PROCESS FOR THE PREPARATION OF PYRIDAZINONE DERIVATIVES

Abstract

The present invention provides, inter alia, a process for producing a compound of formula (I) wherein the substituents are as defined in claim 1. The present invention further provides intermediate compounds utilised in said process, and methods for producing said intermediate compounds.

##STR00001##

Claims

1. A process for the preparation of a compound of formula (I): ##STR00119## wherein A is a 6-membered heteroaryl selected from the group consisting of formula A-I to A-VII below ##STR00120## wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I), p is 0, 1 or 2; and Y is hydrogen or the group Y-I below ##STR00121## wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); and R.sup.1 is hydrogen; R.sup.2 is hydrogen; Q is (CR.sup.1aR.sup.2b).sub.m; m is 1; each R.sup.1a and R.sup.2b are hydrogen; Z is selected from the group consisting of CN, CH.sub.2OR.sup.3, CH(OR.sup.4)(OR.sup.4a), C(OR.sup.4)(OR.sup.4a)(OR.sup.4b), C(O)OR.sup.10, C(O)NR.sup.6R.sup.7 and S(O).sub.2OR.sup.10; or Z is selected from the group consisting of a group of formula Z.sub.a, Z.sub.b, Z.sub.c, Z.sub.d, Z.sub.e and Z.sub.f below ##STR00122## wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); and R.sup.3 is selected from the group consisting of hydrogen, C(O)OR.sup.10a and C(O)R.sup.10a; each R.sup.4, R.sup.4a and R.sup.4b are independently selected from C.sub.1-C.sub.6alkyl; each R.sup.5, R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, R.sup.5e, R.sup.5f, R.sup.5g and R.sup.5h are independently selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; each R.sup.6 and R.sup.7 are independently selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; each R.sup.8 is independently selected from the group consisting of halo, NH.sub.2, methyl and methoxy; R.sup.10 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, phenyl and benzyl; and R.sup.10a is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, phenyl and benzyl; said process comprising: reacting a compound of formula (II): ##STR00123## wherein A is as defined above; R.sup.13 is selected from the group consisting of halogen, O, OR.sup.16 and NR.sup.14R.sup.15; R.sup.14 and R.sup.15 are independently selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; or R.sup.14 and R.sup.15 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from nitrogen, oxygen and sulfur; and R.sup.16 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C(O)OR.sup.10a and C(O)R.sup.10a; R.sup.10a is as defined above; with a compound of formula (III): ##STR00124## wherein Y is as defined above, to produce a compound of formula (I); ##STR00125## wherein A and Y are as defined above.

2. (canceled)

3. (canceled)

4. A process according to claim 1, wherein p is 0.

5. A process according to claim 1, wherein A is selected from the group consisting of formula A-Ia to A-IIIa below, ##STR00126## wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I).

6. A process according to claim 1, wherein Z is selected from the group consisting of CN, CH.sub.2OH, C(O)OR.sup.10, S(O).sub.2OR.sup.10 and CHCH.sub.2.

7. A process according to claim 1, wherein Z is CN or C(O)OR.sup.10.

8. A process according to claim 1, wherein Y is hydrogen.

9. A process according to claim 1 wherein R.sup.13 is selected from the group consisting of chloro, OH, OMe, OEt, N(Me).sub.2, pyrrolidinyl, piperidyl and morpholinyl.

10. A process according to n claim 1 wherein the compound of formula (II) is produced by: reacting a compound of formula (IV) ##STR00127## wherein A is as defined in claim 1; R.sup.14a and R.sup.15a are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl and phenyl; or R.sup.14a and R.sup.15a together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from nitrogen, oxygen and sulfur; with a compound of formula (V) ##STR00128## wherein each R.sup.13a and R.sup.13b are independently selected from the group consisting of halogen, OR.sup.16 and NR.sup.14R.sup.15; or R.sup.13a and R.sup.13b together are O; and wherein R.sup.14, R.sup.15 and R.sup.16 are as defined in claim 1, to produce a compound of formula ##STR00129## wherein A is as defined above and R.sup.13 is as defined in claim 1.

11. A process according to claim 10 wherein the compound of formula (IV) is produced by: reacting a compound of formula (VI) ##STR00130## with a compound of formula (VII) ##STR00131## wherein R.sup.22 is C.sub.1-C.sub.6alkyl; R.sup.23 and R.sup.24 are independently selected from the group consisting of C.sub.1-C.sub.6alkoxy and N.sup.25R.sup.26; R.sup.25 and R.sup.26 are independently selected from C.sub.1-C.sub.6alkyl; or R.sup.25 and R.sup.26 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from nitrogen, oxygen and sulfur; and a compound of formula (VIII) ##STR00132## wherein R.sup.14a and R.sup.15a are as defined above; to produce a compound of formula (IV) ##STR00133## wherein A, R.sup.14a and R.sup.15a are as defined above.

12. A process according to claim 1 wherein the compound of formula (I) is further converted to give an agronomically acceptable salt of formula (Ia) or a zwitterion of formula (Ib), ##STR00134## wherein Y.sup.1 represents an agronomically acceptable anion and j and k represent integers that may be selected from 1, 2 or 3, and A, R.sup.1, R.sup.2 and Q are as defined in claim 1 and Z.sup.2 is C(O)OH or S(O).sub.2OH.

