2214-72-4

Basic information

• Product Name: N,N'-bis-(2-Chloroethyl)urea
• Synonyms: Carmustine Related Compound A (10 mg) (1,3-bis(2-chloroethyl)urea);CarMustine Related CoMpound A;BCU;NSC 36198
• CAS NO: 2214-72-4
• Molecular Formula: C₅H₁₀Cl₂N₂O
• Molecular Weight: 185.05
• Product Categories: Mutagenesis Research Chemicals
• Mol File: 2214-72-4.mol
• Article Data: 8

Chemical Properties

• Melting Point: 128-129 °C
• Boiling Point: 358.2 °C at 760 mmHg
• Flash Point: 170.4 °C
• Appearance: /
• Density: 1.245 g/cm³
• PKA: 12.99±0.46(Predicted)
• CAS DataBase Reference: N,N'-bis-(2-Chloroethyl)urea(CAS DataBase Reference)
• NIST Chemistry Reference: N,N'-bis-(2-Chloroethyl)urea(2214-72-4)
• EPA Substance Registry System: N,N'-bis-(2-Chloroethyl)urea(2214-72-4)

Safety Data

• Hazardous Substances Data: 2214-72-4(Hazardous Substances Data)

Usage

Uses

1,3-Bis(2-chloroethyl)urea is an impurity in the synthesis of Carmustine (C183875), an alkylating and carbamoylating nitrosourea compound. It interacts with DNA, RNA and proteins causing DNA interstrand cross linking which is cytotoxic and leads to apoptotic cell death.

Synthetic route

N-(2-chloroethyl)-1H-imidazole-1-carboxamide + 2-chloroethanamine hydrochloride (870-24-6) → 1,3-bis(2-chloroethyl)urea (2214-72-4)

Conditions	Yield
With potassium carbonate In tetrahydrofuran at 40℃; for 4h; Reagent/catalyst; Time; Temperature;	87.2%

2-chloroethyl isothiocyanate (1943-83-5) + chloroethylamine (689-98-5) → 1,3-bis(2-chloroethyl)urea (2214-72-4)

Conditions	Yield
In dichloromethane 1) 0 deg C, 20 min; 2) room temperature, 18 h;	82%
In diethyl ether Ambient temperature;

di(succinimido) carbonate (74124-79-1) + 2-chloroethanamine hydrochloride (870-24-6) → 1,3-bis(2-chloroethyl)urea (2214-72-4) + N-(2-chloroethyl)carbamic acid N'-hydroxysuccinimide ester (80354-45-6)

Conditions	Yield
With triethylamine In acetonitrile Ambient temperature;	A n/a B 61.5%

2-chloroethanamine hydrochloride (870-24-6) + 1,1'-carbonyldiimidazole (530-62-1) → 1,3-bis(2-chloroethyl)urea (2214-72-4)

Conditions	Yield
With sodium hydroxide In water at 0 - 45℃; pH=8;	57.7%
In tetrahydrofuran at 0 - 30℃; for 36.0833h; Temperature; Inert atmosphere; Large scale;	6 kg
With triethylamine at 10 - 40℃; for 2h;	13 g

ethyleneimine (151-56-4) + phosgene (75-44-5) → 1,3-bis(2-chloroethyl)urea (2214-72-4)

2-chloroethyl isothiocyanate (1943-83-5) → 1,3-bis(2-chloroethyl)urea (2214-72-4)

Conditions	Yield
With water; acetone
With water
With nitromethane; acetone; acetonitrile In N,N-dimethyl-formamide

1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8) → 1,3-bis(2-chloroethyl)urea (2214-72-4) + 2-<(2-chloroethyl)amino>-2-oxazoline (71353-16-7) + 1-(2-chloroethyl)imidazolidin-2-one (2387-20-4) + ethanol (64-17-5) + ethylamine (75-04-7)

Conditions	Yield
With potassium hydroxide; aluminum nickel In methanol Product distribution; Mechanism; degradation under various conditions (HBr in glac. CH3CO2H) with preparation of nonmutagenic reaction mixtures of products;

N,N'-bis(2-hydroxyethyl)urea (15438-70-7) → 1,3-bis(2-chloroethyl)urea (2214-72-4)

Conditions	Yield
With thionyl chloride at 20℃; Large scale;	5.02 kg

1,3-bis(2-chloroethyl)urea (2214-72-4) → 1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8)

Conditions	Yield
With tin(IV) chloride; sodium nitrite In dichloromethane at 20℃; for 2h;	100%
With formic acid; sodium nitrite In dichloromethane; water at 0 - 3℃; for 1h;	87%
With formic acid; sodium nitrite

1,3-bis(2-chloroethyl)urea (2214-72-4) → 2-<(2-chloroethyl)amino>-2-oxazoline (71353-16-7)

