(19)
(11)EP 3 619 198 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
17.06.2020 Bulletin 2020/25

(21)Application number: 18743444.4

(22)Date of filing:  16.07.2018
(51)International Patent Classification (IPC): 
C07D 239/47(2006.01)
(86)International application number:
PCT/EP2018/069193
(87)International publication number:
WO 2019/016111 (24.01.2019 Gazette  2019/04)

(54)

METHOD FOR PREPARATION OF CHLORINATED S-PROPYLTHIOBARBITURIC ACID

VERFAHREN ZUR HERSTELLUNG VON CHLORIERTER S-PROPYLTHIOBARBITURINSÄURE

PROCÉDÉ DE PRÉPARATION D'ACIDE S-PROPYL-THIOBARBITURIQUE CHLORÉ


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 18.07.2017 EP 17181961
18.07.2017 US 201762533838 P

(43)Date of publication of application:
11.03.2020 Bulletin 2020/11

(73)Proprietor: Lonza Ltd
3930 Visp (CH)

(72)Inventors:
  • BERSIER, Michael
    3938 Ausserberg (CH)
  • HANSELMANN, Paul
    3902 Brig-Glis (CH)
  • STOFFEL, Candid
    3932 Visperterminen (CH)


(56)References cited: : 
WO-A1-99/05142
WO-A2-2011/017108
US-A1- 2013 030 176
WO-A2-02/00628
WO-A2-2012/085665
  
  • H. G. DU ET AL: "Synthesis, Antiplatelet Aggregation Activity Evaluation and 3D-QSAR of a Series of Novel 6-Alkylamino(Alkoxyl)-2-Propylthio-8-Azapu rine Nucleosides : Synthesis, Antiplatelet Aggregation Activity Evaluation and 3D-QSAR of a Series of Novel 6-Alkylamino(Alkoxyl)-2-Propylthio-8-Azapu rine Nucleosides", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 54, no. 1, 1 January 2017 (2017-01-01), pages 436-449, XP055425333, US ISSN: 0022-152X, DOI: 10.1002/jhet.2601
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description


[0001] The invention discloses a method for preparation of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine by conversion of 5-nitro-2-propylthiopyrimidine-4,6-diol with phosgene in the presence of DMF.

BACKGROUND OF THE INVENTION



[0002] US 2013/0030176 A1 discloses of method for preparation of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine and its use as intermediate for the preparation of ticagrelor. Example 10 discloses a yield of 233.5 g of the 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (MW 266 g/mol) with a purity of 99.45% is disclosed; with a MW of 229 g/mol for the substrate 5-nitro-2-propylthiopyrimidine-4,6-diol and a starting amount of 200 g the yield is 99.9%, which is admittedly very high.
Nevertheless the method uses phosphorous oxychloride (MW 153 g/mol) as Cl source for the exchange of the OH residues against Cl. The given 425.6 g of phosphorous oxychloride are converted by the reaction ultimately to 271 g phosphoric acid H3PO4 (MW 100). So 1.16 times, of the weight of the product, of phosphoric acid needs to be disposed of. This waste is a serious environmental challenge as well as a cost factor.

[0003] There was a need for a process that does not pose the mentioned waste problem in form of H3PO4.

[0004] An extensive screening of phosgene as alternative Cl source without catalyst, with various catalysts and with various solvents was not successful but showing yields of not more than 32%, instead showing significant amounts of undesired by products, as documented herein under Comparative Examples 1 to 60. Only one combination, the combination of phosgene with DMF, surprisingly showed satisfying yields.

[0005] The method has the advantage of comparably high yields without the problem of generation of H3PO4 as waste.

[0006] The following abbreviations are used, if not otherwise stated:

compound of formula (1) 5-nitro-2-propylthiopyrimidine-4,6-diol, also called 5-nitro-2-propylsulfanyl-pyrimidine-4,6-diol

compound of formula (2) 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine DMF dimethyl formamide

eq equivalent

RT room temperature

MW molecular weight


SUMMARY OF THE INVENTION



[0007] Subject of the invention is a method for the preparation of compound of formula (2)

by a reaction REAC1 of compound of formula (1)

with a compound PHOS in the presence of DMF;
PHOS is selected from the group consisting of phosgene, diphosgene, triphosgene and mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION



[0008] Compound of formula (1) is a known compound and can be produced by known methods.

[0009] Preferably, PHOS is phosgene.