13. A compound of formula (II) ##STR00135## wherein A and R.sup.13 are as defined in claim 1.

14. Use of a compound of formula (IV) for preparing a compound of formula (I) ##STR00136## wherein A, R.sup.14a and R.sup.15a are as defined in claim 1.

15. A compound of formula (IV) ##STR00137## wherein A is a 6-membered heteroaryl selected from the group consisting of formula A-I, A-II, A-III, A-IV, A-V and A-VII below ##STR00138## wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I), p and R.sup.8 are as defined in claim 1, R.sup.14a and R.sup.15a are independently selected from the group consisting of C.sub.2-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl and phenyl; or R.sup.14a and R.sup.15a together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from nitrogen, oxygen and sulfur.

16. (canceled)

17. Use of a compound of formula (VI) for preparing a compound of formula (I) ##STR00139## wherein A is as defined in a claim 1.

18. Use of a compound of formula (III) for preparing a compound of formula (I) ##STR00140## wherein Y is as defined in claim 1.

Description

EXAMPLES

[0276] The following examples further illustrate, but do not limit, the invention. Those skilled in the art will promptly recognise appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

[0277] The following abbreviations are used: s=singlet; br s=broad singlet; d=doublet; dd=double doublet; dt=double triplet; t=triplet, tt=triple triplet, q=quartet, quin=quintuplet, sept=septet; m=multiplet; GC=gas chromatography, RT=retention time, Ti=internal temperature, MH*=molecular mass of the molecular cation, M=molar, Q.sup.1HNMR=quantitative .sup.1HNMR, RT=room temperature, UFLC=Ultra-fast liquid chromatography.

[0278] .sup.1H NMR spectra are recorded at 400 MHz unless indicated otherwise and chemical shifts are recorded in ppm.

LCMS Methods:

Standard:

[0279] Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions, Capillary: 3.00 kV, Cone range: 30 V, Extractor: 2.00 V, Source Temperature: 150 C., Desolvation Temperature: 350 C., Cone Gas Flow: 50 l/h, Desolvation Gas Flow: 650 l/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 m, 302.1 mm, Temp: 60 C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 1.2 min; Flow (ml/min) 0.85

Standard Long:

[0280] Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions), Capillary: 3.00 kV, Cone range: 30V, Extractor: 2.00 V, Source Temperature: 150 C., Desolvation Temperature: 350 C., Cone Gas Flow: 50 l/h, Desolvation Gas Flow: 650 l/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 m, 302.1 mm, Temp: 60 C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 2.7 min; Flow (ml/min) 0.85

Example 1: Preparation of 2-[(2-Pyrrolidin-1-ylvinyl]pyrimidine

[0281] ##STR00095##

[0282] A mixture of 2-methyl-pyrimidine (10 g, 0.1063 mol), pyrrolidine (15.2 g, 0.2125 mol) and N,N-dimethylformamide dimethyl acetal (26.1 g, 0.2125 mol) was heated at 87 C. (internal temperature) for 15 h. After cooling down to room temperature, the mixture was concentrated under vacuum to give a yellowish solid. 300 ml of tButyl-methyl-ether were added to this solid, and it was dissolved at reflux. The solution was then cooled down to 0 C., stirred for 20 minutes, the solid was filtered, washed once with cold tButyl-methyl-ether, collected and dried under high vacuum. 12.3 g of 2-[(E)-2-pyrrolidin-1-ylvinyl] pyrimidine, a white solid, pure at 97% w/w as measured by Quantitative NMR was obtained. The filtrate was concentrated under vacuum and 200 ml of tButyl-methyl-ether was added. After full dissolution was achieved at reflux, the solution was then cooled down to 0 C., stirred for 20 minutes, the solid was filtered, washed once with cold tButyl-methyl-ether, collected and dried under high vacuum. 4.7 g of 2-[2-pyrrolidin-1-ylvinyl]pyrimidine, a white solid, pure at 94% w/w as measured by Quantitative NMR was obtained. The two batches were combined to deliver 17 g of the title compound, pure at 96% w/w (84.1% yield).

[0283] 1H NMR (400 MHz, CDCl3) ppm 1.85-2.05 (m, 4H) 3.28-3.44 (m, 4H) 5.25 (d, 1H) 6.67 (t, 1H) 7.99 (d, 1H) 8.38 (d, 2H).

Example 2: Preparation of 4-[2-pyrimidin-2-ylvinyl]morpholine

[0284] ##STR00096##

[0285] A mixture of 2-ethynylpyrimidine (0.25 g, 2.33 mmol) and morpholine (0.43 g, 4.89 mmol) was heated at 100 C. for 20 minutes. The mixture was then cooled down to room temperature and concentrated under vacuum. The crude title compound was obtained as an orange oil which solidified on standing (0.553 g) with a purity of 75% w/w as measured by Quantitative NMR. Most of the contaminant was residual morpholine.

