[ CAS No. 38076-80-1 ]

Name: 38076-80-1|5-Chloro-2-hydroxynicotinic acid|97%
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Quality Control of [ 38076-80-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 38076-80-1 ]

SDS Specification

Alternatived Products of [ 38076-80-1 ]

Product Details of [ 38076-80-1 ]

CAS No. :	38076-80-1	MDL No. :	MFCD00204158
Formula :	C₆H₄ClNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XBHXNMLFJZTSAS-UHFFFAOYSA-N
M.W :	173.55	Pubchem ID :	162286
Synonyms :

Calculated chemistry of [ 38076-80-1 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	38.23
TPSA :	70.42 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.27 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.0
Log Po/w (XLOGP3) :	1.54
Log Po/w (WLOGP) :	1.14
Log Po/w (MLOGP) :	-0.69
Log Po/w (SILICOS-IT) :	0.92
Consensus Log Po/w :	0.78

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.22
Solubility :	1.04 mg/ml ; 0.00597 mol/l
Class :	Soluble
Log S (Ali) :	-2.63
Solubility :	0.409 mg/ml ; 0.00235 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.44
Solubility :	6.36 mg/ml ; 0.0366 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.51

Safety of [ 38076-80-1 ]

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

Application In Synthesis of [ 38076-80-1 ]

* 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 [ 38076-80-1 ]
Downstream synthetic route of [ 38076-80-1 ]

[ 38076-80-1 ] Synthesis Path-Upstream 1~5

1
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Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: With thionyl chloride In DMF (N,N-dimethyl-formamide) for 3 h; Heating / reflux Stage #2: at 0℃; for 1.25 h; Heating / reflux	A suspension of 5-chloro-2-hydroxy-nicotinic acid (70) (6 g, 3.46 mmol) in thionyl chloride (200 mL) and DMF (1 mL) was refluxed for 3 h to yield a clear solution. The solution was cooled and the excess thionyl chloride was evaporated under vacuum. The residue was cooled in an ice bath and cold anhydrous methanol was added slowly. After stirring 15 min at 0 °C, the solution was refluxed for 1 h under argon. The solution was cooled and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate and washed subsequently by saturated NAHCO3 solution, water and brine. The organic phase was dried over MGS04 and evaporated to yield 4.3 g (60 percent) of 2,5-dichloro-nicotinic acid methyl ester (71) as colorless viscous OIL. IH-NMR (DMSO-d6): d 3.88 (s, 3H), 8.39 (d, J= 2.8 Hz, 1H), 8. 70 (d, J= 2.8 Hz, 1H) ; EIMS M/Z 206 (M).

Reference： [1] Patent: WO2005/21546, 2005, A1, . Location in patent: Page/Page column 121; 187

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[ 67754-03-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 18, p. 2676 - 2688

3
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[ 59782-85-3 ]

Reference： [1] Synthetic Communications, 1989, vol. 19, # 3and4, p. 553 - 560

4
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[ 38076-80-1 ]

