WO2007080430A1

WO2007080430A1 - Novel process

Info

Publication number: WO2007080430A1
Application number: PCT/GB2007/050021
Authority: WO
Inventors: Priyesh S. Vijaykar; Abhay Gaitonde
Original assignee: Generics [Uk] Limited; Merck Development Center Private Limited
Priority date: 2006-01-16
Filing date: 2007-01-16
Publication date: 2007-07-19

Abstract

The present invention relates to a process for the preparation of a carbamoyl chloride RR’N-CO-Cl (I).

Description

Novel Process

Field of the invention

The present invention relates to a process for the preparation of a carbamoyl chloride RR¹N-CO-Cl (I).

Background of the invention

Carbamoyl chloride H₂N-CO-Cl is an unstable, colourless, pungent smelling liquid. It reacts explosively with water to give ammonium chloride and carbon dioxide and it decomposes visibly on standing. It can be stabilized by deep freezing and for a limited time (around 24 hours) by moderate cooling in solution with 1,2- dichloroethane or other solvents.

Carbamoyl chloride H₂N-CO-Cl is used as a chemical intermediate in the production of dyes, pharmaceuticals, and pesticides.

L. Gattermann prepared carbamoyl chloride H₂N-CO-Cl for the first time in 1888 in a batchwise manner by passing a stream of phosgene gas over heated aluminium chloride. Today, carbamoyl chloride H₂N-CO-Cl is normally prepared continuously by reacting ammonia with phosgene in equal molar ratio at about 500°C (Hopf & Ohlinger, Angewandte Chemie, 61 (5), 183, 1949).

US 6 919 471 discloses a process for the preparation of aryl/alkyl chloroformates RO-CO-Cl from alcohols ROH, wherein an alcohol in an organic solvent is added to a mixture of triphosgene, a catalyst, an inorganic metal carbonate or bicarbonate base and an organic solvent, at a temperature of 0⁰C to ambient. The reaction time disclosed is from 1 to 48 hours. However, the disclosure does not teach a method for the preparation of a carbamoyl chloride RR¹N-CO-Cl from the corresponding amine RR¹NH. USSN 2004/0102450 discloses (scheme 19) the chlorocarbonylation of a secondary amine RR¹NH using phosgene or triphosgene in an appropriate solvent such as dichloromethane in the presence of a base additive such as triethylamine or pyridine. However, it was observed that the impurity levels, when triethylamine was used as the base additive, were considerably higher.

Thus, the prior art does not teach a process to obtain a carbamoyl chloride RR'N-CO-Cl (I) starting from the corresponding amine RR¹NH (II) consistently in high purity.

Phosgene gas has the appearance of a white cloud and the characteristic odour of newly mown hay. Odour alone is insufficient for the detection of phosgene exposure, since toxic exposures may occur at concentrations below the olfactory threshold. Although phosgene is one of the most volatile chemical warfare agents, its density is greater than air, and it tends to accumulate in low areas.

Phosgene exerts a direct toxic effect on the respiratory tract, causing extensive cellular damage to the alveolar-capillary membrane. Phosgene reacts with intra- alveolar water to form hydrochloric acid, which injures the alveoli.

The clinical effects of phosgene are dose dependent. At low concentrations, victims may complain only of a mild cough, dyspnea, and chest discomfort. At moderate concentrations, they also may complain of tearing. At high concentrations, victims rapidly develop non-cardiogenic pulmonary oedema within 2 to 6 hours of exposure, producing a clinical picture similar to adult respiratory distress syndrome. Laryngospasm also occurs at higher concentrations, which in turn may cause sudden death. Physical exertion within 72 hours of exposure can trigger dyspnea and pulmonary oedema in otherwise asymptomatic patients. Toxic manifestations often are clinically silent at rest, because patients are able to compensate for pulmonary damage in the absence of stress. Death from phosgene inhalation often is caused by latent non-cardiogenic pulmonary oedema. Phosgene is considered to have poor warning properties and, hence, may reach the lower airways before it is noticed. It is four times heavier than air and is a gas above 47°F (8°C). Because of hydrolysis from atmospheric water, it appears as a white cloud in an outside environment.

