Method for producing 2-amino-4,6-dichloro-5-formamidopyrimidine
Description
2-Amino-4,6-dichloro-5-formamidopyrimidine is a valuable intermediate for
the preparation of purine derivatives, as find use, for example, as active
pharmaceutical ingredients in the treatment of viral diseases, for example in
the treatment of AIDS. Such a medicament and routes to its preparation
have been described in detail (cf. Susan M. Daluge et. al., Nucleosides,
Nucleotides & Nucleic Acids, 19(1&2), 297-327 (2000)).
Routes for the synthesis of 2-amino-4,6-dichloro-5-formamidopyrimidine
have already been described in accordance with the prior art. The known
processes are based on the principle that 2,5-diamino-4,6-dihydroxy-
pyrimidine (or a salt thereof) is reacted with a chlorinating agent and a
formamide and/or a Vilsmeyer-type reagent. In this process, the amino
groups, which tend to side reactions in unprotected form, are protected as
formamidines, the hydroxyl groups are chlorinated and the protecting groups
are removed again partially of fully in subsequent steps. The overall
synthesis sequence can be illustrated with the following scheme:

This reaction has already been considered in detail in the patent literature.
For example, US 6,552,193 describes the reaction of 2,5-diamino-
4,6-dihydroxypyrimidine hemisulfate A with chloromethylenedimethyl-
ammonium chloride (Vilsmeyer reagent) in chloroform to give B
(R1, R2= CH3) in 81% yield, the hydrolysis thereof to give C in 95% yield and
the further reaction of C to give 2-amino-4,6-dichloro-5-formamidopyrimidine
D in a phosphate buffer with 68% yield. The overall yield over all 3 stages is
52%. According to the teaching from US 6,552,193, an inert solvent, for
example dichloromethane, chloroform or dichloroethane, is required for the
first reaction step (the chlorination).
US 5,663,340 and EP 684 236 describe the chlorination of A with
phosphorus oxychloride in the presence of dimethylformamide using an inert
solvent (examples include toluene, xylene, chloroform, dichloromethane,
dichloroethane, chlorobenzene) to form B (R1, R2 = CH3) and further reaction
to give C (without isolation of B) in 85% yield. The conversion of C to D is
effected in the presence of aqueous propionic acid in 64% yield. The overall
yield is thus 54%.
Although these prior art processes mentioned fulfill their purpose of providing
2-amino-4,6-dichloro-5-formamidopyrimidine D as an intermediate for
preparing antiviral pharmaceuticals, they display significant disadvantages.
For the chlorination step a), considerable amounts of chlorinated and/or
aromatic solvents are used. This gives rise to an unfavorable space-time
yield and considerable environmental pollution. The salt-containing
wastewaters obtained from the chlorination step have to be disposed of, but
a reagent (phosphate buffer or propionic acid) again has to be used for the
subsequent hydrolysis step from C to D.
In addition, it is not evident from the prior art - in spite of some experiments
with "one-pot variants" - that a direct process for preparing D from A without
isolating the intermediates might be possible. All of these factors increase
the amount of the raw materials used and the residual materials to be
disposed of, worsen the space-time yield in the production and lead
additionally to considerable environmental pollution.
It was therefore an object of the invention to provide a simple and
environmentally friendly process for preparing 2-amino-4,6-dichloro-
5-formamidopyrimidine from 2,5-diamino-4,6-dihydroxypyrimidine or a salt
Owing to the easy oxidizability of the free base, especially the hemisulfate,
the hydrochloride monohydrate and the anhydrous hydrochloride are
particularly suitable. In order to avoid unnecessary reagent consumption and
undesired sulfate ions, particular preference is given to using anhydrous
2,5-diamino-4,6-dihydroxypyhmidine hydrochloride.
The chlorinating agents used may be various inorganic and organic reagents
having the functionality of an acid chloride. Examples include phosgene,
oxalyl chloride, chloromethylenedimethylammonium chloride (Vilsmeyer
reagent), thionyl chloride, sulfuryl chloride, phosphorus trichloride,
phosphorus pentachloride or phosphorus oxychloride. Particular preference
is given to using phosphorus oxychloride.
