Chemical Process for the Preparation of Herbicidal Pyridazine Compounds

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, comprising reacting a compound of formula (II) in a suitable reaction medium comprising a desulfurization agent formula (II). 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) ##STR00105## wherein A is a 6-membered heteroaryl selected from the group consisting of formula A-I to A-VII below ##STR00106## 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 R.sup.x is hydrogen or C.sub.1-C.sub.6alkyl; R.sup.1 is hydrogen or methyl; R.sup.2 is hydrogen or methyl; Q is (CR.sup.1aR.sup.2b).sub.m; m is 0, 1 or 2; each R.sup.1a and R.sup.2b are independently selected from the group consisting of hydrogen, methyl, —OH and —NH.sub.2; Z is selected from the group consisting of —CN, —C(S)OR.sup.10, —C(S)NR.sup.6R.sup.7, —C(S)SR.sup.10, —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)NHCN, —C(O)NR.sup.6R.sup.7, —C(O)NHS(O).sub.2R.sup.12 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 ##STR00107## wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); and R.sup.3 is hydrogen or —C(O)OR.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 hydrogen and C.sub.1-C.sub.6alkyl; each R.sup.6 and R.sup.7 are independently selected from 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; R.sup.10a is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, phenyl and benzyl; and R.sup.12 is selected from the group consisting of methyl, —NH.sub.2, —N(CH.sub.3).sub.2 and —NHCH.sub.3; said process comprising: reacting a compound of formula (II): ##STR00108## wherein A, R.sup.1, R.sup.2, Q and Z are as defined above, in a suitable reaction medium comprising a desulfurization agent, to give a compound of formula (I).

2. A process according to claim 1, wherein the compound of formula (I) is further subjected to a salt exchange to give a compound of formula (Id), ##STR00109## wherein Y 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, Q and Z are as defined in claim 1.

3. A process according to claim 2, wherein the compound of formula (Id) is a compound of formula (Id-I), ##STR00110## wherein A, R.sup.1, R.sup.2 and Q are as defined in claim 1, Z.sup.1 is selected from the group consisting of —CN, —C(O)OR.sup.10, —C(O)NH.sub.2 and —S(O).sub.2OR.sup.10, and R.sup.10 is selected from the group consisting of C.sub.1-C.sub.6alkyl, phenyl and benzyl; and hydrolysing said compound of formula (Id-I) to a compound of formula (Ie), ##STR00111## wherein 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.

4. A process according to claim 1, wherein the compound of formula (I) is a compound of formula (Ib), ##STR00112## wherein A, R.sup.x, R.sup.1, R.sup.2 and Q are as defined in claim 1, Z.sup.1 is selected from the group consisting of —CN, —C(O)OR.sup.10, —C(O)NH.sub.2 and —S(O).sub.2OR.sup.10, and R.sup.10 is selected from the group consisting of C.sub.1-C.sub.6alkyl, phenyl and benzyl; and hydrolysing said compound of formula (Ib) to a compound of formula (Ic), ##STR00113## wherein A, R.sup.x, 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.

5. A process according to claim 4 wherein the compound of formula (Ic) is further subjected to a salt exchange to give a compound of formula (Ie), ##STR00114## wherein Y 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.

6. A process according to claim 1, wherein Y is chloride and j and k are 1.

7. A process according to claim 1, wherein R.sup.1 and R.sup.2 are hydrogen and R.sup.1a and R.sup.2b are hydrogen.

8. A process according to claim 1, wherein R.sup.x is hydrogen.

9. A process according to claim 1, wherein m is 1.

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

11. A process according to claim 1, wherein A is selected from the group consisting of formula A-Ia to A-IIIa below, ##STR00115## wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I).

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

13. A process according to claim 1, wherein the suitable reaction medium further comprises an acid.

14. A process according to claim 1, wherein the desulfurization agent is a peroxide.

15. A compound of formula (I) ##STR00116## wherein A, R.sup.x, R.sup.1, R.sup.2, Q and Z are as defined in claim 1.

16. A compound of formula (II) ##STR00117## wherein A, R.sup.1, R.sup.2, Q and Z are as defined in claim 1.

17. A process according to claim 1 wherein the compound of formula (II) is produced by: (i) reacting a compound of formula (III) ##STR00118## with a suitable alkylating agent to give a compound of formula (IV) ##STR00119## wherein A, R.sup.1, R.sup.2, Q and Z are as defined in claim 1, and (ii) reacting the compound of formula (IV) with a sulfurizing agent to give a compound of formula (II) ##STR00120##

18. A compound of formula (IV) ##STR00121## wherein A is a 6-membered heteroaryl selected from the group consisting of formula A-I to A-V and p, R.sup.1, R.sup.2, R.sup.8, Q and Z are as defined in claim 1.

