14869-41-1

Usage

Chemical Properties

Light Yellow Oil

Uses

A metabolite of Bis(2-chloroethyl) Ether.

InChI:InChI=1/C4H7ClO3/c5-1-2-8-3-4(6)7/h1-3H2,(H,6,7)

Synthetic route

1,4-dioxane (123-91-1) → (2-chloroethoxy)-acetic acid (14869-41-1)

Conditions	Yield
With dipotassium peroxodisulfate; thionyl chloride at 25℃; for 4h;	96.1%
With hydrogenchloride; sodium hypochlorite

tert-butyl 2-(2-chloroethoxy)acetate → (2-chloroethoxy)-acetic acid (14869-41-1)

Conditions	Yield
With hydrogenchloride; water for 2h;	95%

(2-chloro-ethoxy)-acetic acid ethyl ester (17229-14-0) → (2-chloroethoxy)-acetic acid (14869-41-1)

Conditions	Yield
With sodium hydroxide In tetrahydrofuran	90%

2-(2-Chloroethoxy)ethanol (628-89-7) → (2-chloroethoxy)-acetic acid (14869-41-1)

Conditions	Yield
With chromium(VI) oxide; sulfuric acid In acetone at 0℃; for 6h;	77%
With sodium periodate; ruthenium trichloride In water; acetonitrile at 20℃; for 16h;	74%
Stage #1: 2-(2-Chloroethoxy)ethanol With calcium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate In dichloromethane; water at 20℃; for 0.5h; Stage #2: With sodium metabisulfite In dichloromethane; water	72%

2-chloroethyl cyanomethyl ether (31250-08-5) → (2-chloroethoxy)-acetic acid (14869-41-1)

Conditions	Yield
With hydrogenchloride

carbon dioxide (124-38-9) + (2-chloroethoxy)magnesium chloride (821-50-1) → (2-chloroethoxy)-acetic acid (14869-41-1)

Conditions	Yield
In tetrahydrofuran at -60℃;

1-chloro-2-(2-nitro-ethoxy)-ethane (28547-59-3) → (2-chloroethoxy)-acetic acid (14869-41-1)

Conditions	Yield
With hydrogenchloride

diethylene glycol (111-46-6) → (2-chloroethoxy)-acetic acid (14869-41-1)

Conditions	Yield
With hydrogenchloride; sodium hypochlorite

(2-chloroethoxy)-acetic acid (14869-41-1) + 4-fluoro-2-methoxy-5-nitro-phenylamine (1075705-01-9) → 2-(2-chloroethoxy)-N-(4-fluoro-2-methoxy-5-nitrophenyl)acetamide

Conditions	Yield
With dmap; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide	99%

brecanavir (313682-08-5) + (2-chloroethoxy)-acetic acid (14869-41-1) → (1R,2S)-2-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-1-{[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]methyl}-3-{4-[(2-methyl-1,3-thiazol-4-yl)methoxy]phenyl}propyl (2-chloroethoxy)acetate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 24h;	92%

(2-chloroethoxy)-acetic acid (14869-41-1) + butan-1-ol (71-36-3) → 2-Chlor-aethoxyesssigsaeure-butylester (68448-72-6)

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane Ambient temperature;	91%

(2-chloroethoxy)-acetic acid (14869-41-1) + 2-(1-aminopiperidin-4-yl)isoindoline-1,3-dione → 2-(2-chloroethoxy)-N-(4-(1,3-dioxoisoindolin-2-yl)piperidin-1-yl)acetamide

Conditions	Yield
Stage #1: (2-chloroethoxy)-acetic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 30℃; for 0.333333h; Stage #2: 2-(1-aminopiperidin-4-yl)isoindoline-1,3-dione In N,N-dimethyl-formamide at 30℃; for 16h;	89.3%

(2-chloroethoxy)-acetic acid (14869-41-1) → 2-(2-chloroethoxy)acetyl chloride (39229-33-9)

Conditions	Yield
With thionyl chloride In N,N-dimethyl-formamide	88%
With thionyl chloride; N,N-dimethyl-formamide at 25 - 70℃; for 20h;	83%
With thionyl chloride; N,N-dimethyl-formamide at 60℃; for 1 - 16h; Product distribution / selectivity;	82%

(2-chloroethoxy)-acetic acid (14869-41-1) + (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → levocetirizine (130018-77-8)

Conditions	Yield
With tetrabutylammomium bromide; sodium hydride In N,N-dimethyl-formamide at 95℃; for 5h; Inert atmosphere;	86.5%