[0010] Preferably, the molar amount of PHOS is from 2 to 5 times, more preferably from 2 to 4 times, even more preferably from 2 to 3 times, of the molar amount of compound of formula (1).

[0011] Preferably, the amount of DMF is from 10 to 100 times, more preferably from 15 to 75 times, even more preferably from 15 to 50 times, especially from 15 to 40 times, more specially from 20 to 30 times, of the weight of PHOS.

[0012] Preferably, the reaction temperature TEMPI of REAC1 is from -10 to 50°C, more preferably from -5 to 40°C, even more preferably from -5 to 30°C, especially from -2.5 to 25°C.

[0013] Preferably, the reaction time TIME1 of REAC1 is from 5 h to 48 h, more preferably from 10 h to 24 h, even more preferably of from 12 h to 20 h.

[0014] In one embodiment, REAC1 is in the beginning of TIME1 done at a lower temperature than at the end of TIME1;
preferably, REAC1 is done at first for 4.5 h to 41 h at -10 to 9°C and thereafter for 30 min to 7 h at 10 to 50°C;
more preferably, REAC1 is done at first for 9 h to 21 h at -5 to 7°C and thereafter for 1 h to 3 h at 12 to 40 °C;
even more preferably, REAC1 is done at first for 10.5 h to 19.5 h at -5 to 5°C and thereafter for 1.5 h to 2.5 h at 15 to 30°C;

[0015] Preferably, the DMF acts also as solvent in REAC1.
More preferably, compound of formula (1) is dissolved in DMF to provide a solution SOL-1, and PHOS is dissolved in DMF to provide a solution SOL-PHOS; and SOL-1 and SOL-PHOS are mixed with each other to provide for REAC1; preferably, for the mixing of SOL-1 with SOL-PHOS, SOL-1 is added to SOL-PHOS.

[0016] Therefore in one embodiment, the amount of DMF for preparation of SOL-1 is from 1 to 10 times, more preferably from 1.5 to 7.5 times, even more preferably from 2.5 to 7.5 times, of the weight of compound of formula (1); and
the amount of DMF for preparation of SOL-PHOS is from 10 to 90 times, more preferably from 10 to 50 times, even more preferably from 15 to 40 times, especially from 15 to 30 times, of the weight of PHOS.

[0017] After REAC1, compound of formula (2) can be isolated and purified by conventional methods, which are known to those skilled in the art. These conventional methods include quenching the reaction mixture from REAC1 with water, with a solvent or with both water and a solvent, extraction, distillation, preferably fractional distillation, which can be done under reduced pressure, crystallization, chromatography, filtration, washing or any combination of these methods.
Preferably, the solvent that is used for quenching the reaction mixture is preferably an organic solvent, more preferably toluene; preferably, the quenching is done with water and toluene, thereby two phases are generated; then the phases are separated and the organic phase is evaporated to provide compound of formula (2).
Preferably, after REAC1 toluene and water is added to the reaction mixture.
Preferably, the amount of water is from 5 to 15 times, more preferably from 7.5 to 12.5 times, of the weight of compound of formula (1).
Preferably, the amount of toluene is from 4 to 14 times, more preferably from 6.5 to 11 times, of the weight of compound of formula (1).
Preferably, the addition of toluene and water is done at a temperature of from -10 to 30°C, more preferably of from -5 to 20°C, even more preferably of from -5 to 15°C, especially of from -5 to 10°C, more especially of from -5 to 5°C, even more especially of from -2.5 to 2.5°C.

Examples



[0018] 






GC Method


Instrument:



[0019] Hewlett Packard gas chromatograph 6890 with a split injector and a flame ionisation detector or an instrument with corresponding performance and quality.

Column:



[0020] HP-1 (SIMDIST), 15 m x 0.53 mm, 0.15 micrometer film-thickness, polydimethylsiloxane (or an equivalent column).

Instrument. Settings:



[0021] 
OVEN:
INITIAL TEMP 50°C
HOLD 2 min
RAMP 1 20°C / min
NEXT TEMP 320°C
HOLD 10 min
INJECTOR:
Injection volume 1 microliter
Check the auto-injector parameters.
INLETS:
INJ. MODE Split
INJ TEMP 250°C
SPLIT FLOW 200 ml / min
SPLIT RATIO 25 : 1
MODE constant flow 8.0 ml / min
DETECTORS:
DET TEMP 300°C
Check the FID gas flow rates.

[0022] The GC results are given in area %.