Conditions	Yield
In water Heating;	72%

1,3-bis(2-chloroethyl)urea (2214-72-4) → N,N'-Bis-<2-iod-ethyl>-harnstoff (13908-87-7)

Conditions	Yield
With sodium iodide
With sodium iodide In acetone Heating;

1,3-bis(2-chloroethyl)urea (2214-72-4) → 2-<(2-chloroethyl)amino>-2-oxazoline hydrochloride (73771-48-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 72 percent / H2O / Heating 2: 45 percent / n-butyl nitrite, sodium methoxide / diethyl ether / 12 h / Ambient temperature 3: HCl(g) / diethyl ether / 0.5 h / 0 - 4 °C View Scheme

1,3-bis(2-chloroethyl)urea (2214-72-4) → 2-<(2'-chloroethyl)imino>-3-nitroso-2-oxazolidine (76310-08-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 72 percent / H2O / Heating 2: 45 percent / n-butyl nitrite, sodium methoxide / diethyl ether / 12 h / Ambient temperature View Scheme

1,3-bis(2-chloroethyl)urea (2214-72-4) → C5H9I2N3O2 (13907-75-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaI / acetone / Heating 2: NaNO2, HCO2H View Scheme

Upstream product

• 1943-83-5 2-chloroethyl isothiocyanate 
• 154-93-8 1,3-bis(2-chloroethyl)-1-nitrosourea 
• 689-98-5 chloroethylamine 
• 15438-70-7 N,N'-bis(2-hydroxyethyl)urea 
• 870-24-6 2-chloroethanamine hydrochloride 
• 530-62-1 1,1'-carbonyldiimidazole 
• 74124-79-1 di(succinimido) carbonate 
• 151-56-4 ethyleneimine 
• 75-44-5 phosgene 

Downstream Products

• 154-93-8 1,3-bis(2-chloroethyl)-1-nitrosourea 
• 13908-87-7 N,N'-Bis-<2-iod-ethyl>-harnstoff 
• 13907-75-0 C₅H₉I₂N₃O₂ 
• 76310-08-2 2-<(2'-chloroethyl)imino>-3-nitroso-2-oxazolidine 
• 73771-48-9 2-<(2-chloroethyl)amino>-2-oxazoline hydrochloride 

Relevant articles and documents

Substituted 2-methylene-1,3-oxazolidines, -1,3-thiazolidines, -1,3-benzothiazines, -1,3-oxazines, and substituted imidazopyrimidinediones from Cl(CH2)nNCO and Cl(CH2)nNCS and active methylene compounds

The reaction of ω-chloroalkyl isocyanates Cl(CH2) nNCO (n = 2 (2), 3 (4)) and isothiocyanate Cl(CH2) 2-NCS (3) with active methylene compounds CH2YY′ 1 in the presence of Et3N or Na give 2-YY′-methylene-1,3- oxazolidines, (E,Z)-1,3-thiazolidines, and 1,3-oxazines from 2, 3, and 4, respectively. 2-(Chloromethyl)-phenyl isocyanate 8 gives with 1 the corresponding benzo-oxazines. Ethyl 2-isothiocyanatobenzoate 10 gives the corresponding benzothiazolinone, whereas the analogous isocyanate 12 gives noncyclic enols. Ethoxycarbonyl isothiocyanate 14 gives an open-chain thioenol or an enol-thioamide. The cyanoamides CH2(CN)CONHR, R = H, Me, CHPh2, give with Et3N and 2 the bicyclic imidazopyrimidinediones 16, derived from two molecules of 2, but with their preformed Na salt they give the 1,3-oxazolidines. Reaction of cyanoacetamide with 3 in the presence of Na gave a tricyclic triaza(thia)indacene, derived from two molecules of 3. A reaction mechanism involving an initial attack of the anion 1- on the N=C=X (X = O, S) moiety gives an anion 18, which cyclizes intramolecularly and after tautomerization gives the mono-ring heterocycle. With the cyanoamides, the N- site of the ambident ion 18 attacks another molecule of 2 giving the anion 20, which by intramolecular attack on the CN, followed by expulsion of the Cl- gives the bicyclic 16 after tautomerization.

SAFE AND EFFICIENT PROCESS FOR THE PREPARATION OF CARMUSTINE

Carmustine may be safely and efficiently produced by reacting 2-chloroethylamine hydrochloride and 1,1′-carbonyldiimidazole to afford 1,3-bis(2-chloroethyl)-1-urea, followed by nitrosation to give the final product.

PROCESS FOR PREPARATION OF CARMUSTINE

The present invention relates to an improved process for preparation of carmustine (I). The present invention also relates to preparation of 1,3-bis(2-chloroethyl)urea (II) an intermediate used in preparation of carmustine.