[0286] 1H NMR (400 MHz, CDCl3) ppm 3.23-3.33 (m, 4H) 3.74-3.79 (m, 4H) 5.49 (d, J=13.57 Hz, 1H) 6.78 (t, J=4.95 Hz, 1H) 7.66 (d, J=13.20 Hz, 1H) 8.44 (d, J=4.77 Hz, 2H)

Example 3: Preparation of 2-[2-(1-piperidyl)vinyl]pyrimidine

[0287] ##STR00097##

[0288] A mixture of 2-ethynylpyrimidine (0.25 g, 2.33 mmol) and piperidine (4.89 mmol) was heated at 100 C. for 20 minutes. The mixture was then cooled down to room temperature and concentrated under vacuum. The crude title compound was obtained.

[0289] 1H-NMR (400 MHz, THF-d8) ppm 8.37 (d, J=4.77 Hz, 2H), 7.76 (d, J=13.57 Hz, 1H), 6.70 (t, J=4.77 Hz, 1H), 5.43 (d, J=13.20 Hz, 1H), 3.19-3.30 (m, 4H), 1.56-1.67 (m, 6H)

Example 4: Preparation of 2-morpholino-3-pyrimidin-2-yl-2H-furan-5-one from 2-[(2-pyrrolidin-1-ylvinyl]pyrimidine

[0290] ##STR00098##

[0291] To a cold (1 C.) solution of 2-[(E)-2-pyrrolidin-1-ylvinyl]pyrimidine (pure at 96% w/w) (5.04 g, 27.6 mmol) and morpholin-4-ium 2,2-dimorpholinoacetate (1.2 eq, 33.1 mmol) was added acetic acid (5 eq, 138 mmol) dropwise over a period of 25 minutes. The cold temperature (1 C.) was maintained for another 15 minutes before the solution allowed to warm at room temperature and stirred for 2 h30. The solution was then cooled down to 2 C. and stirred for another 30 minutes. The resulting suspension was then filtered, the solid was washed with cold (5 C.) methanol (12.5 ml) twice, collected and dried under reduced pressure until constant weight (5.76 g). The title compound was thus obtained as a white solid with a purity of 98% w/w as measured by Quantitative NMR (82.5% yield).

[0292] 1H NMR (400 MHz, CDCl3) ppm 2.75-2.88 (m, 4H) 3.53-3.69 (m, 4H) 6.27 (d, J=1.4 Hz, 1H) 6.94 (d, J=1.4 Hz, 1H) 7.34 (t, J=4.7 Hz, 1H) 8.85 (d, J=4.7 Hz, 2H)

Example 5: Preparation of 3-pyrimidin-2-yl-2-pyrrolidin-1-yl-2H-furan-5-one and 2-hydroxy-3-pyrimidin-2-yl-2H-furan-5-one from 2-[(2-pyrrolidin-1-ylvinyl]pyrimidine

[0293] ##STR00099##

Preparation of 2-hydroxy-2-pyrrolidin-1-ium-1-yl-acetate

[0294] To a solution of glyoxylic acid monohydrate (4 g, 42.1 mmol, 1.0 eq.) in ethanol (8.6 mL). The resulting solution was cooled to 0 C. A solution of a solution of Pyrrolidine (1.05 equiv., 44.2581 mmol, 99.5 mass %) in ethanol (1.7 mL) was added dropwise at 0 C. After addition reaction was stirred at 0 C. for 2 h. The resulting beige solid which had formed was filtered, washed with Et2O (3) and dried to give white crystals (3.3 g) of 2-hydroxy-2-pyrrolidin-1-yl-acetic acid which was used as such.

[0295] A vial was charged at room temperature with 2-[2-pyrrolidin-1-ylvinyl]pyrimidine (0.3 g, 1.71 mmol, 1 eq.) and 2-hydroxy-2-pyrrolidin-1-ium-1-yl-acetate (0.271 g, 1.89 mmol, 1.1 eq.) and then dissolved in methanol (2.57 mL, 1.5 mL/mmol). To this solution was added acetic acid (0.49 mL, 5 eq) dropwise over a period of 10 min then the reaction mixture was stirred for 2.5 h at rt. The solvent was carefully removed by using a pipette after settling of the reaction mixture. The resulting solid was washed with Et2O (35 mL). Et2O removed with pipette. The remaining solid was then dried under reduced pressure to yielding the hydrolyzed product (2-hydroxy-3-pyrimidin-2-yl-2H-furan-5-one) as a yellow solid (49.4 mg).

[0296] 2-hydroxy-3-pyrimidin-2-yl-2H-furan-5-one: 1H NMR (400 MHz, D6-DMSO) ppm 6.66 (dd, 1H) 6.94 (d, 1H) 7.60 (t, 1H) 8.06 (d, 1H) 8.99 (d, J=5.14 Hz, 2H)

[0297] Filtrate was concentrated then submitted to a separation on Normal Phase chromatography (Isco Combiflash) to give the title compound as a white solid (43.5 mg). Chromatography as purification technique does lead to partial formation of 2-hydroxy-3-pyrimidin-2-yl-2H-furan-5-one as well.

[0298] 3-pyrimidin-2-yl-2-pyrrolidin-1-yl-2H-furan-5-one: 1H NMR (400 MHz, d6-DMSO) ppm 1.65 (br t, 4H) 2.60-2.78 (m, 4H) 6.62 (d, 1H) 6.90 (d, 1H) 7.58 (t, 1H) 8.97 (d, 2H)

Example 6: Preparation of 2-(1-piperidyl)-3-pyrimidin-2-yl-2H-furan-5-one from 2-[2-(1-piperidyl)vinyl]pyrimidine

[0299] ##STR00100##

Preparation of 2-hydroxy-2-piperidin-1-ium-1-yl-acetate

[0300] To a solution of glyoxylic acid monohydrate (5.00 g, 53.23 mmol, 1 eq.) in Toluene (40 mL).