Thus it is highly dangerous to use reactions which directly use the addition of phosgene.

Some disadvantages of the prior art processes for the preparation of carbamoyl chlorides RR¹N-CO-Cl (I) are:

Phosgene, which is a highly toxic gas, is used.

Phosgene has to be absorbed into the reaction medium, which requires a lot of time.

The reaction using phosgene is sluggish and requires a long time for completion.

There are associated hazards involved in the generation, storage, usage and disposal of phosgene, as it is a highly toxic gas.

The carbamoyl chlorides RR¹N-CO-Cl (I) obtained using phosgene are impure.

Thus there is a need to develop a process for the preparation of carbamoyl chlorides RR¹N-CO-Cl (I), in particular ethyl methyl carbamoyl chloride, from the corresponding amines RR'NH (II) in high purity without addition of phosgene.

The present inventors have found that a safe, simple and cost effective process for the preparation of a carbamoyl chloride RR'N-CO-Cl (I), in particular ethyl methyl carbamoyl chloride, from the corresponding amine RR'NH (II) may be provided, where phosgene is generated in situ by the dropwise addition of the amine.

Objects of the invention

It is thus an object of the present invention to provide a process for the preparation of a carbamoyl chloride RR'N-CO-Cl (I), in particular ethyl methyl carbamoyl chloride, in which addition of harmful chemicals, such as phosgene, is avoided. It is a further object of the present invention to provide a process for the preparation of a carbamoyl chloride RR'N-CO-Cl (I), in particular ethyl methyl carbamoyl chloride, in which phosgene is generated in situ.

It is a further object of the present invention to provide a pure carbamoyl chloride RR'N-CO-Cl (I), in particular pure ethyl methyl carbamoyl chloride.

Another object of the present invention is to provide a process for the preparation of a carbamoyl chloride RR'N-CO-Cl (I), in particular ethyl methyl carbamoyl chloride, which is simple, safe and cost effective.

Another object is directed to an improvement in the manufacture of a carbamoyl chloride RR'N-CO-Cl (I) giving a carbamoyl chloride RR'N-CO-Cl (I) which is substantially free of urea, in particular an improvement in the manufacture of ethyl methyl carbamoyl chloride giving ethyl methyl carbamoyl chloride which is substantially free of urea.

Accordingly, the present invention provides a process for the preparation of carbamoyl chloride (I), comprising reaction of amine (II)

NH _(π) R¹ with triphosgene (III)

in the presence of an inorganic base and a halogenated organic solvent to yield carbamoyl chloride (I)

In a preferred embodiment, the present invention provides a process for the preparation of ethyl methyl carbamoyl chloride (IA), comprising reaction of ethyl methyl amine (HA)

NH _(IIA)

Me with triphosgene (III)

in the presence of an inorganic base and a halogenated organic solvent to yield ethyl methyl carbamoyl chloride (IA)

Summary of the invention

A first aspect of the present invention provides a process for the preparation of a carbamoyl chloride (I)

comprising reacting an amine (II)

^R\

NH _(II)

R' with triphosgene (III)

in the presence of a base and a solvent to yield the carbamoyl chloride (I), wherein R and R' are independently hydrogen or an alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkenylaryl, alkynylaryl, arylalkyl, arylalkenyl or arylalkynyl group, each of which may optionally be substituted and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton.