The formamide of the formula (I) serves to formylate the amino groups of the
starting material and to protect them as the formamidine.

The intermediates obtained in stage a) are the 2,5-diformamidino-
4,6-dichloropyrimidines of the formula (II):
The particular R1 and R2 radicals are detached again in the further reaction
to give the end product, so that, irrespective of the amide of the formula I
used, the same end product is always obtained. The R1 and R2 radicals are
each independently a C1 to C4-alkyl radical and in particular methyl, ethyl,
n-propyl or/and n-butyl. Alternatively, the R1 and R2 radicals can be joined via
a single bond and can assume the definition -(CH2)n- where n = from 4 to 6
or -(CH2)2-O-(CH2)2-- Preferred amides of the formula (I) are N,N-dimethyl-
formamide, N-formylpyrrolidine, N-formylpiperidine and N-formylmorpholine.
Particular preference is given to N,N-dimethylformamide.
The molar ratios of the reactants in the chlorination step can be varied within
wide limits. Preference is given to using from 1 to 5 mol of formamide of the
formula (I) per 1 mol of 2,5-diamino-4,6-dihydroxypyrimidine. Preference is
further given to using from 3 to 7 mol of chlorinating agent per 1 mol of
2,5-diamino-4,6-dihydroxypyrimidine. For the special case of use of
phosphorus oxychloride and N,N-dimethylformamide, preference is given to
using from 3 to 5 mol of phosphorus oxychloride and from 1 to 3 mol of
N,N-dimethylformamide per mole of 2,5-diamino-4,6-dihydroxypyrimidine.
In a preferred embodiment, the chlorinating agent is first mixed with the
formamide and only in a second step is the 2,5-diamino-
4,6-dihydroxypyrimidine, as the case may be, metered in slowly or added in
portions. In this way, it is ensured that the insoluble 2,5-diamino-
4,6-dihydroxypyrimidine added is reacted continually to give soluble
subsequent products of the structure (II), so that stirrability remains ensured.
In a preferred embodiment, the chlorinating agent is initially charged. The
N,N-dialkylformamide is then added at a temperature of from 20 to 100°C,
preferably from 40 to 70°C, and the reaction mixture is allowed to react at
this temperature for a period of from 5 to 180 minutes. The 2,5-diamino-
4,6-dihydroxypyrimidine is metered in at a temperature of from 50 to 130°C,
preferably from 50 to 100°C, over the course of from 15 minutes to 5 hours.
Subsequently, continued reaction is effected over from 1 to 30 hours at a
temperature of from 50 to 130°C, preferably from 70 to 110°C.
In a preferred embodiment, reaction step a) is effected within a temperature
range from 70 to 110°C.
The subsequent hydrolysis step can in principle be carried out in two
different ways. One is to meter the amount of water required directly into the
chlorination mixture. This is advantageous since no further reaction vessel is
required, but has the disadvantage of a metering time which is longer owing
to the high heat production. Alternatively, with the same result, the
chlorination mixture can be metered into initially charged water.
The added or initially charged water should be sufficient, after the end of the
hydrolysis, to obtain a readily stirrable reaction mixture. According to the
invention, from 2 to 5 liters of water per 1 mol of 2,5-diamino-4,6-
dihydroxypyrimidine used are sufficient for this purpose.
The hydrolysis step b) should be effected within the temperature range from
0 to 100°C. The range from 20 to 60°C is considered to be preferable.
Subsequently, the resulting reaction mixture is adjusted to a certain pH with
an inorganic base and partially hydrolyzed in this way.
Suitable inorganic bases are in principle all bases which form soluble
chloride salts. Preference is given to sodium hydroxide solution, sodium
hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium
hydroxide solution, potassium hydroxide, potassium carbonate and
potassium hydrogencarbonate. Particular preference is given to sodium
hydroxide solution. The amount of base added depends upon the pH to be
established and it is typically from 2 to 3 mol per mole of chlorinating agent
used.