19. Use of a compound of formula (III-I) for preparing a compound of formula (I) ##STR00122## wherein X is S or O and A is as defined in claim 1.

20. A compound of formula (III-I)a ##STR00123## wherein X is S or O.

Description

EXAMPLES

[0239] 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.

[0240] 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, T.sub.i=internal temperature, MH.sup.+=molecular mass of the molecular cation, M=molar, Q.sup.1HNMR=quantitative .sup.1HNMR, RT=room temperature, TBME=tert-butyl methyl ether, UFLC=Ultra-fast liquid chromatography.

[0241] UFLC (UPLC) Methods:

[0242] Standard:

[0243] 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 μm, 30×2.1 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

[0244] Standard Long:

[0245] 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 μm, 30×2.1 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

[0246] Standard Long Polar:

[0247] Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII or ZQ 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 μm, 30×2.1 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: 0-10% B in 2.5 min; Flow (ml/min) 0.85

[0248] Apolar:

[0249] 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 μm, 30×2.1 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: 40-100% B in 1.2 min; Flow (ml/min) 0.85

[0250] .sup.1H NMR spectra are recorded at 400 MHz unless indicated otherwise and chemical shifts are recorded in ppm.

Preparation of Ethyl 3-(6-oxo-4-pyrimidin-2-yl-pyridazin-1-yl) propanoate (5A)

[0251] ##STR00072##

[0252] General Procedure 1—Alkylation:

[0253] To a three neck round bottom flask (250 mL), charge 2-methyltetrahydrofuran (50 mL) at 24° C. under N.sub.2 atmosphere. Start stirring at 300-400 rpm. Charge 4-pyrimidin-2-yl-1H-pyridazin-6-one (5.00 g, 25.40 mmol). Charge K.sub.2CO.sub.3 (1.40 g, 0.40 eq., 10.20 mmol) followed by tetrabutylammonium bromide (0.42 g, 0.05 eq., 1.27 mmol, 98.00 mass %). Heat the reaction mixture to 80° C. Charge ethyl prop-2-enoate (7.71 g, 3.00 eq., 76.20 mmol) dropwise with syringe pump over a period of 15 min. Continue the reaction at 80° C. for 60 min with monitoring the progress on UFLC. Cool the reaction to 24° C., add water (50 mL) and stir for 20 min. Evaporate the volatile solvents under vacuum at 45-50° C. Charge water (50 mL), stir for 15 min, filter and dry under vacuum to give ethyl 3-(6-oxo-4-pyrimidin-2-yl-pyridazin-1-yl) propanoate (5A) (6.70 g, 88% yield, 91.5% assay).

[0254] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (t, J=7.09 Hz, 3H) 2.81 (t, J=6.97 Hz, 2H) 4.05 (q, J=7.09 Hz, 2H) 4.34 (t, J=6.91 Hz, 2H) 7.60-7.65 (m, 2H) 8.65 (d, J=2.08 Hz, 1H) 9.00 (d, J=4.89 Hz, 2H)

Preparation of Ethyl 3-(4-pyrimidin-2-yl-6-thioxo-pyridazin-1-yl)propanoate (6A)

[0255] ##STR00073##

[0256] General Procedure 2—Sulfurization:

[0257] To a three neck round bottom flask (250 mL), charge Chlorobenzene (150 mL) at 24° C. under N.sub.2 atmosphere. Start stirring at 300-400 rpm. Charge P.sub.2S.sub.5 (5.25 g, 23.38 mmol, 0.45 eq.), N,N-diethylaniline (3.48 g, 23.38 mmol, 0.45 eq.). Heat to 100° C. Charge ethyl 3-(6-oxo-4-pyrimidin-2-yl-pyridazin-1-yl)propanoate (1) (15.00 g, 51.95 mmol, 1.00 eq.) portionwise over 60 min. Stir the reaction at 100° C. for 120 min and monitor the progress on UFLC. Cool the reaction mixture to 24° C. and filter through Celite® bed. Wash the filtrate with water (60 mL) and separate layers. To the chlorobenzene layer, charge water (60 mL) and adjust pH=12 with 2-5% aq. NaOH solution. Separate the layers and wash chlorobenzene layer with water (45 mL) and brine (25 mL). Separate layers. Distill out ˜90% of chlorobenzene from chlorobenzene layer under reduced pressure (100-150 mbar) at 65° C. Add methylcyclohexane (292 mL) at 65° C. and stir for 10-15 min. Cool the reaction mixture and stir at 0° C. for 60 min. Filter the desired product ethyl 3-(4-pyrimidin-2-yl-6-thioxo-pyridazin-1-yl)propanoate (6A) as orange color solid (13.64 g, 85% yield, 94.0% assay).