For the purposes of the present invention, an "alkyl" group is defined as a monovalent saturated hydrocarbon, which may be straight-chained or branched, or be or include cyclic groups. An alkyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of alkyl groups are methyl, ethyl, ^-propyl, i-propyl, %-butyl, /-butyl, /-butyl and /z-pentyl groups. Preferably an alkyl group is straight-chained or branched, and does not include any heteroatoms in its carbon skeleton. Preferably an alkyl group is a C₁-C₁₂ alkyl group, which is defined as an alkyl group containing from 1 to 12 carbon atoms. More preferably an alkyl group is a C₁-C₆ alkyl group, which is defined as an alkyl group containing from 1 to 6 carbon atoms. An "alkylene" group is similarly defined as a divalent alkyl group.

An "alkenyl" group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon double bond, which may be straight-chained or branched, or be or include cyclic groups. An alkenyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of alkenyl groups are vinyl, allyl, but-1-enyl and but-2-enyl groups. Preferably an alkenyl group is straight-chained or branched, and does not include any heteroatoms in its carbon skeleton. Preferably an alkenyl group is a C₂-C₁₂ alkenyl group, which is defined as an alkenyl group containing from 2 to 12 carbon atoms. More preferably an alkenyl group is a C₂-C₆ alkenyl group, which is defined as an alkenyl group containing from 2 to 6 carbon atoms. An "alkenylene" group is similarly defined as a divalent alkenyl group.

An "alkynyl" group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon triple bond, which may be straight-chained or branched, or be or include cyclic groups. An alkynyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of alkynyl groups are ethynyl, propargyl, but-1-ynyl and but-2-ynyl groups. Preferably an alkynyl group is straight-chained or branched, and does not include any heteroatoms in its carbon skeleton. Preferably an alkynyl group is a C₂-C₁₂ alkynyl group, which is defined as an alkynyl group containing from 2 to 12 carbon atoms. More preferably an alkynyl group is a C₂-C₆ alkynyl group, which is defined as an alkynyl group containing from 2 to 6 carbon atoms. An "alkynylene" group is similarly defined as a divalent alkynyl group.

An "aryl" group is defined as a monovalent aromatic hydrocarbon. An aryl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton.

Examples of aryl groups are phenyl, naphthyl, anthracenyl and phenanthrenyl groups. Preferably an aryl group does not include any heteroatoms in its carbon skeleton. Preferably an aryl group is a C₄-C₁₄ aryl group, which is defined as an aryl group containing from 4 to 14 carbon atoms. More preferably an aryl group is a C₆- C₁₀ aryl group, which is defined as an aryl group containing from 6 to 10 carbon atoms. An "arylene" group is similarly defined as a divalent aryl group.

For the purposes of the present invention, where a combination of groups is referred to as one moiety, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule. A typical example of an arylalkyl group is benzyl.

For the purposes of this invention, an optionally substituted alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group may be substituted with one or more of -F, -Cl, -Br, -I, -CF₃, -CCl₃, -CBr₃, -CI₃, -OH, -SH, -NH₂, -CN, -NO₂, -COOH, -R'-O-R², -R'-S-R², -R'-SO-R², -R^SO₂-R², -R^SO₂-OR², -R¹O-SO₂-R², -R¹-SO₂-N(R²)₂, -R'-NR'-SO.-R², -R¹O-SO₂-OR², -R¹O-SO₂-N(R²)₂, -R^NR'-SO^OR², -R¹-NR²-SO₂-N(R²)₂, -R^N(R²),, -R¹-N(R²)₃ ⁺, -R^α-P(R²)₂, -R^Si(R²),, -R^J-CO-R², -R'-CO-OR², -R¹O-CO-R², -R^CO-N(R²),, -R^NR^CO-R², -R¹O-CO-OR², -R¹O-CO-N(R²)₂, -R^NR^CO-OR²,

-R¹-NR²-CO-N(R²)₂, -R'-CS-R², -R'-CS-OR², -R¹O-CS-R², -R^CS-N(R²),, -R^NR^CS-R², -R¹O-CS-OR², -R¹O-CS-N(R²J₂, -R'-NR^CS-OR², -R¹-NR²-CS-N(R²)₂ or -R². In this context, -R¹- is independently a chemical bond, a C₁-C₁₀ alkylene, C₁-C₁₀ alkenylene or C₁-C₁₀ alkynylene group. -R² is independently hydrogen, unsubstituted C₁-C₆ alkyl or unsubstituted C₆-C₁₀ aryl. Optional substituent(s) are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituent(s). Preferably a substituted group comprises 1, 2 or 3 substituents, more preferably 1 or 2 substituents, and even more preferably 1 substituent.