Yield	Reaction Conditions	Operation in experiment
95.6%	With hydrogenchloride; sodium hydroxide; sodium hypochlorite; chlorine; sodium hydrogensulfite In water; acetone	EXAMPLE 7 5-Chloro-2-hydroxy-3-pyridinecarboxylic acid Sodium hypochlorite solution was prepared by first adding 35.41 kg (442.6 mole) of 50percent sodium hydroxide solution to 44 kg of flaked ice in a jacketed vessel having external circulating coolant; then adding 61.6 kg more flaked ice and introducing 7.87 kg (110.9 mole) of chlorine below the surface, all with agitation. To the sodium hypochlorite solution was added, portionwise, 15.0 kg of 98percent purity (105.7 mole) 2-hydroxynicotinic acid (solids). The reaction temperature rose to 35° C. during the addition of the solids. Coolant was removed from the jacket and the mixture was stirred overnight at room temperature. A sample was withdrawn and acidified with concentrated hydrochloric acid to give precipitate which when analyzed by ¹ H-NMR showed 75:25 ratio of title compound to starting 2-hydroxynicotinic acid. A second solution of sodium hypochlorite prepared as above from 10.57 kg of 50percent sodium hydroxide solution (132.1 mole), 29.1 kg of ice and 3.65 kg (51.5 mole) of chlorine was added to the reaction mixture and the mixture was stirred overnight. This time a sample precipitated with concentrated hydrochloric acid showed no starting 2-hydroxynicotinic acid was present. Sodium bisulfite, 208 g (2.0 mole) was added to decompose unreacted excess sodium hypochlorite. Seven liters of isopropyl alcohol was then added to reduce expected foaming in the next step. The reaction mixture was added slowly to 41.48 kg (34.9 liters, 419.3 mole) of concentrated hydrochloric acid using external cooling to keep the mixture at 15°-25° C. pH of the mixture was 1.0. The slurry was filtered and the filter cake was washed with about 20 liters of water followed by 7 liters of acetone. The crystals were dried at 100° F. to a water content of about 5percent; then milled and redried at 120° F. to a water content of 0.4percent. The amount of crystals obtained was 17.42 kg (95.6percent yield). ¹ H-NMR analysis as described in Example 3 showed a trace of 3,5-dichloro-2-hydroxypyridine was present.
78%	Stage #1: With sodium hydroxide; sodium hypochlorite In water at 20℃; for 48 h; Stage #2: With sodium sulfite In water at 20℃; for 0.5 h;	Sodium hypochlorite (14 percent available chlorine, 35 mL, 82.21 mmol) solution was added to a stirred solution of 2-hydroxynicotinic acid (7 g, 50. 3 mmol) in 10 percent aqueous NaOH solution. The solution was stirred for 48 h at room temperature. An aqueous solution of sodium sulfite (3.150g, 25 mmol) was added and further stirred for 30 min at room temperature. The solution was diluted by cold water and pH was adjusted to 2 by cold dilute HCI. The solids formed were filtered, washed by cold water and dried to yield 6.8 g (78 percent) OF 5-CHLORO-2-HYDROXY-NICOTINIC acid (70) as white solids. MP: 276 °C ; 1H-NMR (DMSO-d6): d 8.23 (d, J= 2.8 Hz, 1H), 8.29 (d, J= 2.8 Hz, 1H); EIMS : 174 (M+1).
85%	With hydrogenchloride; sodium hydroxide; sodium hydrogensulfite In water; chlorine; acetone	EXAMPLE 3 5-Chloro-2-hydroxy-3-pyridinecarboxylic acid 2-Hydroxynicotinic acid was chlorinated in aqueous solution by using 2 additions in sequence (time interval between) of freshly prepared aqueous sodium hypochlorite solution resulting from reaction of chlorine and excess sodium hydroxide. The overall molar ratio of hydroxynicotinic acid:sodium hypochlorite:excess hydroxide in the chlorinating reaction was about 1:1.5:2.4 considering the totals in both additions. The detailed procedure used was as follows: Sodium hydroxide, 10.05 kg of 50percent solution (125.6 mole) in 30 kg of ice was treated with bubbling chlorine gas while stirring until 2.22 kg (31.3 mole) of chlorine was taken into the solution. To the resulting basic sodium hypochlorite solution was added 4.26 kg (30 mole) of 2-hydroxynicotinic acid. External cooling with tap-water was used to keep the temperature between 20°-35° C. Stirring was continued over the weekend (72 hr) after which time ¹³ C-NMR analysis showed that about 70percent of the 2-hydroxynicotinic acid was chlorinated. Another solution of basic sodium hypochlorite solution was prepared by the above procedure by absorbing 1.05 kg (14.8 mole) of chlorine gas in a mixture of 3.0 kg of 50percent solution (37.5 mole) of sodium hydroxide and 8.3 kg of ice. This hypochlorite solution was added to the main reaction mixture and stirring was continued for about 12 hr, after which time ¹³ C-NMR indicated no 2-hydroxynicotinic acid remained. A solution of 104 g (1.0 mole) of sodium bisulfite in 300 ml of water was added to destroy the remaining sodium hypochlorite. The reaction mixture was added gradually to 9.9 liters (119 mole) of concentrated hydrochloric acid containing 2 liters of isopropyl alcohol (to control foam), keeping temperature between 13°-23° C. The mixture was cooled and the precipitate was collected by filtration, washing with a small amount of water followed by 2 liters of acetone. The precipitate was dried to give 4.44 kg (85percent) of the title compound, m.p. starts at 245° C. and decomposes at 250° C. Analysis of the ¹ H-NMR chart showed that approximately 4percent of the product was 3,5-dichloro-2-hydroxypyridine. This was done by ¹ H-NMR (DMSO-d₆ ppm), integrating the area under the curves to determine relative amounts under the appropriate signals which are for 2-hydroxy-5-chloronicotinic acid: 8.25 (multiplet) and for 3,5-dichloro-2-hydroxypyridine: 7.90 to 7.60 (quartet).