The pH is crucial, since it controls the selective reaction of B via C to D. In
the case of incorrectly selected pH, a reduced yield and/or undesired by-
products in the product are obtained. According to the invention, the pH is
adjusted at a defined value in the range between pH 1.0 and 6.0, preferably
from pH 2.0 to 5.0, more preferably from 3.0 to 4.0, the pH being measured
by means of a glass electrode at a temperature of 20°C. If appropriate, the
pH can be readjusted continuously in the course of the reaction which
follows by adding further base under pH control.
The further reaction is carried out by heating the aqueous mixture to a
temperature of from 70 to 120°C, preferably from 80 to 100°C. In the course
of a reaction time of from 1 to 20 hours, the unisolated intermediates form
the desired target product 2-amino-4,6-dichloro-5-formamidopyrimidine. This
is insoluble in the reaction mixture and can be removed, washed and dried
by means of process steps familiar to those skilled in the art.
It is considered to be essential to the invention that this last reaction step is
effected in the absence - even of traces - of a solvent. This is because it has
been found to be capable of starting to dissolve the water-insoluble 2-amino-
4,6-dichloro-5-formamidopyrimidine in the reaction mixture, which makes the
pyrimidine more vulnerable to a further hydrolysis, so that the ultimate result
is reduced yields and/or contamination of the product with 2,5-diamino-
4,6-dichloropyrimidine, the subsequent product of the hydrolysis.
The process according to the invention affords satisfactory yields which are
only slightly below the yields of the prior art processes. On the other hand, it
offers the advantage of higher purity of the end products. The considerably
reduced reaction volumes, the savings of solvents, assistants and residual
substances, and the considerably simplified process in process technology
terms, give rise to distinctly more favorable preparation costs for 2-amino-
4,6-dichloro-5-formylaminopyrimidine.
A further aspect of the invention relates to the use of the 2-amino-
4,6-dichloro-5-formylaminopyrimidine prepared by the process according to
the invention for preparing purine derivatives. The invention further relates to
the use of the 2-amino-4,6-dichloro-5-formylaminopyrimidine prepared by the
process according to the invention for preparing active pharmaceutical
ingredients, in particular for antiviral medicaments, for example for the
treatment of AIDS.
The examples which follow serve to illustrate the process found without
restricting the scope of the invention.
Examples
Example 1
61.33 g (0.40 mol) of phosphorus oxychloride were initially charged. At 50°C,
18.27 g (0.25 mol) of dimethylformamide were added dropwise within 45
minutes. The mixture was then heated to 70°C and 17.86 g (0.10 mol) of
2,5-diamino-4,6-dihydroxypyrimidine hydrochloride were added by spatula
within 45 minutes. Subsequently, the mixture was heated to 90°C and stirred
for 20 hours. A dark, moderately viscous, but homogeneous and readily
stirrable mixture formed. It was cooled to 20°C and admixed with 200 g of
water with external cooling. Addition of 82.03 g of 50% sodium hydroxide
solution adjusted the pH from -0.6 to 4.0, and the reaction mixture was
heated to 90°C and stirred for 8 hours. The mixture was cooled to 18°C, and
the precipitated product was filtered off with suction, washed with water and
dried under reduced pressure.
8.28 g of pure 2-amino-4,6-dichloro-5-formamidopyrimidine were obtained
with a content of 98.7%. The yield based on 2,5-diamino-4,6-dihydroxy-
pyrimidine used was 39.5%.
Example 2
61.33 g (0.40 mol) of phosphorus oxychloride were initially charged and
heated to 50°C. Within 45 minutes, 29.24 g (0.40 mol) of dimethylformamide
were added dropwise. The mixture was then heated to 72°C and 17.86 g
(0.10 mol) of 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride were added
within 45 minutes. The mixture was heated to 90°C and stirred for 17 hours.
The mixture was then cooled to 20°C and admixed with 200 g of water with
external cooling. Addition of 88.35 g of 50% sodium hydroxide solution
adjusted the pH from -0.5 to 3.6, and the reaction mixture was heated to
97°C and stirred for 4 hours. The mixture was cooled to 18°C, and the
precipitated product was filtered off with suction, washed with water and
dried under reduced pressure.
7.92 g of pure 2-amino-4,6-dichloro-5-formamidopyrimidine were obtained
with a content of 97.6%. The yield based on 2,5-diamino-4,6-dihydroxy-
pyrimidine used was 37.4%.