Any optional substituent may be protected. Suitable protecting groups for protecting optional substituents are known in the art, for example from "Protective Groups in Organic Synthesis" by T.W. Greene and P.G.M. Wuts (Wiley- Interscience, 3^rd edition, 1999).

Preferably, R and R¹ are independently C_1-6 alkyl or C₅__lo arylalkyl. More preferably, R and R' are independently C_1-6 alkyl. More preferably, one of R and R¹ is methyl and the other is ethyl, i.e. R is methyl and R' is ethyl or R is ethyl and R' is methyl.

Preferably, R and R' are not cyclic and do not comprise any cyclic groups. Preferably, R and R' are independently hydrogen or a straight-chained or branched alkyl, alkenyl or alkynyl group, each of which may optionally be substituted and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton.

Preferably, the base is an amine base or an inorganic base.

In one embodiment, the base is an amine base, such as pyridine, a dialkylamine (such as ethylmethylamine, diethylamine or diisopropylamine), a trialkylamine (such as triethylamine or diisopropylethylamine) or a cyclic alkylamine (such as pyrrolidine). In alternative embodiment, the reaction is carried out in the absence of any amine other than amine (II).

In a preferred embodiment, the base is an inorganic base, preferably a bicarbonate, a carbonate or a hydroxide. Preferably, the inorganic base is a bicarbonate. Preferably, the inorganic base is potassium bicarbonate, potassium carbonate, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium hydroxide, lithium bicarbonate, lithium carbonate, or lithium hydroxide. More preferably, the inorganic base is sodium bicarbonate. Preferably, the sodium bicarbonate is used in an amount of 1.7-2.2 eq relative to the amine (II), preferably in an amount of about 2 eq relative to the amine (II).

Preferably, the solvent is an organic solvent, a halogenated solvent or an organic halogenated solvent. In a preferred embodiment, the solvent is an organic halogenated solvent, such as dichloromethane, trichloromethane, carbon tetrachloride, tetrachloroethane, or a mixture thereof. More preferably, the organic halogenated solvent is dichloromethane. Preferably, the dichloromethane is used in a volume ratio of 20-50 volumes relative to the amine (II), preferably in a volume ratio of about 35 volumes.

Preferably, the triphosgene (III) is used in an amount of 0.5-0.75 eq relative to the amine (II), preferably in an amount of about 0.66 eq relative to the amine (II).

Preferably, the reaction is carried out at a temperature of 5-120°C, preferably 5-100°C, preferably 5-50°C, preferably 5-30°C, preferably 10-15⁰C.

Preferably, the reaction is carried out for 10 hours or less, preferably 8 hours or less, preferably 5 hours or less.

Preferably, the amine (II) in solvent is added to the base and the triphosgene (III) in solvent. Preferably, the addition is carried out dropwise. Preferably, the addition is carried out over 0.5-8 hours, preferably over 1-5 hours, preferably over 1-3 hours. Preferably, the reaction mixture is stirred during the addition.

Preferably, the reaction is carried out without the direct addition of phosgene Cl-CO-Cl. Preferably, phosgene Cl-CO-Cl is generated in situ during the reaction. Preferably, the carbamoyl chloride (I) obtained is substantially pure. For the purposes of the present invention, "substantially pure" carbamoyl chloride (I) comprises less than 5% impurities, preferably less than 2%, preferably less than 1%, preferably less than 0.5%.