Reference： [1] Patent: US4960896, 1990, A,
[2] Synthetic Communications, 1989, vol. 19, # 3and4, p. 553 - 560
[3] Patent: WO2005/21546, 2005, A1, . Location in patent: Page/Page column 121; 186-187
[4] Journal of Medicinal Chemistry, 1993, vol. 36, # 18, p. 2676 - 2688
[5] Patent: US4960896, 1990, A,
[6] Patent: US4960896, 1990, A,

5
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Yield	Reaction Conditions	Operation in experiment
81.8%	With hydrogenchloride; sodium hydroxide In sodium hypochlorite; water	EXAMPLE 5 5-Chloro-2-hydroxy-3-pyridinecarboxylic acid To an agitated solution of 216.0 g of sodium hydroxide pellets in 2.25 liters of 5percent (1.51 moles) sodium hypochlorite solution was added 150.1 g (1.08 mole) of 2-hydroxynicotinic acid. Temperature of the reaction mixture was 20° C. Four hours later 750 ml of 5percent (0.50 mole) of sodium hypochlorite solution was added and stirring was continued overnight. The reaction mixture was mixed with 12N hydrochloric acid in an agitated vessel in such a manner that the receiving solution was always strongly acid and temperature was kept below 20° C. with an ice bath. The amount of 12N acid used was 600 ml. The mixture was readily filtered on a sintered glass suction funnel. The crystalline filter cake was washed with 800 ml of water followed by 800 ml of 1:1 isopropyl ether/isopropyl alcohol. Crystals were powdery when dry. The weight of dry crystals was 153.2 g (81.8percent yield). Analysis by ¹ H-NMR showed the dried product contained no starting material and contained about 5percent of 3,5-dichloro-2-hydroxypyridine. See Example 3 for method of computing impurity.
76.6%	With hydrogenchloride; sodium hydroxide In sodium hypochlorite; water	EXAMPLE 6 5-Chloro-2-hydroxy-3-pyridinecarboxylic acid To an agitated solution of 216.0 g of sodium hydroxide pellets in 2.25 liters of 5percent (1.51 moles) of sodium hypochlorite solution was added 150.4 g of 2-hydroxynicotinic acid. Temperature of the reaction mixture was 19° C. Three hours later 750 ml (0.50 mole) of sodium hypochlorite was added and stirring was continued overnight. The reaction mixture was mixed with 12N hydrochloric acid in an agitated vessel in such a manner that the receiving solution was always strongly acid and temperature was kept below 20° C. with an ice bath. The amount of 12N acid used was 600 ml. The mixture was readily filtered on a sintered glass suction funnel. The crystalline filter cake was washed with 600 ml of water followed by 800 ml of 1:1 isopropyl ether/isopropyl alcohol. Weight of the dry crystals was 143.5 g (76.6percent yield). Analysis by ¹ H-NMR analysis showed the dried product contained no starting material and about 5percent 3,5 -dichloro-2-hydroxypyridine. See Example 3 for method of computing impurity.

