75438-57-2

Usage

Physical and Chemical Properties

ensity: 1.52g/cm3, boiling point:? 364.7 °C at 760 mmHg, flash point: 174.3 °C, crystallization, melting point: 217-219 degrees Celsius.

Preparation

5-amino-4,6-dichloro-2-methyl pyrimidine and 1-acetyl-2-imidazolin-2-one. The product, reacting with sodium methanol can produce moxonidine.

Precautions

There may be dry mouth, fatigue and headache at the beginning of treatment, occasional dizziness, insomnia, and weakness in the legs and so on. Sick sinus syndrome, the sinus node and atrioventricular Ⅱ-Ⅲ degree block, resting bradycardia (50 beats/min), unstable angina, severe liver disease, progressive renal dysfunction, angioedema patients should not use it.

References

https://en.wikipedia.org/wiki/Moxonidine

Originator

Beiersdorf (Germany)

Biological Activity

Mixed I 1 imidazoline receptor and α 2 -adrenergic agonist; displays 40-fold higher affinity for I 1 receptors versus α 2 -adrenoceptors. Centrally acting antihypertensive agent.

Clinical Use

Antihypertensive agent (centrally acting agonist at I1 receptor, imidazoline and alpha2 adrenoceptors)

Drug interactions

Potentially hazardous interactions with other drugs None known

Metabolism

10-20% metabolised, predominantly to 4,5-dehydromoxonidine and to an aminomethanamidine derivative both of which are much less active than moxonidine. Moxonidine and its metabolites are almost entirely eliminated via the kidney. More than 90% of the dose is eliminated in the first 24 hours via the kidney, while approximately 1% is eliminated in the faeces

InChI:InChI=1/C9H12ClN5O/c1-5-13-7(10)6(8(14-5)16-2)15-9-11-3-4-12-9/h3-4H2,1-2H3,(H2,11,12,15)

Synthetic route

mono-Moxonidine oxalate (287099-40-5) → 4,6-dichloro-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (352457-35-3) + 4,6-dimethoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (75439-01-9) + moxonidine (75438-57-2)

Conditions	Yield
With sodium hydroxide In water at 20℃; for 1h; pH=10 - 11; Product distribution / selectivity;	A n/a B n/a C 94%

methanol (67-56-1) + 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (75438-54-9) → 4,6-dimethoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (75439-01-9) + moxonidine (75438-57-2)

Conditions	Yield
With potassium carbonate at 65℃; for 3h; Product distribution / selectivity;	A n/a B 90.7%

methanol (67-56-1) + 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (75438-54-9) → 4,6-dichloro-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (352457-35-3) + 4,6-dimethoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (75439-01-9) + moxonidine (75438-57-2)

Conditions	Yield
With sodium hydrogencarbonate In water at 65℃; for 6h; Product distribution / selectivity;	A n/a B n/a C 88.3%
With potassium hydrogencarbonate In water at 65℃; for 10h; Product distribution / selectivity;	A n/a B n/a C 88.3%
With potassium hydroxide; potassium carbonate at 20℃; for 16h; Product distribution / selectivity;	A n/a B n/a C 85.9%

methanol (67-56-1) + 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (75438-54-9) → 4,6-dichloro-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (352457-35-3) + moxonidine (75438-57-2)

Conditions	Yield
With sodium hydroxide In water at 25℃; for 24h; Product distribution / selectivity;	A n/a B 88.3%
With potassium hydroxide at 25℃; for 12h; Product distribution / selectivity;	A n/a B 88.3%

4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (75438-54-9) + sodium methylate (124-41-4) → 4,6-dichloro-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (352457-35-3) + 4,6-dimethoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (75439-01-9) + moxonidine (75438-57-2)

Conditions	Yield
In methanol at 0 - 65℃; for 1.5 - 48h; Product distribution / selectivity;	A n/a B n/a C 84.7%
In tetrahydrofuran at 25℃; for 30h; Product distribution / selectivity;	A n/a B n/a C 76.4%
In toluene at 25℃; for 30h; Product distribution / selectivity;	A n/a B n/a C 66.8%

methanol (67-56-1) + 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (75438-54-9) → moxonidine (75438-57-2)