[0301] Piperidine (4.65 g, 54.11 mmol, 1.02 eq.) was added drop-wise with vigorous stirring. The reaction vessel was stoppered & placed in freezer overnight. The crystals were collected by vacuum filtration and the cake was filtered. The cake was washed with Et2O (225 mL) to give 2-hydroxy-2-piperidin-1-ium-1-yl-acetate (8.1814 g, 50.7 mmol, 95.3% yield) as fine white powder which was used as such.

[0302] A 100 ml 3 necked RBF was charged with 2-(1-piperidyl)-3-pyrimidin-2-yl-2H-furan-5-one (0.20 g, 1.05 mmol, 1 eq.) and 2-hydroxy-2-piperidin-1-ium-1-yl-acetate (0.184 g, 1.16 mmol, 1.1 eq) and dissolved in methanol (1.5 mL/mmol) then acetic acid (0.32 g, 5.3 mmol, 5 eq) was added dropwise and then the reaction was stirred for 3 h at rt. The solvent was carefully removed by using a pipette after settling of the reaction mixture. The resulting solid was washed with Et2O (35 mL). Et2O removed with pipette. The remaining solid was then dried under reduced pressure to yielding the desired product and traces of hydrolyzed product as a yellow solid (46.1 mg). Filtrate was concentrated then submitted to a separation on Normal Phase chromatography (Isco Combiflash) to give the title compound as a white solid (43.5 mg).

[0303] 2-(1-piperidyl)-3-pyrimidin-2-yl-2H-furan-5-one: 1H NMR (400 MHz, D6-DMSO) ppm 1.19-1.47 (m, 6H) 2.55-2.74 (m, 4H) 6.41 (d, 1H) 6.92 (d, 1H) 7.57-7.62 (m, 1H) 8.95-9.01 (m, 2H)

Example 7: Preparation of 2-hydroxy-3-pyrimidin-2-yl-2H-furan-5-one from 2-methylpyrimidine

[0304] ##STR00101##

Step 1:

[0305] Potassium tert-butoxide (2.50 eq, 1.45 g, 12.5 mmol, 2.5 eq.) was dissolved in N,N-dimethylformamide (7.50 mL) then 2-methylpyrimidine (0.48 g, 5.00 mmol, 1 eq.) was added and then the resulting mass was stirred at room temperature for 12 h. Potassium 2-pyrimidin-2-ylethenolate was used without any work up or determination of yield for step 2.

Step 2:

[0306] A 50 ml three neck round bottom flask equipped with a thermometer, a gas inlet, a bubbler and a septum, was charged with glyoxylic acid monohydrate (0.61 g, 6.50 mmol, 1.30 eq) and dissolved with methanol (10.0 mL). The resulting reaction mixture was cooled down to 5 C. and acetic acid (2.87 mL, 50.0 mmol, 10 eq) was added then a solution of Potassium 2-pyrimidin-2-ylethenolate (from step 1) in Methanol (2 ml) was added dropwise at 5 C. Reaction temperature was maintained under 0 C. during the addition. Reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was evaporated to dryness to give 7.2 g of the title compound as a black liquid (contained unquantified amounts of acetic acid and DMF). NMR and LC-MS consistent with the structure of desired product (7.2 g, 9% strength (determined by quant 1H NMR), 73% yield).

[0307] 1H NMR (400 MHz, D6-DMSO) ppm 6.66 (dd, J=8.25, 0.92 Hz, 1H) 6.94 (d, J=0.73 Hz, 1H) 7.60 (t, J=4.95 Hz, 1H) 8.06 (d, J=8.44 Hz, 1H) 8.99 (d, J=5.14 Hz, 2H)

Example 8: Preparation of 2-methoxy-3-pyrimidin-2-yl-2H-furan-5-one from 2-hydroxy-3-pyrimidin-2-yl-2H-furan-5-one

[0308] ##STR00102##

[0309] A vial was charged with 2-hydroxy-3-pyrimidin-2-yl-2H-furan-5-one (0.45 mmol, 80 mg, 1.0 eq), trimethoxymethane (0.25 mL, 2.25 mmol, 5.0 eq), p-MsOH (8.0 mg, 0.046 mmol, 0.1 eq.) and methanol (0.3 ml). The reaction was heated to 80 C. and stirred for 4 h and then stored at 20 C. overnight. Solvent was removed then the crude was purified. The crude was then purified by column chromatography (DCM/MeOH) followed by a second purification on Reverse phase chromatography (C18) to yield a white solid (12.9 mg).