Comparative Examples 1 to 42 - with Base



[0023] 5.0 g (21.62 mmol, 1 eq) of compound of formula (1) were dissolved in 25 mL of solvent SOLV and base was added. 100 mL of SOLV were mixed with 4.7 g of phosgene (47.56 mmol. 2.2 eq) at 0°C. The solution of compound of formula (1) and base was added at 0°C to the mixture of SOLV with phosgene. After stirring for 5 h at 0°C and then for 2 h at RT, a sample from the reaction mixture was taken and analysed with GC. Result are shown in Table 1 with the following abbreviations:
CE
Comparative Example
DPA-2.2
Diisopropylamine, 2.2 eq
DPA-2.5
Diisopropylamine, 2.5 eq
EMP-2.2
5-Ethyl-2-methylpyridine, 2.2 eq
NMM-2.2
N-Methylmorpholine, 2.2 eq
TEA-2.2
Triethylamine (2.2 eq.)
(2)
compound of formula (2)
(3)
compound of formula (2)
(4)
compound of formula (4)
 Table 1    
CEBaseSOLVGC Results  
   (2)(3)(4)
1 DPA-2.2 Dichloromethane 20% 15% 10%
2 DPA-2.2 Toluene 25% 12% 8%
3 DPA-2.2 Acetonitrile 30% 17% 12%
4 DPA-2.2 Chlorobenzene 10% 18% 9%
5 DPA-2.2 Sulfolane 32% 12% 14%
6 DPA-2.2 Dimethyl carbonate 12% 19% 5%
7 DPA-2.5 Dichloromethane 20% 15% 10%
8 DPA-2.5 Toluene 25% 12% 8%
9 DPA-2.5 Acetonitrile 30% 17% 12%
10 DPA-2.5 Chlorobenzene 10% 18% 9%
11 DPA-2.5 Sulfolane 32% 12% 14%
12 DPA-2.5 Dimethyl carbonate 12% 19% 5%
13 3-Picoline (2.2 eq.) Dichloromethane 21% 18% 11%
14 3-Picoline (2.2 eq.) Toluene 28% 13% 8%
15 3-Picoline (2.2 eq.) Acetonitrile 31% 12% 7%
16 3-Picoline (2.2 eq.) Chlorobenzene 17% 22% 15%
17 3-Picoline (2.2 eq.) Sulfo lane 22% 18% 10%
18 3-Picoline (2.2 eq.) Dimethyl carbonate 28% 11% 15%
19 TEA-2.2 Dichloromethane 20% 14% 8%
20 TEA-2.2 Toluene 25% 12% 8%
21 TEA-2.2 Acetonitrile 30% 17% 12%
22 TEA-2.2 Chlorobenzene 10% 18% 9%
23 TEA-2.2 Sulfolane 32% 12% 14%
24 TEA-2.2 Dimethyl carbonate 12% 19% 5%
25 Pyridine (2.2 eq.) Dichloromethane 20% 15% 10%
26 Pyridine (2.2 eq.) Toluene 25% 12% 8%
27 Pyridine (2.2 eq.) Acetonitrile 30% 17% 12%
28 Pyridine (2.2 eq.) Chlorobenzene 12% 19% 5%
29 Pyridine (2.2 eq.) Sulfolane 20% 15% 10%
30 Pyridine (2.2 eq.) Dimethyl carbonate 25% 12% 8%
31 EMP-2.2 Dichloromethane 30% 17% 12%
32 EMP-2.2 Toluene 10% 18% 9%
33 EMP-2.2 Acetonitrile 32% 12% 14%
34 EMP-2.2 Chlorobenzene 12% 19% 5%
35 EMP-2.2 Sulfolane 21% 18% 11%
36 EMP-2.2 Dimethyl carbonate 28% 13% 8%
37 NMM-2.2 Dichloromethane 16% 15% 8%
38 NMM-2.2 Toluene 20% 15% 15%
39 NMM-2.2 Acetonitrile 18% 15% 5%
40 NMM-2.2 Chloro benzene 20% 18% 10%
41 NMM-2.2 Sulfo lane 22% 18% 10%
42 NMM-2.2 Dimethyl carbonate 28% 15% 8%

Comparative Examples 43 to 60 - without Base



[0024] 5.0 g (21.62 mmol, 1 eq) of compound of formula (1) were dissolved in 125 mL of solvent SOLV and Catalyst was added. 4.7 g of phosgene (47.56 mmol, 2.2 eq) were added at 0°C. After 5 h at 0°C, then 2 h at RT and then 2 h at 40°C, a sample from the reaction mixture was taken and analysed with GC.