Example 3 (comparative)
180 ml of toluene and 76.7 g (0.5 mol) of phosphorus oxychloride were
initially charged. At 50°C, 29.2 g of dimethylformamide were added dropwise
within 45 minutes. At 70°C, 17.86 g (0.1 mol) of 2,5-diamino-4,6-dihydroxy-
pyrimidine hydrochloride were then added in portions. Subsequently, the
mixture was stirred at 90°C for 20 hours. A viscous mass formed, which
adhered to stirrer and flask wall and was only partially soluble in toluene.
After cooling, 300 g of water were metered into the mixture, the pH was
adjusted to 5.0 by adding 89.6 g of 50% sodium hydroxide solution and the
toluene phase was removed. An interface layer which was difficult to remove
formed. After the toluene phase had been evaporated, 15.9g of crude
2,5-bis(dimethylaminomethyleneamino)-4,6-dichloropyrimidine remained.
The water phase was extracted 3 times with 200 ml each time of ethyl
acetate, and the organic phases were concentrated by evaporation. 9.8 g of
a second, less pure fraction of 2,5-bis(dimethylaminomethyleneamino)-
4,6-dichloropyrimidine remained.
250 g of water and 5.7 g of 85% phosphoric acid were initially charged, and
adjusted to pH 4.0 with 3.7 g of sodium hydroxide solution, and the mixture
of the two crude products was added. The mixture was again adjusted to pH
4.0 with 10.5 g of phosphoric acid. The mixture was stirred at 100°C for 4
hours. After cooling, the precipitated product was filtered off, washed and
dried. 11.3 g of 2-amino-4,6-dichloro-5-formamidopyrimidine were obtained
with a content of 83.8%. The pure yield based on 2,5-diamino-
4,6-dihydroxypyrimidine used was 45.7%.
An experiment carried out analogously using chlorobenzene instead of
toluene lead to better stirrability of the reaction mixture. After extracting 3
times with chlorobenzene and analogous reaction in a phosphate buffer,
12.4 g of 2-amino-4,6-dichloro-5-formamidopyrimidine were obtained with a
content of 78.3%. It was found that chlorobenzene distilled off incompletely
had brought about partial further hydrolysis to 2,5-diamino-
4,6-dichloropyrimidine.
New act of cTaiius-
Claims 1-20
1. A process for preparing 2-amino-4,6-dichloro-5-formamidopyrimidine
from 2,5-diamino-4,6-dihydroxypyrimidine or a salt thereof,
characterized in that
a) the 2,5-diamino-4,6-dihydroxypyrimidine or salt or tautomeric forms
thereof is reacted with a chlorinating agent and a formamide of the
formula (I)

where
R1 and R2 are each independently a Ci-C4-alkyl radical, or -R1-R2- is
-(CH2)n- where n = from 4 to 6 or -(CH2)2-0-(CH2)2-, without addition
of a solvent at from 50 to 130°C,
b) the reaction product from stage a) is reacted at from 0 to 100°C with
water and adjusted to a pH of from 1.0 to 6.0 with an inorganic base
and
c) the aqueous reaction mixture from stage b) is reacted at from 70 to
120°C with hydrolysis to give 2-amino-4,6-dichloro-5-formamido-
pyrimidine.
2. The process as claimed in claim 1,
characterized in that
the starting material used is 2,5-diamino-4,6-dihydroxypyrimidine as the
hemisulfate, hydrochloride monohydrate or as the anhydrous
hydrochloride, preferably anhydrous 2,5-diamino-4,6-dihydroxypyrimidine
hydrochloride as the raw material.
3. The process as claimed in claim 1 or 2,
characterized in that
the chlorinating agent used is a reagent having the functionality of an
acid chloride, preferably phosgene, oxalyl chloride, chloromethylene-
dimethylammonium chloride, thionyl chloride, sulfuryl chloride,
phosphorus trichloride, phosphorus pentachloride or phosphorus
oxychloride, more preferably phosphorus oxychloride.
4. The process as claimed in one of claims 1 to 3,
characterized in that
the amide of the formula (I) is reacted with the chlorinating agent in a
preceding step and the 2,5-diamjno-4,6-dihydroxypyrimidine is only then
added in portions.