[0310] .sup.1H NMR (400 MHz, CDCl3) ppm 3.68 (s, 3H) 6.41 (d, J=0.73 Hz, 1H) 7.00 (d, J=1.10 Hz, 1H) 7.35 (t, J=4.77 Hz, 1H) 8.88 (d, J=5.14 Hz, 2H)

Example 9: Preparation of 2-ethoxy-3-pyrimidin-2-yl-2H-furan-5-one 3 from 2-hydroxy-3-pyrimidin-2-yl-2H-furan-5-one

[0311] ##STR00103##

[0312] A vial was charged with 2-hydroxy-3-pyrimidin-2-yl-2H-furan-5-one (80 mg, 0.45 mmol, 1.0 eq), diethoxymethoxyethane (2.25 mmol, 0.37 mL, 5.0 eq), catalytic amount of p-MsOH (8.0 mg, 0.046 mmol, 0.1 eq.) and EtOH (0.22 mL). The reaction was heated to 80 C. and stirred for 4 h and then stored at 20 C. overnight. The solvent was then evaporated yielding a brown solid (157.4 mg). The crude was then purified by automated column chromatography (DCM/MeOH) yielding a white solid (35.6 mg). A second purification Reverse phase chromatography (C.sub.18) to yield a white solid (18.1 mg).

[0313] .sup.1H NMR (400 MHz, CDCl3) ppm 1.30 (t, J=6.97 Hz, 3H) 3.89-4.04 (m, 2H) 6.47 (d, J=0.73 Hz, 1H) 6.98 (d, J=0.73 Hz, 1H) 7.34 (t, J=4.95 Hz, 1H) 8.86 (d, J=4.77 Hz, 2H)

Example 10: Preparation of 2-chloro-3-pyrimidin-2-yl-2H-furan-5-one furanone from 2-hydroxy-3-pyrimidin-2-yl-2H-furan-5-one

[0314] ##STR00104##

[0315] A vial was charged with 2-hydroxy-3-pyrimidin-2-yl-2H-furan-5-one (0.45 mmol, 80 mg, 1.0 eq) and dissolved with 1,2-dichloroethane (0.9 mL, 2 mL/mmol). Thionyl chloride (0.075 g, 0.63 mmol, 0.046 mL, 1.4 eq) was added dropwise and catalytic amount of DMF to the solution, which was then stirred for 1 h at 80 C. The solvent was then evaporated yielding a black solid (136.2 mg). The crude was then absorbed on isolute and purified by automated column chromatography using Cyclohexane/EtOAc to yielding a dark brown solid (35.7 mg)

[0316] .sup.1H NMR (400 MHz, CDCl3) ppm 7.07 (d, J=0.73 Hz, 1H) 7.17 (d, J=1.10 Hz, 1H) 7.40 (t, J=4.77 Hz, 1H) 8.91 (d, J=5.14 Hz, 2H)

Example 11: Preparation of 3-(6-oxo-4-pyrimidin-2-yl-pyridazin-1-yl)propanenitrile

[0317] ##STR00105##

General Procedure 1:

[0318] To a suspension of 2-morpholino-3-pyrimidin-2-yl-2H-furan-5-one (pure at 93% w/w) (0.25 g, 0.94 mmol) in methanol (1 ml) was added acetic acid (0.54 ml) and 3-hydrazinopropanenitrile (1.04 mmol). The yellow mixture was heated at 40 C. for 1 hour, then it was allowed to cool down to room temperature.

Work Up:

[0319] Reaction mixture was extracted with water and ethyl acetate, the organic phase was washed once with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. 0.19 g of the title compound (purity 88% w/w as measured by Quantitative NMR) was obtained (78% chemical yield). The crude product was purified by chromatography column (DCM/MeOH gradient). 0.13 g of the title compound was isolated as a beige solid, with a purity of 99% w/w as measured by NMR.

[0320] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 2.98 (t, J=6.97 Hz, 2H) 4.53 (t, J=6.97 Hz, 2H) 7.39 (t, J=4.95 Hz, 1H) 7.97 (d, J=1.83 Hz, 1H) 8.84 (d, J=1.83 Hz, 1H) 8.90 (d, J=4.77 Hz, 2H)

Example 12: Preparation of tert-butyl 3-(6-oxo-4-pyrimidin-2-yl-pyridazin-1-yl)propanoate

[0321] ##STR00106##

Procedure:

[0322] The title compound was prepared according to General Procedure 1 (above), from 2-morpholino-3-pyrimidin-2-yl-2H-furan-5-one (250 mg, 1.00 mmol), tert-butyl 3-hydrazinopropanoate (185 mg, 1.09 mmol, 1.1 eq.), acetic acid (0.567 ml) in MeOH (0.932 mL). The title compound was isolated as a white solid (56 mg) after filtration, with a purity of 97.9% w/w as measured by quantitative NMR (18.3% Isolated Yield).

[0323] 1H NMR (400 MHz, CDCl.sub.3) ppm 1.46 (s, 9H) 2.82 (t, J=7.15 Hz, 2H) 4.50 (t, J=7.15 Hz, 2H) 7.37 (t, J=4.95 Hz, 1H) 7.93 (d, J=2.20 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 8.89 (d, J=4.77 Hz, 2H)

Example 13: Preparation of 3-(6-oxo-4-pyrimidin-2-yl-pyridazin-1-yl)propanoic acid

[0324] ##STR00107##

Procedure:

[0325] The title compound was prepared according to General Procedure 1 (above), from 2-morpholino-3-pyrimidin-2-yl-2H-furan-5-one (150 mg, 0.528 mmol), 3-hydrazinopropanoic acid (91 mg, 0.581 mmol, 1.1 eq.), acetic acid (0.302 ml) in MeOH (2.1 mL). The title compound was isolated as a white solid (89 mg) after filtration. Crude recovery mass 64%.