[0025] Result are shown in Table 2 with the following abbreviations:
(2)
compound of formula (2)
CE
Comparative Example
TPP-0.1
Triphenylphosphine, 0.1 eq
TPP-0.3
Triphenylphosphine, 0.3 eq
CETable 2  
 CatalystSOLVRemarks
43 TPP-0.1 Dichloromethane less than 0.5% of (2)
44 TPP-0.1 Toluene less than 0.5% of (2)
45 TPP-0.1 Acetonitrile less than 0.5% of (2)
46 TPP-0.1 Chlorobenzene less than 0.5% of (2)
47 TPP-0.1 Sulfolane less than 0.5% of (2)
48 TPP-0.1 Dimethyl carbonate less than 0.5% of (2)
49 TPP-0.3 Dichloromethane less than 0.5% of (2)
50 TPP-0.3 Toluene less than 0.5% of (2)
51 TPP-0.3 Acetonitrile less than 0.5% of (2)
52 TPP-0.3 Chlorobenzene less than 0.5% of (2)
53 TPP-0.3 Sulfolane less than 0.5% of (2)
54 TPP-0.3 Dimethyl carbonate less than 0.5% of (2)
55 no catalyst Dichloromethane less than 0.5% of (2)
56 no catalyst Toluene less than 0.5% of (2)
57 no catalyst Acetonitrile less than 0.5% of (2)
58 no catalyst Chlorobenzene less than 0.5% of (2)
59 no catalyst Sulfolane less than 0.5% of (2)
60 no catalyst Dimethyl carbonate less than 0.5% of 2

Example 1 - with DMF



[0026] 5.0 g (21.62 mmol, 1 eq) compound of formula (1) were dissolved in 25 mL of DMF. 100 mL of DMF were mixed with 4.7 g of phosgene (47.56 mmol, 2.2 eq) at 0°C. The solution of compound of formula (1) was added to the mixture of DMF with phosgene at 0°C. After 14 h stirring at 0°C and then 2 h at RT, 50 mL of water and 50 mL of toluene were added at 0°C. The mixture was stirred 15 min and the phases were separated. The organic phase was evaporated under vacuum. 5 g of compound of formula (2) were isolated (83% yield, 98.2% purity, GC analysis showed 1.1% of compound of formula (3), 0.32% of compound of formula (4) and 0.35% of compound of formula (5)).

Example 2 - with DMF



[0027] 50 g (216.2 mmol, 1 eq) of compound of formula (1) were dissolved in 250 mL of DMF. 1000 mL of DMF were mixed with 47 g of phosgene (475.6 mmol, 2.2 eq) at 0°C. The solution of compound of formula (1) was added to the mixture of DMF with phosgene at 0°C. After 14 h stirring at 0°C and then 2 h at RT, 500 mL of water and 500 mL of toluene were added at 0°C. The mixture was stirred 30 min and the phases were separated. The organic phase was evaporated under vacuum. 54 g of compound of formula (2) were isolated (93% yield, 98.4% purity, GC analysis showed 1.1% of compound of formula (3), 0.26% of compound of formula (4) and 0.24% of compound of formula (5)).


Claims

1. Method for the preparation of compound of formula (2)

by a reaction REAC1 of compound of formula (1)

with a compound PHOS in the presence of DMF;
PHOS is selected from the group consisting of phosgene, diphosgene, triphosgene and mixtures thereof.
 
2. Method according to claim 1, wherein
PHOS is phosgene.
 
3. Method according to claim 1 or 2, wherein
the molar amount of PHOS is from 2 to 5 times of the molar amount of compound of formula (1).
 
4. Method according to one or more of claims 1 to 3, wherein
the amount of DMF is from 10 to 100 times of the weight of PHOS.
 
5. Method according to one or more of claims 1 to 4, wherein
the reaction temperature TEMPI of REAC1 is from -10 to 50°C.
 
6. Method according to one or more of claims 1 to 5, wherein
the reaction time TIME1 of REAC1 is from 5 h to 48 h.
 
7. Method according to one or more of claims 1 to 6, wherein
compound of formula (1) is dissolved in DMF to provide a solution SOL-1, and PHOS is dissolved in DMF to provide a solution SOL-PHOS; and SOL-1 and SOL-PHOS are mixed with each other to provide for REAC1.
 
8. Method according to claim 7, wherein
for the mixing of SOL-1 with SOL-PHOS, SOL-1 is added to SOL-PHOS.
 
9. Method according to one or more of claims 1 to 8, wherein
after REAC1 toluene and water is added to the reaction mixture.
 