Preferably, the carbamoyl chloride (I) obtained is substantially free of urea H₂N-CO-NH₂. For the purposes of the present invention, carbamoyl chloride (I), which is "substantially free" of urea H₂N-CO-NH₂, comprises less than 5% urea H₂N-CO-NH₂, preferably less than 2%, preferably less than 1%, preferably less than 0.5%.

Preferably, the carbamoyl chloride (I) is obtained in a yield of 90%, 95%, 98% or more.

The process of the present invention is suitable for industrial scale manufacture of carbamoyl chloride (I). Preferably, carbamoyl chloride (I) is obtained on an industrial scale, such as in batches of 5kg, 10kg, 50kg, 100kg, 500kg, 1000kg or more.

A second aspect of the present invention provides carbamoyl chloride (I)

which is substantially pure. For the purposes of the present invention, "substantially pure" carbamoyl chloride (I) comprises less than 5% impurities, preferably less than 2%, preferably less than 1%, preferably less than 0.5%.

The second aspect of the present invention further provides carbamoyl chloride (I)

which is substantially free of urea H₂N-CO-NH₂. For the purposes of the present invention, carbamoyl chloride (I), which is "substantially free" of urea H₂N-CO-NH₂, comprises less than 5% urea H₂N-CO-NH₂, preferably less than 2%, preferably less than 1%, preferably less than 0.5%.

Detailed description of the invention

The present inventors have addressed the need for a process for the preparation of ethyl methyl carbamoyl chloride, in which the use of harmful chemicals, such as phosgene, is avoided.

Accordingly, the process of the present invention comprises reaction of amine (II)

NH _(II)

R' with triphosgene (III)

to yield carbamoyl chloride (I)

Preferably, the process of the present invention comprises reaction of ethyl methyl amine (HA)

^Et\

NH _(IIA)

Me with triphosgene (III)

to yield ethyl methyl carbamoyl chloride (IA)

The reaction is preferably carried out with halogenated solvents, such as dichloromethane, trichloromethane, carbon tetrachloride, and tetrachloroethane. A most preferable solvent is dichloromethane in a volume ratio of 20-50 volumes, preferably 35 volumes.

The base used is preferably an inorganic base, such as a bicarbonate. A preferred base is sodium bicarbonate, which is preferably used in an amount of 1.7-2.2 eq, most preferably 2 eq. Other inorganic bases that are used are potassium bicarbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, and sodium carbonate.

Triphosgene is added in an amount of 0.5-0.75 eq, preferably 0.66 eq.

The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting illustrative examples.

Examples

Example 1

A solution of ethyl methyl amine (10Og, 1.69mol) in dichloromethane (1.51) is added dropwise to a slurry of sodium bicarbonate (284g, 3.384mol) and triphosgene (332g, 1.117mol) in dichloromethane (21) at 10-15°C over 2 hours. The reaction mixture is stirred at room temperature for 3 hours. The reaction mass is filtered to remove sodium chloride and the filtrate is concentrated under vacuum to give 189g of ethyl methyl carbamoyl chloride as a light yellow oil (yield: 92%). Example 2

The process of example 1 was repeated using several bases with toluene as the solvent. The other conditions remained the same. The results obtained are summarized in Table 1 below.

Table 1

Therefore, it was concluded that inorganic bases were better than triethylamine, and that sodium bicarbonate was the base of choice among the inorganic bases. Specifically, it was concluded that the best combination was using toluene and sodium bicarbonate.

Example 3

The process of example 2 was repeated but the solvent was changed to dichloromethane. The other conditions were similar. The results are provided in Table 2 below.

Table 2

The yield was found to be consistent at greater than 98%. Therefore, it was concluded that there exists a synergy between dichloromethane, triphosgene and sodium bicarbonate for preparing ethyl methyl carbamoyl chloride in high purity and high yield without the addition of hazardous phosgene.