[0326] NMR data: .sup.1H NMR (400 MHz, D6-DMSO) ppm 2.75 (t, J=7.34 Hz, 2H) 4.32 (t, J=7.15 Hz, 2H) 7.66 (t, J=4.95 Hz, 1H) 7.66 (d, J=2.20 Hz, 1H) 8.69 (d, J=2.20 Hz, 1H) 9.03 (d, J=4.77 Hz, 2H) 11.9 (bs, 1H)

Example 14: Preparation of 2-(dimethylamino)-3-pyridazin-3-yl-2H-furan-5-one

[0327] ##STR00108##

Procedure:

[0328] To a solution of N,N-dimethyl-2-pyridazin-3-yl-ethenamine (0.300 mg, 2.0 mmol) in methanol (2 ml) was added glyoxylic acid (0.25 mL, 2.3 mmol, 1.1 eq). The mixture was heated at 50 C. overnight, then it was allowed to cool down to room temperature and then the reaction mixture filtered and concentrated in vacuo to give a black solid (0.4 g)

Work Up:

[0329] The residue was partitioned between saturated solution of NaHCO.sub.3 and EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give an orange film (10.1 mg).

[0330] NMR data: 1H NMR (400 MHz, CHLOROFORM-d)) ppm 9.26 (dd, 1H), 7.95 (dd, 1H), 7.59 (dd, 1H), 7.13 (d, 1H), 6.18 (d, 1H), 2.46 (s, 6H)

Example 15: Preparation of tert-butyl 3-(6-oxo-4-pyridazin-3-yl-pyridazin-1-yl)propanoate

[0331] ##STR00109##

Procedure:

[0332] To a solution of 2-morpholino-3-pyridazin-3-yl-2H-furan-5-one (0.350 mg, 1.36 mmol) in methanol (2 ml) was added 2,2,2-trifluoroacetic acid (0.11 ml, 1.36 mmol, 1 eq.) at 0 C. and then tert-butyl 3-hydrazinopropanoate (255 mg, 1.5 mmol, 1.1 eq.). The reaction mixture was allowed to warm to room temperature and left under stirring for the night.

Work Up:

[0333] The reaction mixture was partitioned between saturated solution of water and EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give the crude title compound with a purity of 20% w/w as measured by Quantitative NMR (18% yield).

[0334] NMR data: 1H NMR (400 MHz, CDCl3-d3) ppm 1.49 (s, 9H), 2.77 (t, 2H) 4.5 (t, 2H) 7.40 (s, 1H) 7.67 (dd, 1H), 7.9 (d, 1H), 8.71 (d, 1H) 9.35 (dd, 1H)

Example 16: Preparation of 3-(6-oxo-4-pyridazin-3-yl-pyridazin-1-yl)propanenitrile

[0335] ##STR00110##

Procedure:

[0336] To a solution of 2-morpholino-3-pyridazin-3-yl-2H-furan-5-one (0.100 mg, 0396 mmol) in methanol (0.375 ml) was added acetic acid (0.05 ml, 0.796 mmol, 2 eq.) and then 3-hydrazinopropanenitrile (255 mg, 1.5 mmol, 1.1 eq.). The reaction mixture was heated to 40 C. and stirred for 2 h.

Work Up:

[0337] The reaction mixture was concentrated afford the crude title compound as a black gum with a purity of 32% w/w as measured by Quantitative NMR (60% yield).

[0338] NMR data: NMR data: 1H NMR (400 MHz, CDCl3-d3) ppm 3.00 (t, 2H) 4.5 (t, 2H) 7.45 (s, 1H) 7.70 (dd. 1H). 7.90 (d. 1H). 8.80 (d. 1H) 9.35 (dd. 1H)

Example 17: Preparation of 2,2-dimethylpropyl 2-(6-oxo-4-pyridazin-3-yl-pyridazin-1-yl)ethanesulfonate

[0339] ##STR00111##

Procedure:

[0340] To a solution of 2-hydroxy-3-pyridazin-3-yl-2H-furan-5-one prepared freshly by mixing N,N-dimethyl-2-pyridazin-3-yl-ethenamine (120 mg, 0.67 mmol), 2-hydroxy-2-morpholino-acetic acid (175 mg, 0.945 mmol, 1.4 eq.) and acetic acid (2.4 ml) was added in one portion 2,2-dimethylpropyl 2-hydrazinoethanesulfonate (183 mg, 0.57 mmol, 1 eq.). The reaction mixture was stirred at rt for 1 h.

Work Up:

[0341] Reaction mass was dissolved in methylene chloride then washed with saturated solution of NaHCO.sub.3. Organics were combined and dried over MgSO4 then filtered. Organics was concentrated to dryness to afford the title compound as a black gum with a purity of 43% w/w as measured by Quantitative NMR (40% yield).