Conditions	Yield
With pyrographite; 1,8-diazabicyclo[5.4.0]undec-7-ene at 65℃; for 3.5h;	84.4%
With potassium hydroxide at 20℃; for 30h; Product distribution / selectivity;	83.5%
With tetrabutylammomium bromide; water; sodium hydroxide In dichloromethane at 20 - 35℃; for 2.5h; pH-value; Reagent/catalyst; Solvent; Temperature;	3.43 g

4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (75438-54-9) → moxonidine (75438-57-2)

Conditions	Yield
With potassium hydroxide In methanol; water at 20℃; for 31h;	83.5%
With sodium methylate In methanol; water
In tetrahydrofuran; methanol

4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (75438-54-9) + sodium methylate (124-41-4) → 4,6-dichloro-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (352457-35-3) + moxonidine (75438-57-2)

Conditions	Yield
In methanol at 0℃; for 48h; Product distribution / selectivity;	A n/a B 77.6%

4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (75438-54-9) + sodium methylate (124-41-4) → 4,6-dimethoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (75439-01-9) + moxonidine (75438-57-2)

Conditions	Yield
In dimethyl sulfoxide at 25℃; for 30h; Product distribution / selectivity;	A n/a B 76.4%

4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (75438-54-9) → 4,6-dichloro-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (352457-35-3) + 4,6-dimethoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (75439-01-9) + moxonidine (75438-57-2)

Conditions	Yield
Stage #1: 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine With potassium carbonate In methanol at 47 - 52℃; for 5h; Stage #2: With water; acetic acid In methanol for 0.5h; Stage #3: With ammonia In methanol; water for 1h; Product distribution / selectivity;

methanol (67-56-1) + 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (75438-54-9) + 1-[1-((4,6-dichloro-2-methyl-pyrimidin-5-yl)imino)-ethyl]-imidazolidin-2-one (438000-58-9) + sodium methylate (124-41-4) → 1-[1-[(4-chloro-2-methyl-6-methoxy-pyrimidin-5-yl)imino]ethyl]-imidazolidin-2-one (1033401-62-5) + moxonidine (75438-57-2)

Conditions	Yield
at 20℃;	A 0.12 %Chromat. B 96.66 %Chromat.

methanol (67-56-1) + 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (75438-54-9) + sodium methylate (124-41-4) → 4,6-dichloro-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (352457-35-3) + 4,6-dimethoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (75439-01-9) + moxonidine (75438-57-2)

Conditions	Yield
for 2h; Heating / reflux;	A 1.45 - 1.48 %Chromat. B 5.27 - 5.32 %Chromat. C 93.22 - 93.25 %Chromat.

methanol (67-56-1) + 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (75438-54-9) + sodium methylate (124-41-4) → moxonidine (75438-57-2)

Conditions	Yield
at 30 - 35℃; for 0.75h;	520 mg

5-amino-4-methoxy-6-chloro-2-methyl-pyrimidine (88474-31-1) → moxonidine (75438-57-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium carbonate; trichlorophosphate / dimethyl sulfoxide / 49 h / 5 - 60 °C / Inert atmosphere 2: hydrogenchloride / isopropyl alcohol / 8 h / 20 °C 3: base / water / pH 9 View Scheme

4-chloro-6-methoxy-2-methyl-5-(2-imidazolin-2-yl)aminopyrimidine hydrochloride → moxonidine (75438-57-2)

Conditions	Yield
With base In water pH=9;

1-acetylimidazolidin-2-one (5391-39-9) + 5-amino-4-methoxy-6-chloro-2-methyl-pyrimidine (88474-31-1) → moxonidine (75438-57-2)