Claims

1. A process for the preparation of a carbamoyl chloride (I)

comprising reacting an amine (II)

NH _(II)

R with triphosgene (III)

2. A process as claimed in claim 1, wherein R and R¹ are independently C_t.₆ alkyl or C_5.10 arylalkyl.

3. A process as claimed in claim 1 or 2, wherein R and R¹ are independently C_1-6 alkyl.

4. A process as claimed in any one of the preceding claims, wherein one of R and R' is methyl and the other is ethyl.

5. A process as claimed in any one of the preceding claims, wherein the base is an amine base or an inorganic base.

6. A process as claimed in claim 5, wherein the amine base is pyridine, a dialkylamine, a trialkylamine or a cyclic alkylamine.

7. A process as claimed in any one of the preceding claims, wherein the reaction is carried out in the absence of any amine other than amine (II).

8. A process as claimed in claim 5, wherein the inorganic base is a bicarbonate, a carbonate or a hydroxide.

9. A process as claimed in claim 8, wherein the inorganic base is a bicarbonate.

10. A process as claimed in claim 8, wherein the inorganic base is potassium bicarbonate, potassium carbonate, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium hydroxide, lithium bicarbonate, lithium carbonate, or lithium hydroxide.

11. A process as claimed in claim 10, wherein the inorganic base is sodium bicarbonate.

12. A process as claimed in claim 11, wherein the sodium bicarbonate is used in an amount of 1.7-2.2 eq relative to the amine (II).

13. A process as claimed in claim 12, wherein the sodium bicarbonate is used in an amount of about 2 eq relative to the amine (II).

14. A process as claimed in any one of the preceding claims, wherein the solvent is an organic solvent, a halogenated solvent or an organic halogenated solvent.

15. A process as claimed in claim 14, wherein the organic halogenated solvent is dichloromethane, trichloromethane, carbon tetrachloride, tetrachloroethane, or a mixture thereof.

16. A process as claimed in claim 15, wherein the organic halogenated solvent is dichloromethane.

17. A process as claimed in claim 16, wherein the dichloromethane is used in a volume ratio of 20-50 volumes relative to the amine (II).

18. A process as claimed in claim 17, wherein the dichloromethane is used in a volume ratio of about 35 volumes relative to the amine (II).

19. A process as claimed in any one of the preceding claims, wherein the triphosgene (III) is used in an amount of 0.5-0.75 eq relative to the amine (II).

20. A process as claimed in claim 19, wherein the triphosgene (III) is used in an amount of about 0.66 eq relative to the amine (II).

21. A process as claimed in any one of the preceding claims, wherein the reaction is carried out at a temperature of 5-120°C, preferably 5-100°C, preferably 5-50°C, preferably 5-30°C, preferably 10-15⁰C.

22. A process as claimed in any one of the preceding claims, wherein the reaction is carried out for 10 hours or less, preferably 8 hours or less, preferably 5 hours or less.

23. A process as claimed in any one of the preceding claims, wherein the amine (II) in solvent is added to the base and the triphosgene (III) in solvent.

24. A process as claimed in any one of the preceding claims, wherein the reaction is carried out without the direct addition of phosgene Cl-CO-Cl.

25. A process as claimed in any one of the preceding claims, wherein phosgene Cl-CO-Cl is generated in situ during the reaction.

26. A process as claimed in any one of the preceding claims, wherein the carbamoyl chloride (I) obtained is substantially pure.

27. A process as claimed in any one of the preceding claims, wherein the carbamoyl chloride (I) obtained is substantially free of urea H₂N-CO-NH₂.

28. A process as claimed in any one of the preceding claims, wherein the carbamoyl chloride (I) is obtained in a yield of 90%, 95%, 98% or more.

29. Carbamoyl chloride (I)

which is substantially pure.

30. Carbamoyl chloride (I)

which is substantially free of urea H₂N-CO-NH₂.