ml) at 25-30°C. The reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20ml) charged to the reaction mass at 25-30°C. Reaction mass was stirred 15-20 at 25-30°C to obtain red brown slurry mass. 16-Bromohexadecanoic acid ethyl ester (5.45 gm) and MEK (5 ml) charged to the reaction mass at 25- 30°C. Reaction mass was stirred for 25-30 minutes at 25-30°C to obtain red brown slurry mass. The reaction mass was refluxed for 35-40 hrs at 70-75°C. The reaction completion was monitored with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass adjusted to 3-4 with 30 ml acetic acid. 75 ml water was added and sticky oily mass stirred for 15-20 minutes at 25-30°C. It was then filtered and washed with water and hexane. The solid isolated was weighed 2.5 gm (un-reacted Atovaquone). The Hexane layer (containing the product) was washed with water (2 x 50 ml). The Hexane layer was concentrated on rota evaporator under vacuum at 35-40°C. The final crude mass weighing 5.8 gm was taken for column chromatographyusing ethyl acetate: n-Hexane (5:95) as mobile phase. After column chromatography 2.6 gm material thus obtained was take in 4 ml n-Hexane, cooled to -10°C for 2.0 hrs and then filtered and washed with chilled n- hexane (-10°C). It was then suck dried initially and dried on rota evaporator under vacuum at 30-35°C subsequently. Product was yellow coloured powder with net weight of 1.7 gm and Purity of 98% as determined by HPLC.
1.7 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; Stage #2: ethyl 16-bromohexadecanoate In lithium hydroxide monohydrate; butanone at 20 - 75℃;	12 Charged NaHCCh (13.8 gm) and water (25 ml) at 25-30°C. The reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20ml) charged to the reaction mass at 25-30°C. Reaction mass was stirred 15-20 at 25-30°C to obtain red brown slurry mass. 16-Bromohexadecanoic acid ethyl ester (5.45 gm) and MEK (5 ml) charged to the reaction mass at 25- 30°C. Reaction mass was stirred for 25-30 minutes at 25-30°C to obtain red brown slurry mass. The reaction mass was refluxed for 35-40 hrs at 70-75°C. The reaction completion was monitored with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass adjusted to 3-4 with 30 ml acetic acid. 75 ml water was added and sticky oily mass stirred for 15-20 minutes at 25-30°C. It was then filtered and washed with water and hexane. The solid isolated was weighed 2.5 gm (un-reacted Atovaquone). The Hexane layer (containing the product) was washed with water (2 x 50 ml). The Hexane layer was concentrated on rota evaporator under vacuum at 35-40°C. The final crude mass weighing 5.8 gm was taken for column chromatographyusing ethyl acetate: n-Hexane (5:95) as mobile phase. After column chromatography 2.6 gm material thus obtained was take in 4 ml n-Hexane, cooled to -10°C for 2.0 hrs and then filtered and washed with chilled n- hexane (-10°C). It was then suck dried initially and dried on rota evaporator under vacuum at 30-35°C subsequently. Product was yellow coloured powder with net weight of 1.7 gm and Purity of 98% as determined by HPLC.

Reference： [1]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 45; 46
[2]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 45; 46

42
[ 50530-12-6 ]
[ 95233-18-4 ]
[ 2797982-09-1 ]

Yield	Reaction Conditions	Operation in experiment
2.2 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; for 0.166667h; Stage #2: ω-bromodecanoic acid In lithium hydroxide monohydrate; butanone Reflux;	1 Charged NaHCOi (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 10-Bromodecanoic acid (5.14 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred 30 minutes at 25-30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C, pH of reaction mass was adjusted to 3-4 with acetic acid. Colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25-30°C, final pH was 3-4. The mass was stirred for 20-30 minutes. Semisolid oily mass was filtered and subsequently washed with water (2x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml) and solvent distilled out. The weight obtained was 21 gm. Compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). Column purified product re-crystallized in n- Hexane at -10°C. Filtered at -10°C and washed with chilled n-Hexane (-10°C). Suck dried and further product was dried on rota evaporator under vacuum at 30-35°C. Pure product was yellow colour powder of weight 2.2 g and purity 97% as estimated by HPLC.
2.2 g	Stage #1: trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; butanone at 25 - 30℃; for 0.166667h; Stage #2: ω-bromodecanoic acid In lithium hydroxide monohydrate; butanone at 20 - 75℃;	1 Charged NaHCOi (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 10-Bromodecanoic acid (5.14 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred 30 minutes at 25-30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C, pH of reaction mass was adjusted to 3-4 with acetic acid. Colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25-30°C, final pH was 3-4. The mass was stirred for 20-30 minutes. Semisolid oily mass was filtered and subsequently washed with water (2x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml) and solvent distilled out. The weight obtained was 21 gm. Compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). Column purified product re-crystallized in n- Hexane at -10°C. Filtered at -10°C and washed with chilled n-Hexane (-10°C). Suck dried and further product was dried on rota evaporator under vacuum at 30-35°C. Pure product was yellow colour powder of weight 2.2 g and purity 97% as estimated by HPLC.

Reference： [1]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 28; 29
[2]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 28; 29

43
[ 95233-18-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide In lithium hydroxide monohydrate at 25 - 30℃;	13.2 Example 13: Preparation of 10-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl)oxy)-10-oxodecanoic acid. Thionyl chloride (63.7 gm) was charged under nitrogen atmosphere and cooled to 0°C. Decanedioic acid (15 gm) was charged at 0°C to 5oC under nitrogen atmosphere within 15 minutes. The reaction mass was warmed up to 25-30°C within 30 minutes. The reaction mass was refluxed for 3.0 hrs at 80-83°C. The reaction mass was a clear solution. The reaction mass was cooled to 25-30°C under nitrogen atmosphere and diluted with MDC (50 ml). Parallelly, in another 4-neck round botom flask, Atovaquone (11.39 gm) and MDC (570 ml) was charged at 25-30°C. 456 ml 10% NaOH aq. solution was added slowly to the reaction mass at 25-30°C. The reaction mass was maintained at 25-30°C for 4-5 hrs. The reaction mass colour was reddish brown biphasic. To the reaction mass, the above prepared Decanedioic acid chloride solution was added within 30 minutes drop wise under vigorous stirring and under nitrogen atmosphere at 20±2°C. The reaction mass turned to light yellowish biphasic solution and the pH of reaction mass was 10, as estimated using pH paper. The reaction mass was stirred for 1.0 hr at 25±2°C. The reaction completion was monitored with TLC and HPLC. The reaction mass pH was adjusted to 3-4 is using acetic acid. It was then stirred for 30 minutes and subsequently taken for layer separation. The aqueous layer was extracted with MDC (120 ml). Combined organic layer was filtered to remove un-reacted decanedioic acid. The organic layer was washed with water till the neutral pH of 7 was attained. The organic layer was taken for distillation. The crude product thus obtained was weighed 20 gm. The crude product was taken for column chromatography. The mobile phase was Methanol: MDC (1:99). The Product was pale yellow coloured powder and the net weight was 8 gm and purity 98% as estimated using HPLC.

Reference： [1]Current Patent Assignee: IPCA LABORATORIES LIMITED - WO2022/144920, 2022, A1 Location in patent: Page/Page column 47; 48

44
[ 95233-18-4 ]
[ 2797982-21-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydroxide / lithium hydroxide monohydrate / 25 - 30 °C 2: 1 h / 20 - 25 °C / Inert atmosphere