[0342] NMR data: 1H NMR (400 MHz, CHLOROFORM-d) ppm 9.32 (dd, J=4.77, 1.47 Hz, 1H), 8.79 (d, J=2.20 Hz, 1H), 7.90 (dd, J=8.62, 1.65 Hz, 1H), 7.65-7.72 (m, 1H), 7.42 (d, J=2.20 Hz, 1H), 4.68-4.74 (m, 2H), 3.95 (s, 2H), 3.68-3.73 (m, 2H), 1.01 (s, 9H)

Example 18: Preparation of 4-pyrimidin-2-yl-1H-pyridazin-6-one

[0343] ##STR00112##

[0344] To a solution of 2-morpholino-3-pyrimidin-2-yl-2H-furan-5-one (5.00 g, 19.6 mmol, 1.0 eq.) in MeOH (40 g) was added acetic acid (11.8 g, 196 mmol, 10.0 eq) at 25 C. The resulting suspension was stirred at room temperature and heated to 40 C. Hydrazine hydrate (1.09 g, 21.6 mmol, 1.10 eq.) was added over a period of 60 min via syringe pump. The resulting mixture was stirred at 40 C. for 2 h. The mixture was then allowed to cool to 24 C. and water (2.5 Vol) was added. Stirring was continued for another 1 h.

[0345] The resulting suspension was filtered through buchner funnel and the collected solid was washed with 1 vol of MeOH:Water (3.2:1). The collected solid was dried under reduced pressure at 60 C. The title compound was obtained as a solid (2.6 g, 74% yield, 97% purity as determined by quant 1 HNMR using 1,3,5 trimethoxybenzene as an internal standard)

[0346] 1H NMR (400 MHz, DMSO-d6) ppm 7.59-7.67 (m, 2H) 8.65 (d, J=1.96 Hz, 1H) 9.02 (d, J=4.89 Hz, 2H) 13.34 (br s, 1H)

Example 19: Preparation of ethyl 3-(6-oxo-4-pyrimidin-2-yl-pyridazin-1-yl)propanoate

[0347] ##STR00113##

[0348] To a solution of 4-pyrimidin-2-yl-1H-pyridazin-6-one (5.00 g, 27.8 mmol, 1 eq.) in MeTHF (20 g) at room temperature was added K2CO3 (0.78 g, 5.57 mmol, 0.20 eq.) at once followed by Tetrabutylammonium bromide (0.46 g, 1.39 mmol, 0.05 eq), The reaction mixture was heated at 76 C. Ethyl prop-2-enoate (1.10 equiv., 30.6 mmol) was added dropwise via syringe pump over a period of 60 min. After end dosing, heating was continued for 10 mins and water (5 vol) was added over period of 20 min. The reaction mixture was allowed to cool to 25 C. and then cooled to 0-3 C. The resulting suspension was filtered on a sintered funnel and washed with cold (0-5 C.) water (7 vol). The solid was dried on the filter under vacuum (P=150-250 mbar) for 1 h and then under high vacuum (P=5-10 mbar at Toven=60 C.) to give the title compound (6.35 g, 98% yield, 82% purity as determined by quant 1H NMR) as a white solid.

[0349] 1H NMR (400 MHz, DMSO-d6) ppm 1.15 (t, J=7.15 Hz, 3H) 2.81 (t, J=6.97 Hz, 2H) 4.05 (q, J=7.13 Hz, 2H) 4.35 (t, J=6.97 Hz, 2H) 7.63-7.67 (m, 2H) 8.67 (d, J=2.08 Hz, 1H) 9.02 (d, J=4.89 Hz, 2H)

Example 20: Preparation of 4-pyridazin-3-yl-1H-pyridazin-6-one

[0350] ##STR00114##

[0351] To a solution of 2-morpholino-3-pyridazin-3-yl-2H-furan-5-one (5.00 g, 18.6 mmol, 1.0 eq.) in NMP (26.3 g) was added acetic acid (11.2 g, 186 mmol, 10.0 eq) at 24 C. The resulting suspension was stirred at 24 C. and then heated to 50 C. Hydrazine hydrate (1.03 g, 20.5 mmol, 1.1 eq.) was added over a period of 120 min via syringe pump at 50 C. After end of addition, the mixture was maintained at 50 C. for 2 h. The mixture was then allowed to cool to 24 C. and water (2.5 Vol) was added. Stirring was continued for another 1 h. The resulting yellow solid was filtered through a buchner funnel and washed with water (2 vol). The collected yellow solid was dried under reduced pressure at 60 C. to give the title compound (2.35 g, 69% yield, 95% purity as determined by quant 1HNMR using 1,3,5 trimethoxybenzene as internal standard)

[0352] 1H NMR (400 MHz, DMSO-d6) ppm 7.59 (d, J=1.96 Hz, 1H) 7.89 (dd, J=8.68, 5.01 Hz, 1H) 8.40 (dd, J=8.68, 1.59 Hz, 1H), 8.66 (d, J=2.08 Hz, 1H) 9.34 (dd, J=5.01, 1.47 Hz, 1H) 13.32 (br s, 1H)

Example 21: Preparation of ethyl 3-(6-oxo-4-pyridazin-3-yl-pyridazin-1-yl)propanoate

[0353] ##STR00115##

[0354] To a solution of 4-pyridazin-3-yl-1H-pyridazin-6-one (5.00 g, 27.3 mmol, 1.0 eq.) in pyridine (25 g) at 24 C. were added benzyl(triethyl)ammoniumchloride (0.32 g, 1.36 mmol, 0.05 eq.) and K2CO3 (1.52 g, 10.9 mmol, 0.40 eq.) at once. The resulting mixture was then heated at 75 C. for 1 h. Ethyl prop-2-enoate (3.03 g, 30.0 mmol, 1.1 eq.) was added dropwise via a syringe pump over a period of 4 h at 75 C. After end of addition the mixture was stirred at 75 C. for an additional hour. An additional amount of pyridine (5 mL) was then added and the mixture was then cooled to 24 C. The brown suspension was filtered through a sintered funnel to provide a brown pyridine solution of the title compound (35.2 g, 79% yield, 16.8% strength as determined by quant NMR using 1,3,5-trimethoxybenzene as an internal standard).