10. Method according to one or more of claims 1 to 9, wherein
the addition of toluene and water is done at a temperature of from -10 to 30°C.
 


Ansprüche

1. Verfahren zur Herstellung der Verbindung der Formel (2)

durch eine Reaktion REAC1 der Verbindung der Formel (1)

mit einer Verbindung PHOS in Gegenwart von DMF; wobei PHOS aus der Gruppe bestehend aus Phosgen, Diphosgen, Triphosgen und Mischungen davon ausgewählt wird.
 
2. Verfahren nach Anspruch 1, wobei
es sich bei PHOS um Phosgen handelt.
 
3. Verfahren nach Anspruch 1 oder 2, wobei
sich die molare Menge von PHOS auf das 2- bis 5-fache der molaren Menge der Verbindung der Formel (1) beläuft.
 
4. Verfahren nach einem oder mehreren der Ansprüche 1 bis 3, wobei
sich die Menge von DMF auf das 10- bis 100-fache des Gewichts von PHOS beläuft.
 
5. Verfahren nach einem oder mehreren der Ansprüche 1 bis 4, wobei
die Reaktionstemperatur TEMP1 von REAC1 -10 bis 50 °C beträgt.
 
6. Verfahren nach einem oder mehreren der Ansprüche 1 bis 5, wobei
die Reaktionszeit TIME1 von REAC1 5 h bis 48 h beträgt.
 
7. Verfahren einem oder mehreren der Ansprüche 1 bis 6, wobei
die Verbindung der Formel (1) in DMF gelöst wird, was eine Lösung SOL-1 ergibt, und PHOS in DMF gelöst wird, was eine Lösung SOL-PHOS ergibt, und SOL-1 und SOL-PHOS miteinander gemischt werden, wodurch REAC1 bereitgestellt wird.
 
8. Verfahren nach Anspruch 7, wobei
zum Mischen von SOL-1 mit SOL-PHOS SOL-1 zu SOL-PHOS gegeben wird.
 
9. Verfahren nach einem oder mehreren der Ansprüche 1 bis 8, wobei
nach REAC1 Toluol und Wasser zur Reaktionsmischung gegeben werden.
 
10. Verfahren nach einem oder mehreren der Ansprüche 1 bis 9, wobei
die Zugabe von Toluol und Wasser bei einer Temperatur von -10 bis 30 °C erfolgt.
 


Revendications

1. Procédé de préparation d'un composé de formule (2)

par une réaction REAC1 d'un composé de formule (1)

avec un composé PHOS en présence de DMF ;
PHOS est choisi dans le groupe constitué de phosgène, diphosgène, triphosgène et des mélanges de ceux-ci.
 
2. Procédé selon la revendication 1, dans lequel
PHOS est le phosgène.
 
3. Procédé selon la revendication 1 ou 2, dans lequel la quantité molaire de PHOS est de 2 à 5 fois la quantité molaire du composé de formule (1).
 
4. Procédé selon une ou plusieurs des revendications 1 à 3, dans lequel
la quantité de DMF est de 10 à 100 fois le poids de PHOS.
 
5. Procédé selon une ou plusieurs des revendications 1 à 4, dans lequel
la température de réaction TEMPI de REAC1 est de -10 à 50 °C.
 
6. Procédé selon une ou plusieurs des revendications 1 à 5, dans lequel
le temps de réaction TIME1 de REAC1 est de 5 h à 48 h.
 
7. Procédé selon une ou plusieurs des revendications 1 à 6, dans lequel
un composé de formule (1) est dissous dans du DMF pour produire une solution SOL-1, et PHOS est dissous dans du DMF pour produire une solution SOL-PHOS ; et SOL-1 et SOL-PHOS sont mélangées l'une avec l'autre pour produire REAC1.
 
8. Procédé selon la revendication 7, dans lequel
pour le mélange de SOL-1 avec SOL-PHOS, SOL-1 est ajouté à SOL-PHOS.
 
9. Procédé selon une ou plusieurs des revendications 1 à 8, dans lequel
après REAC1, du toluène et de l'eau sont ajoutés au mélange de réaction.
 
10. Procédé selon un ou plusieurs des revendications 1 à 9, dans lequel
l'ajout de toluène et d'eau est effectué à une température de -10 à 30 °C.
 






Cited references

REFERENCES CITED IN THE DESCRIPTION



This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description