Reference： [1] Patent: US4960896, 1990, A,
[2] Patent: US4960896, 1990, A,

[ 38076-80-1 ] Synthesis Path-Downstream 1~18

1
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Yield	Reaction Conditions	Operation in experiment
95.6%	With hydrogenchloride; sodium hydroxide; sodium hypochlorite; chlorine; sodium hydrogensulfite; In water; acetone;	EXAMPLE 7 5-Chloro-2-hydroxy-3-pyridinecarboxylic acid Sodium hypochlorite solution was prepared by first adding 35.41 kg (442.6 mole) of 50% sodium hydroxide solution to 44 kg of flaked ice in a jacketed vessel having external circulating coolant; then adding 61.6 kg more flaked ice and introducing 7.87 kg (110.9 mole) of chlorine below the surface, all with agitation. To the sodium hypochlorite solution was added, portionwise, 15.0 kg of 98% purity (105.7 mole) 2-hydroxynicotinic acid (solids). The reaction temperature rose to 35 C. during the addition of the solids. Coolant was removed from the jacket and the mixture was stirred overnight at room temperature. A sample was withdrawn and acidified with concentrated hydrochloric acid to give precipitate which when analyzed by 1 H-NMR showed 75:25 ratio of title compound to starting 2-hydroxynicotinic acid. A second solution of sodium hypochlorite prepared as above from 10.57 kg of 50% sodium hydroxide solution (132.1 mole), 29.1 kg of ice and 3.65 kg (51.5 mole) of chlorine was added to the reaction mixture and the mixture was stirred overnight. This time a sample precipitated with concentrated hydrochloric acid showed no starting 2-hydroxynicotinic acid was present. Sodium bisulfite, 208 g (2.0 mole) was added to decompose unreacted excess sodium hypochlorite. Seven liters of isopropyl alcohol was then added to reduce expected foaming in the next step. The reaction mixture was added slowly to 41.48 kg (34.9 liters, 419.3 mole) of concentrated hydrochloric acid using external cooling to keep the mixture at 15-25 C. pH of the mixture was 1.0. The slurry was filtered and the filter cake was washed with about 20 liters of water followed by 7 liters of acetone. The crystals were dried at 100 F. to a water content of about 5%; then milled and redried at 120 F. to a water content of 0.4%. The amount of crystals obtained was 17.42 kg (95.6% yield). 1 H-NMR analysis as described in Example 3 showed a trace of 3,5-dichloro-2-hydroxypyridine was present.
78%		Sodium hypochlorite (14 % available chlorine, 35 mL, 82.21 mmol) solution was added to a stirred solution of 2-hydroxynicotinic acid (7 g, 50. 3 mmol) in 10 % aqueous NaOH solution. The solution was stirred for 48 h at room temperature. An aqueous solution of sodium sulfite (3.150g, 25 mmol) was added and further stirred for 30 min at room temperature. The solution was diluted by cold water and pH was adjusted to 2 by cold dilute HCI. The solids formed were filtered, washed by cold water and dried to yield 6.8 g (78 %) OF 5-CHLORO-2-HYDROXY-NICOTINIC acid (70) as white solids. MP: 276 C ; 1H-NMR (DMSO-d6): d 8.23 (d, J= 2.8 Hz, 1H), 8.29 (d, J= 2.8 Hz, 1H); EIMS : 174 (M+1).
4.44 kg (85%)	With hydrogenchloride; sodium hydroxide; sodium hydrogensulfite; In water; chlorine; acetone;	EXAMPLE 3 5-Chloro-2-hydroxy-3-pyridinecarboxylic acid 2-Hydroxynicotinic acid was chlorinated in aqueous solution by using 2 additions in sequence (time interval between) of freshly prepared aqueous sodium hypochlorite solution resulting from reaction of chlorine and excess sodium hydroxide. The overall molar ratio of hydroxynicotinic acid:sodium hypochlorite:excess hydroxide in the chlorinating reaction was about 1:1.5:2.4 considering the totals in both additions. The detailed procedure used was as follows: Sodium hydroxide, 10.05 kg of 50% solution (125.6 mole) in 30 kg of ice was treated with bubbling chlorine gas while stirring until 2.22 kg (31.3 mole) of chlorine was taken into the solution. To the resulting basic sodium hypochlorite solution was added 4.26 kg (30 mole) of 2-hydroxynicotinic acid. External cooling with tap-water was used to keep the temperature between 20-35 C. Stirring was continued over the weekend (72 hr) after which time 13 C-NMR analysis showed that about 70% of the 2-hydroxynicotinic acid was chlorinated. Another solution of basic sodium hypochlorite solution was prepared by the above procedure by absorbing 1.05 kg (14.8 mole) of chlorine gas in a mixture of 3.0 kg of 50% solution (37.5 mole) of sodium hydroxide and 8.3 kg of ice. This hypochlorite solution was added to the main reaction mixture and stirring was continued for about 12 hr, after which time 13 C-NMR indicated no 2-hydroxynicotinic acid remained. A solution of 104 g (1.0 mole) of sodium bisulfite in 300 ml of water was added to destroy the remaining sodium hypochlorite. The reaction mixture was added gradually to 9.9 liters (119 mole) of concentrated hydrochloric acid containing 2 liters of isopropyl alcohol (to control foam), keeping temperature between 13-23 C. The mixture was cooled and the precipitate was collected by filtration, washing with a small amount of water followed by 2 liters of acetone. The precipitate was dried to give 4.44 kg (85%) of the title compound, m.p. starts at 245 C. and decomposes at 250 C. Analysis of the 1 H-NMR chart showed that approximately 4% of the product was 3,5-dichloro-2-hydroxypyridine. This was done by 1 H-NMR (DMSO-d6 ppm), integrating the area under the curves to determine relative amounts under the appropriate signals which are for 2-hydroxy-5-chloronicotinic acid: 8.25 (multiplet) and for 3,5-dichloro-2-hydroxypyridine: 7.90 to 7.60 (quartet).