Conditions	Yield
Stage #1: 1-acetylimidazolidin-2-one; 5-amino-4-methoxy-6-chloro-2-methyl-pyrimidine With sodium carbonate; trichlorophosphate In dimethyl sulfoxide at 5 - 60℃; for 50.5h; Cooling with acetone-dry ice; Inert atmosphere; Stage #2: With hydrogenchloride In water; isopropyl alcohol at 20℃; for 8h;

oxalic acid (144-62-7) + moxonidine (75438-57-2) → 4,6-dimethoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (75439-01-9) + mono-Moxonidine oxalate (287099-40-5)

Conditions	Yield
In methanol; diethyl ether Product distribution / selectivity; Heating / reflux;	A n/a B 95%
In methanol; propan-1-ol at 0 - 20℃; for 3.5h; Product distribution / selectivity; Heating / reflux;	A n/a B 83.6%
In propan-1-ol; dimethyl sulfoxide Product distribution / selectivity; Heating / reflux;	A n/a B 58%

formic acid (64-18-6) + moxonidine (75438-57-2) → 4,6-dimethoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (75439-01-9) + mono-Moxonidine formate (1008754-14-0)

Conditions	Yield
In propan-1-ol at 0 - 20℃; for 4h; Product distribution / selectivity; Heating / reflux;	A n/a B 92.7%
In isopropyl alcohol at 0 - 20℃; for 4h; Product distribution / selectivity; Heating / reflux;	A n/a B 85%
In N,N-dimethyl-formamide at 0 - 20℃; for 4h; Product distribution / selectivity; Heating / reflux;	A n/a B 84%
In dimethyl sulfoxide at 0 - 20℃; for 4h; Product distribution / selectivity; Heating / reflux;	A n/a B 66%

oxalic acid (144-62-7) + moxonidine (75438-57-2) → 4,6-dichloro-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (352457-35-3) + mono-Moxonidine oxalate (287099-40-5)

Conditions	Yield
In propan-1-ol at 0 - 20℃; for 2h; Product distribution / selectivity; Heating / reflux;	A n/a B 87.3%

oxalic acid (144-62-7) + moxonidine (75438-57-2) → 4,6-dichloro-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (352457-35-3) + 4,6-dimethoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine (75439-01-9) + mono-Moxonidine oxalate (287099-40-5)

Conditions	Yield
In methanol; propan-1-ol at 0 - 20℃; for 3.5h; Heating / reflux;	A n/a B n/a C 87%

moxonidine (75438-57-2) → 4-methoxy-2-methyl-6-methylthio-5-(2-imidazolin-2-yl)-aminopyrimidine (75438-60-7)

Conditions	Yield
In toluene

Upstream product

• 5391-39-9 1-acetylimidazolidin-2-one 
• 88474-31-1 5-amino-4-methoxy-6-chloro-2-methyl-pyrimidine 
• 75438-54-9 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine 
• 67-56-1 methanol 
• 287099-40-5 mono-Moxonidine oxalate 
• 124-41-4 sodium methylate 
• 75438-58-3 4-chloro-6-methoxy-2-methyl-5-(2-imidazolin-2-yl)aminopyrimidine hydrochloride 
• 438000-58-9 1-[1-((4,6-dichloro-2-methyl-pyrimidin-5-yl)imino)-ethyl]-imidazolidin-2-one 

Downstream Products

• 75439-01-9 4,6-dimethoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine 
• 287099-40-5 mono-Moxonidine oxalate 
• 1008754-14-0 mono-Moxonidine formate 
• 352457-35-3 4,6-dichloro-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine 

Relevant academic research and scientific papers

SYNTHESIS OF SUBSTITUTED AMINOPYRIMIDINES

The present invention relates to a novel process for the manufacture of certain substituted aminopyrimidines having Formula (I) or a tautomer or salt thereof, wherein R1 is selected from hydrogen, halogen, C1-4alkoxy, C1-4alklthio, C1-4alkyl, C3-5cycloalkyl, for example R1 is halogen such as chloro; R2 is C1-4alkyl, for example methyl, ethyl, i-propyl, n-propyl or butyl (any isomer), such as methyl; and R3 is selected from hydrogen, C1-4alkoxy, C1-4alkylthio, C1-4alkyl, C3-5cycloalkyl, for example C1-4alkyl such as methyl, ethyl, i-propyl, n-propyl or butyl (any isomer), for example methyl; crystalline forms thereof as well as chemical intermediates suitable for use in performing the process.