(2-chloroethoxy)-acetic acid (14869-41-1) + 4-nitro-aniline (100-01-6) → 4-(2-(2-chloroethoxy)acetamido)1-nitrobenzene (811450-82-5)

Conditions	Yield
With phenylboronic acid In toluene at 110 - 111℃; Dean-Stark; Reflux;	83%

(2-chloroethoxy)-acetic acid (14869-41-1) + methyl 5-(((allyloxy)carbonyl)(1-aminopiperidin-4-yl)carbamoyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate → methyl 5-(((allyloxy)carbonyl)(1-(2-(2-chloroethoxy)acetamido)piperidin-4-yl)carbamoyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 16.5h;	79%

(2-chloroethoxy)-acetic acid (14869-41-1) + (S)-5-[2-[3-(3-chloro-2-fluorophenyl)-1H-pyrazole-3-carboxamido]-3-(4-aminophenyl)-propionamido] -1H-indole-2-carboxylic acid ethyl ester → (S)-ethyl 5-(2-(5-(3-chloro-2-fluorophenyl)-1H-pyrazole-3-carboxamido)-3-(4-(3-oxomorpholino)phenyl)-propanamido)-1H-indole-2-carboxylate

Conditions	Yield
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In tetrahydrofuran at 60℃; for 4h;	76%
Stage #1: (2-chloroethoxy)-acetic acid; (S)-5-[2-[3-(3-chloro-2-fluorophenyl)-1H-pyrazole-3-carboxamido]-3-(4-aminophenyl)-propionamido] -1H-indole-2-carboxylic acid ethyl ester With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In tetrahydrofuran at 60℃; for 4h; Inert atmosphere; Stage #2: With sodium hydride In tetrahydrofuran at 20 - 30℃; for 5h; Inert atmosphere;	76%

(2-chloroethoxy)-acetic acid (14869-41-1) + (S)-2-{4-[(methoxycarbonyl)amino]benzamido}-3-(4-aminophenyl)propionic acid methyl ester → (S)-2-(4-((methoxycarbonyl)amino)benzamido)-3-(4-(3-oxomorpholin-4-yl)phenyl)propionic acid methyl ester

Conditions	Yield
Stage #1: (2-chloroethoxy)-acetic acid; (S)-2-{4-[(methoxycarbonyl)amino]benzamido}-3-(4-aminophenyl)propionic acid methyl ester With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In tetrahydrofuran at 60℃; for 4h; Stage #2: With sodium hydride In tetrahydrofuran at 20℃; for 5h;	76%

(2-chloroethoxy)-acetic acid (14869-41-1) + 2-bromo-4-fluoro-5-nitrophenylamine (346433-97-4) → N-(2-bromo-4-fluoro-5-nitrophenyl)-2-(2-chloroethoxy)acetamide

Conditions	Yield
Stage #1: (2-chloroethoxy)-acetic acid With pyridine; thionyl chloride In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-bromo-4-fluoro-5-nitrophenylamine With dmap; triethylamine In dichloromethane at 20℃; for 18h; Inert atmosphere;	51%

(2-chloroethoxy)-acetic acid (14869-41-1) + ethyl 6-(3-amino-3-azabicyclo[3.1.0]hexan-6-yl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate → ethyl 6-(3-(2-(2-chloroethoxy)acetamido)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Conditions

Yield

Stage #1: (2-chloroethoxy)-acetic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 0.5h; Stage #2: ethyl 6-(3-amino-3-azabicyclo[3.1.0]hexan-6-yl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate In dichloromethane at 25℃; for 16h;

50%

piperazine (110-85-0) + (2-chloroethoxy)-acetic acid (14869-41-1) + piperazine dihydrochloride (142-64-3) → 2-(1-piperazinyl)ethoxyacetic acid dihydrochloride

Conditions	Yield
With ammonium acetate; hydrogenchloride In ethanol; water; isopropyl alcohol	12%

(2-chloroethoxy)-acetic acid (14869-41-1) → p-dioxanone (3041-16-5)

Conditions	Yield
With sodium hydroxide unter vermindertem Druck;

methanol (67-56-1) + (2-chloroethoxy)-acetic acid (14869-41-1) → (2-Chloro-ethoxy)-acetic acid methyl ester (83881-47-4)

Conditions	Yield
With thionyl chloride

(2-chloroethoxy)-acetic acid (14869-41-1) + (2R)-2-[(2R)-4-(4-aminophenyl)-3-oxomorpholin-2-yl]-N-(4-cyanophenyl)-2-hydroxyacetamde (1228772-75-5) → (2R)-N-(4-cyanophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-[4-(3-oxomorpholin-4-yl)phenyl]morpholin-2-yl]acetamide (1228772-88-0)