With sodium hydroxide; In sodium hypochlorite;

EXAMPLE 4 5-Chloro-2-hydroxy-3-pyridinecarboxylic acid To an agitated solution of 216.0 g (5.4 mole) of sodium hydroxide pellets in 2.25 liters of 5% (1.51 moles) sodium hypochlorite solution was added 150.0 g (1.08 mole) of 2-hydroxynicotinic acid. Temperature of the mixture was 20-32 C. After 4 hr mass spectrographic analysis showed some starting 2-hydroxynicotinic acid was present. An additional liter of 5% (0.67 moles) of sodium hypochlorite solution was added and stirring was continued overnight. Starting 2-hydroxynicotinic acid was no longer present. Slow acidification with 690 ml of concentrated of the reaction mixture under agitation over a 1.25 hr period resulted in conversion to a mass of porous fluffy salt crystals.

Reference： [1]Patent: US4960896,1990,A
[2]Synthetic Communications,1989,vol. 19,p. 553 - 560
[3]Patent: WO2005/21546,2005,A1 .Location in patent: Page/Page column 121; 186-187
[4]Journal of Medicinal Chemistry,1993,vol. 36,p. 2676 - 2688
[5]Patent: US4960896,1990,A
[6]Patent: US4960896,1990,A

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Reference： [1]Synthetic Communications,1989,vol. 19,p. 553 - 560

3
[ 38076-80-1 ]
[ 78686-87-0 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2676 - 2688
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 2137 - 2146

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[ 67754-03-4 ]