5. The process as claimed in one of claims 1 to 4,
characterized in that
N,N-dimethylformamide, N-formylpyrrolidine, N-formylpiperidine or
N-formylmorpholine, preferably N,N-dimethylformamide, is used.
6. The process as claimed in one of claims 1 to 5,
characterized in that
from 1.0 to 5.0 mol of amide of the formula (I) per mole of 2,5-diamino-
4,6-dihydroxypyrimidine are used.
7. The process as claimed in one of claims 1 to 6,
characterized in that
from 3.0 to 7.0 mol of chlorinating agent per mole of 2,5-diamino-
4,6-dihydroxypyrimidine are used.
8. The process as claimed in one of claims 1 to 7,
characterized in that
reaction step a) is effected within a temperature range from 70 to 110°C.
9. The process as claimed in one of claims 1 to 8,
characterized in that
the inorganic base used in step b) is a base which forms soluble chloride
salts, preferably one or more compounds which are selected from the
group of sodium hydroxide solution, sodium hydroxide, sodium
carbonate, sodium hydrogencarbonate, potassium hydroxide solution,
potassium hydroxide, potassium carbonate and potassium hydrogen-
carbonate.
10. The process as claimed in one of claims 1 to 9,
characterized in that
the base used is sodium hydroxide solution.
11. The process as claimed in one of claims 1 to 10,
characterized in that
from 2 to 3 mol of the inorganic base are used per mole of chlorinating
agent.
12. The process as claimed in one of claims 1 to 11,
characterized in that
the partial neutralization in step b) is effected up to a pH of from 2.0 to
5.0, preferably from 3.0 to 4.0.
13. The process as claimed in one of claims 1 to 12,
characterized in that
the reaction product from stage a) is reacted at from 20 to 60°C.
14. The process as claimed in one of claims 1 to 13,
characterized in that
the hydrolysis in step c) is effected at a temperature of 70-120°C,
preferably from 80 to 100°C.
15. The process as claimed in one of claims 1 to 13,
characterized in that
step c) is effected in the absence of a solvent.
16. The process as claimed in one of claims 1 to 15,
characterized in that
the claimed reaction is effected without isolation of intermediates, i.e. as
a one-pot reaction.
17. A process for preparing purine derivatives, comprising the process steps
according to one of claims 1 to 16 and also the conversion of 2-amino-
4,6-dichloro-5-formamidopyrimidine to a purine derivative.
18. A process for preparing active pharmaceutical ingredients, comprising
the process steps according to claim 17 and also the conversion of the
purine derivative to an active pharmaceutical ingredient.
19. The process as claimed in claim 18, wherein the active pharmaceutical
ingredient is an antiviral medicament.
20. The process according to claim 19, wherein the antiviral medicament is a
medicament for the treatment of AIDS.

The invention relates to a method for producing 2-amino-4,6-dichloro-5-formamidopyrimidine
from 2,5-diamino-4,6-dihydroxypyrimidine or a salt thereof- According to said method, a)
2,5-diamino-4,6-dihydroxypyrimidine or the salt or tautomer forms thereof are reacted with a chlorination
agent and a formamide of formula (I) wherein R1 and R2 independently represent a C1-C4 alkyl
radical or -R1-R2- represents -(CH2)n- where n = 4-6, or -(CH2)2-0-(CH2)2-, without adding a solvent,
at a temperature of between 50 and 130°C, b) the reaction product obtained in step a) is reacted with
water at a temperature of between 0 and 100°C, and regulated to a pH value of between 1 and 6 with an inorganic base, and c) the
aqueous reaction mixture obtained in step b) is left to react at a temperature of between 70 and 120 °C under hydrolysis to form
2-amino-4,6-dichloor-5-formamidopyrimidine. The inventive method enables satisfactory yields and high levels of purity of the end
product to be obtained. As a result of the significantly reduced reaction volumes due to the solvent, auxiliary substances and residual
substances saved, and the significantly simplified method, the costs incurred in the production of 2-amino 4,6-dichloro-5-formy-
laminopyrimidine are significantly reduced.