[0355] 1H NMR (400 MHz, DMSO-d6) ppm 1.13-1.22 (m, 3H), 2.79-2.88 (m, 2H), 4.02-4.12 (m, 2H), 4.34-4.38 (m, 2H), 7.66-7.67 (s, 1H), 7.90-7.94 (m, 1H), 8.41-8.45 (m, 1H), 8.72 (m, 1H), 9.34-9.36 (m, 1H)

Example 22: Preparation of 3-[2-pyrrolidin-1-ylvinyl]pyridazine from 3-methylpyridazine, triethyl orthoformate and pyrrolidine in the presence of 2,6-Di-tert-butyl-4-methylphenol as catalyst

[0356] ##STR00116##

[0357] A 10 mL-microwave vial was charged with 3-methlypyridazine (0.55 g, 5.7 mmol), pyrrolidine (0.51 g, 7.2 mmol), triethyl orthoformate (1.14 g, 7.6 mmol) and 2,6-Di-tert-butyl-4-methylphenol (22 mg, 0.10 mmol, 2 mol %). The mixture was heated under stirring in a microwave reactor at 190 C. for 12 h. After cooling to room temperature, the reaction mixture was weighted, sampled and analyzed by quantitative 1H NMR (in DMSO-d6 with 1,3,5-trimethoxybenzene as standard), indicating the title compound had been formed in 55% chemical yield or 95% chemical yield based on converted starting material (58% conversion).

[0358] NMR data: 1H NMR (400 MHz, CDCl3) ppm: 8.60 (dd, J=4.6 Hz, 1.7 Hz, 1H), 7.80 (d, J=13.5 Hz, 1H), 7.31-7.23 (m, 2H), 5.10 (d, J=13.5 Hz, 1H), 3.28 (m, 4H), 1.88 (m, 4H).

Example 23: Preparation of 3-[2-pyrrolidin-1-ylvinyl]pyridazine from 3-methylpyridazine, trimethyl orthoformate and pyrrolidine in the presence of 2,6-Di-tert-butyl-4-methylphenol as catalyst

[0359] ##STR00117##

[0360] A 10 mL-microwave vial was charge with 3-methlypyridazine (0.97 g, 10 mmol), pyrrolidine (0.85 g, 12 mmol), trimethyl orthoformate (1.61 g, 15 mmol) and 2,6-Di-tert-butyl-4-methylphenol (45 mg, 0.20 mmol, 2 mol %). The mixture was heated under stirring in a microwave reactor at 200 C. for 9 h. After cooling to room temperature, the reaction mixture was weighted, sampled and analyzed by quantitative 1H NMR (in DMSO-d6 with 1,3,5-trimethoxybenzene as standard), indicating the title compound had been formed in 33% chemical yield or quantitative chemical yield based on converted starting material (33% conversion).

[0361] NMR data: 1H NMR (400 MHz, CDCl3) ppm: 8.60 (dd, J=4.6 Hz, 1.7 Hz, 1H), 7.80 (d, J=13.5 Hz, 1H), 7.31-7.23 (m, 2H), 5.10 (d, J=13.5 Hz, 1H), 3.28 (m, 4H), 1.88 (m, 4H).

Example 24: Preparation of 2-[2-pyrrolidin-1-ylvinyl]pyrimidine from 2-methylpyrimidine, triethyl orthoformate and pyrrolidine in the presence of 2,6-Di-tert-butyl-4-methylphenol as catalyst

[0362] ##STR00118##

[0363] A 10 mL-microwave vial was charge with 2-methylpyrimidine (0.94 g, 10 mmol), pyrrolidine (0.85 g, 12 mmol), triethyl orthoformate (2.25 g, 15 mmol) and 2,6-Di-tert-butyl-4-methylphenol (45 mg, 0.20 mmol, 2 mol %). The mixture was heated under stirring in a microwave reactor at 220 C. for 4 h. After cooling to room temperature, the reaction mixture was weighted, sampled and analyzed by quantitative 1H NMR (in DMSO-d6 with 1,3,5-trimethoxybenzene as standard), indicating the title compound had been formed in 39% chemical yield or quantitative chemical yield based on converted starting material (39% conversion).

[0364] NMR data: 1H NMR (400 MHz, CDCl3) ppm: 8.34 (d, J=4.8 Hz, 2H), 7.91 (d, J=13.1 Hz, 1H), 6.75 (t, J=4.8 Hz, 1H), 5.04 (d, J=13.1 Hz, 1H), 3.28 (m, 4H), 1.88 (m, 4H).