Conditions	Yield
With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In N,N-dimethyl-formamide at 20℃;

(2-chloroethoxy)-acetic acid (14869-41-1) → 4-chloro-2-oxabutanyl-1-phosphonic acid (1391871-33-2)

Conditions	Yield
With phosphorus(III) oxide; methanesulfonic acid at 20 - 30℃; for 2h;
Stage #1: (2-chloroethoxy)-acetic acid With phosphorus trichloride In chlorobenzene at 50℃; for 4h; Inert atmosphere; Stage #2: With water In chlorobenzene Inert atmosphere;

(2-chloroethoxy)-acetic acid (14869-41-1) + C22H28N6O2S2 → C26H33ClN6O4S2

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; acetonitrile at 0 - 25℃; for 18h;	484 mg

(2-chloroethoxy)-acetic acid (14869-41-1) + 6-(1-aminopiperidin-4-yl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one → 2-(2-chloroethoxy)-N-(4-(7-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)piperidin-1-yl)acetamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 12℃; for 16h;	2.8 g

(2-chloroethoxy)-acetic acid (14869-41-1) + 6-(1-aminopiperidin-4-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one → 2-(2-chloroethoxy)-N-(4-(1-(4-methoxyphenyl)-7-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)piperidin-1-yl)acetamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 16h;	900 mg

(2-chloroethoxy)-acetic acid (14869-41-1) + ethyl 6-(1-aminopiperidin-4-yl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3, 4-c]pyridine-3-carboxylate → ethyl 6-(1-(2-(chloromethoxy)acetamido)piperidin-4-yl)-1-(4-methoxyphenyl)-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 12h;

Upstream product

• 31250-08-5 2-chloroethyl cyanomethyl ether 
• 111-46-6 diethylene glycol 
• 628-89-7 2-(2-Chloroethoxy)ethanol 
• 17229-14-0 (2-chloro-ethoxy)-acetic acid ethyl ester 
• 123-91-1 1,4-dioxane 
• 28547-59-3 1-chloro-2-(2-nitro-ethoxy)-ethane 
• 124-38-9 carbon dioxide 
• 821-50-1 (2-chloroethoxy)magnesium chloride 

Downstream Products

• 811450-82-5 4-(2-(2-chloroethoxy)acetamido)1-nitrobenzene 
• 130018-77-8 levocetirizine 
• 1228772-88-0 (2R)-N-(4-cyanophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-[4-(3-oxomorpholin-4-yl)phenyl]morpholin-2-yl]acetamide 
• 83881-47-4 (2-Chloro-ethoxy)-acetic acid methyl ester 
• 3041-16-5 p-dioxanone 
• 39229-33-9 2-(2-chloroethoxy)acetyl chloride 

Relevant academic research and scientific papers

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Preparation method of levocetirizine

The invention provides a preparation method of levocetirizine. The preparation method comprises following steps: carrying out a reaction on a compound represented by a formula (I) under the action ofa reduction system and L-tartaric acid to obtain a compound represented by a formula (II); and reacting the compound shown in a formula (II) with a compound shown in a formula (III) under the action of NaH, N,N-dimethyl formamide and tetrabutyl ammonium bromide to obtain levocetirizine. The levocetirizine is prepared by taking the compound shown by the formula (I) and the compound shown by the formula (III) as raw materials, at first, the compound shown by the formula (I) is de-protected and then racemized to obtain the compound shown by the formula (II); and the compound shown by the formula(II) and the compound shown by the formula (III) carry out reactions to obtain levocetirizine. The provided method is short in reaction route, the yield can reach 54% or above, and the purity can reach 99.65% at most.

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PROCESS FOR PRODUCING 3-ACYLAMINOBENZOFURAN-2-CARBOXYLIC ACID DERIVATIVE

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Catalytic enantioselective synthesis of the second generation histamine antagonist cetirizine hydrochloride

The first enantioselective synthesis of cetirizine hydrochloride (1) has been developed using the highly stereospecific chiral oxazaborolidine (CBS) reduction of 4-[η6-chromium tricarbonylbenzoyl]chlorobenzene to establish the benzhydryl stereocenter. The chromium tricarbonyl unit also served as stereocontroller to allow the stereospecific displacement of hydroxyl by amino at the benzylic stereocenter, as outlined in Scheme 1.