Synthesis of substituted aminopyridines

The present invention relates to a novel process for the manufacture of certain substituted aminopyridines having Formula (I) or a tautomer or salt thereof, wherein R1 is selected from hydrogen, halogen, C1-4alkoxy, C1-4alklthio, C1-4alkyl, C3-5cycloalkyl, for example R1 is halogen such as chloro; R2 is C1-4alkyl, for example methyl, ethyl, i-propyl, n-propyl or butyl (any isomer), such as methyl; and R3 is selected from hydrogen, C1-4alkoxy, C1-4alkylthio, C1-4alkyl, C3-5cycloalkyl, for example C1-4alkyl such as methyl, ethyl, i-propyl, n-propyl or butyl (any isomer), for example methyl; crystalline forms thereof as well as chemical intermediates suitable for use in performing the process.

PROCESS FOR THE PRODUCTION OF MOXONIDINE

4,6-dichloro-2-methyl-5-(1-acyl-2-imidazolin-2-yl)-aminopyrimidine is reacted with methanol in the presence of a non-ionic organic base, and moxonidine is obtained directly from the reaction mixture.

Method by means of phase transfer catalysis

The invention relates to a method for preparing a compound having the formula (I): where R is an aliphatic and/or aromatic radical, wherein 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine and an alcohol are caused to react in the presence of a phase transfer catalyst.

Process for the preparation of moxonidine

The present invention provides an improved process for the preparation of 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)aminopyrimidine. The present invention also provides an improved process for the preparation of moxonidine. The present invention further provides a process for the purification of moxonidine.

Polymorphs of moxonidine and processes for preparation therefor

Three crystalline forms of Moxonidine designated as Moxonidine form I, form II and form III and processes for their preparation are disclosed.

MOXONIDINE ANALOGS, PREPARATION PROCESSES AND USES THEREFOR

The present invention provides derivatives of moxonidine, 1-[l-[(4,6-dichloro-2-methyl-6-5-pyrimidinyl)imino]ethyl]-2-imidazolidinone of formula (V) and l-[l-[(4-chloro-2-methyl-6-methoxy-5-pyrimidinyl)imino]ethyl]-2-imidazolidinone of formula (VI), which can be used for testing the purity or monitoring the production of moxonidine, and process for preparing the derivatives. Also provided is an improved process for preparing 4,6- dichloro-2-methyl-5-(l-acetyl-2-imidazolin-2-yl)-aminopyrimidine (DMAIA) and a method of utilizing the process to produce moxonidine.

Novel purification process of moxonidine

The present invention provides a novel purification process of Moxonidine avoiding nitromethane and using instead class 3 solvents or selected class 2 solvents for preparing highly pure Moxonidine, e.g, the crystalline Moxonidine form I.

The use of moxonidine salts for purification of moxonidine

The present invention provides crystalline Moxonidine salts e.g., mono-Moxonidine oxalate and mono-Moxonidine formate. Also provided by the present invention is a novel purification process of Moxonidine using these crystalline Moxonidine salts. By precipitating a Moxonidine salt from the reaction mixture and reacting it with a base, highly pure crystalline Moxonidine base is obtained in high yield.

Improved process for producing moxonidine

The present invention provides improved process for production of highly pure Moxonidine comprising reacting the starting material 6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (DMAIA) with different bases (e.g., sodium hydroxide or potassium hydroxide), thus avoiding the use of sodium methoxide while carrying out the reaction at milder conditions. While using sodium methoxide, is not needed to use methanol as solvent and a more friendly class 3 solvent (e.g., DMSO) is used instead. The reaction may be carried out at ambient temperature and it is not necessary to use two-fold excess of the base as about 1.0-1.1 molar excess of sodium methoxide in relation to DMAIA is sufficient.