[0258] 6A: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.12-1.21 (m, 3H) 2.93-3.01 (m, 2H) 4.03-4.15 (m, 2H) 4.74-4.85 (m, 2H) 7.62-7.70 (m, 1H) 8.38-8.46 (m, 1H) 8.97-9.10 (m, 3H)

Preparation of Ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate hydrogen sulfate (7A)

[0259] ##STR00074##

[0260] General Procedure 3—Desulfurization, Formic Acid-H.sub.2O.sub.2 as Oxidant

[0261] To a three neck round bottom flask (250 mL), charge ethyl acetate (40 mL), water (20 mL) and formic acid (10 mL) at 24° C. under N.sub.2 atmosphere. Start stirring at 300-400 rpm. Charge ethyl 3-(4-pyrimidin-2-yl-6-thioxo-pyridazin-1-yl)propanoate (6A) (10.00 g, 33.72 mmol, 1.00 eq., 97.79 mass %) at 24° C. and stir for 10 min. Dose H.sub.2O.sub.2 (11.50 mL, 101.20 mmol, 3.00 eq., 27% in H.sub.2O) over the period of 180 min. Stir the reaction for 180 min and monitor the progress on UFLC. Charge water (80 mL), stir for 15 min and separate the layers. Extract the aqueous layer with ethyl acetate (3×30 mL) and separate the layers. Quench the unreacted H.sub.2O.sub.2 in aqueous layer with charcoal (1 g) and stir for 15 h at 24° C. Filter through Celite® bed to give clear aqueous layer (103.86 g). The aqueous layer was analysed by quantitative 1HNMR using an internal standard and was composed of ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate hydrogen sulfate (7A) (7.73% w/w, 67% yield) and 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid hydrogen sulfate (7B) (0.71% w/w, 6.7% yield).

[0262] 7A: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: 10.12-10.13 (m, 1H), 9.92-9.90 (m, 1H), 9.36-9.34 (m, 1H), 9.15-9.11 (m, 1H), 8.57-8.54 (m, 1H), 8.06-8.02 (m, 1H), 5.18-5.13 (m, 2H), 4.07 (q, J=8.0 Hz, 2H), 3.27 (t, J=8.0 Hz, 2H), 1.12 (t, J=8.0 Hz, 3H).

[0263] General Procedure 4—Desulfurization, Acetic Acid-H.sub.2O.sub.2 as Oxidant

[0264] To a solution of ethyl 3-(4-pyrimidin-2-yl-6-thioxo-pyridazin-1-yl)propanoate (6A) (3 g, 10.13 mmol, 1 eq.) in acetic acid (68 ml) was added slowly hydrogen peroxide (30% w/w in H.sub.2O, 33.42 mmol, 3.3 eq.). The reaction was stirred at room temperature for 2 hours, before solid sodium metabisulfite (5.07 mmol) was added to the mixture. The reaction mixture was concentrated under vacuum to yield the title compound 7A as an orange solid (5.5 g, 59% assay, 90% yield).

[0265] 7A: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: 10.12-10.13 (m, 1H), 9.92-9.90 (m, 1H), 9.36-9.34 (m, 1H), 9.15-9.11 (m, 1H), 8.57-8.54 (m, 1H), 8.06-8.02 (m, 1H), 5.18-5.13 (m, 2H), 4.07 (q, J=8.0 Hz, 2H), 3.27 (t, J=8.0 Hz, 2H), 1.12 (t, J=8.0 Hz, 3H).

Preparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid hydrogen sulfate (7B)

[0266] ##STR00075##

[0267] General Procedure 5—Sulfuric Acid Hydrolysis

[0268] To a three neck round bottom flask (250 mL), charge aqueous layer containing ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate hydrogen sulfate (7A), and 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid hydrogen sulfate (7B) (103.10 g, 68% w/w of 7A and 7.8% w/w of 7B) at 24° C. under N.sub.2 atmosphere. Start stirring at 300-400 rpm. Charge sulfuric acid (50.00 mg, 0.51 mmol, cat.). Heat the reaction mass to 95° C. for 240 min and monitor the hydrolysis on UFLC. Cool the reaction mass to 24° C. and evaporate to dryness to give desired product (11.60 g, 79% yield over 2 steps, 75.6% assay). Crystallization in water/isopropanol/acetone (1:2:2) (67 mL), followed by filtration gives 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid hydrogen sulfate (7B) as an off-white solid (8.54 g, 70% from 6A, 91.3% assay).

[0269] 7B: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: 3.32 (t, J=6.11 Hz, 2H), 5.18 (t, J=6.11 Hz, 2H), 7.71 (t, J=5.00 Hz, 1H), 9.06 (d, J=5.08 Hz, 2H), 9.25 (dd, J=6.19, 2.38 Hz, 1H), 9.93 (d, J=6.19 Hz, 1H), 10.23 (d, J=1.90 Hz, 1H).

Preparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride (7E)

[0270] ##STR00076##

[0271] General Procedure 6—Salt Exchange, Amberlite Salt Switch Method

[0272] To a three neck round bottom flask (250 mL), charge water (80 mL) at 24° C. under N.sub.2 atmosphere. Start stirring at 300-400 rpm. Charge 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid hydrogen sulfate (7B) (8.32 g, 23.10 mmol, 1 eq.). Charge amberlite resin (IRN78 hydroxide form) (4.67 g, 2.00 eq. g, 47.40 mmol, 2.00 eq.) at 24° C. and stir for 10 min. Filter the resulting suspension on sintered funnel. Wash the resin bed with water (3×10 mL) and combine the aqueous layers. Add conc. HCl (2.53 g, 24.30 mmol, 1.00 eq., 35% in H.sub.2O) to the aqueous layer and stir for 30 min at 24° C. Concentrate the acidic solution at 50° C. under reduced pressure to afford 7E as off white solid (5.77 g, 92% yield from 7B, 98% assay).

[0273] 7E: .sup.1H NMR (400 MHz, D.sub.2O) 6 ppm: 3.33 (t, J=6.03 Hz, 2H), 5.20 (t, J=6.03 Hz, 2H), 7.73 (t, J=5.00 Hz, 1H), 9.08 (d, J=5.08 Hz, 2H), 9.27 (dd, J=6.19, 2.22 Hz, 1H), 9.94 (d, J=6.19 Hz, 1H), 10.25 (s, 1H).

[0274] General Procedure 7—Salt Exchange, BaCl.sub.2 Salt Switch Method

[0275] To a three neck round bottom flask (250 mL), charge aqueous layer containing ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate hydrogen sulfate (7A), and 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid hydrogen sulfate (7B) (103.10 g, 68% w/w of 7A and 7.8% w/w of 7B) (273.13 g, 6% strength) at 24° C. under N.sub.2 atmosphere. Start stirring at 300-400 rpm. Dose BaCl.sub.2 (66.80 g, 1.00 eq. 1M solution) over the period of 5-7 min. Heat the reaction mixture at 95-100° C. for 120-180 min and monitor the progress on UFLC. Cool to 95-100° C. and filter the precipitated BaSO.sub.4 over Celite® bed. Distill out the aqueous under 40 mbar at T.sub.i=60° C. to keep 0.75 volume in the flask. Add isopropanol (62 mL) and acetone (16 mL) and stir for 10-15 min. Cool to 10° C. in 30 min and continue stirring for 60 min. Filter off the desired product 7E as off-white solid (11.52 g, 62.00% yield (from 6A), 97% assay).

[0276] 7E: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: 3.33 (t, J=6.03 Hz, 2H), 5.20 (t, J=6.03 Hz, 2H), 7.73 (t, J=5.00 Hz, 1H), 9.08 (d, J=5.08 Hz, 2H), 9.27 (dd, J=6.19, 2.22 Hz, 1H), 9.94 (d, J=6.19 Hz, 1H), 10.25 (s, 1H).

tert-butyl 3-(6-oxo-4-pyrimidin-2-yl-pyridazin-1-yl)propanoate (5D)

[0277] ##STR00077##

[0278] 5D Can be prepared from 4A via general alkylation procedure 1 using tert-butyl prop-2-enoate. 5D: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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)

3-(6-oxo-4-pyrimidin-2-yl-pyridazin-1-yl)propanoic acid (5B)

[0279] ##STR00078##

[0280] 5B Can be prepared from 5D via general hydrolysis procedures well known in the art.

[0281] .sup.1H NMR (400 MHz, D6-DMSO) δ 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)

tert-butyl 3-(4-pyrimidin-2-yl-6-thioxo-pyridazin-1-yl)propanoate 6D

[0282] ##STR00079##

[0283] Prepared from 5D via general procedure 2 in 83% yield.

[0284] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.48 (s, 9H) 2.95 (t, J=7.15 Hz, 2H) 4.95 (t, J=7.15 Hz, 2H) 7.38 (t, J=4.95 Hz, 1H) 8.76 (d, J=2.57 Hz, 1H) 8.89 (d, J=5.14 Hz, 2H) 9.04 (d, J=2.20 Hz, 1H)

tert-butyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate hydrogen sulfate 7D

[0285] ##STR00080##

[0286] Prepared from 6D via general desulfurization procedure 4 in 57% yield as a solid.

[0287] 7D: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm 1.38 (s, 9H) 3.24 (t, J=6.3 Hz, 2H) 5.17 (t, J=6.3 Hz, 2H) 7.72 (t, J=5.03 Hz, 1H) 9.06 (d, J=5 Hz, 2H) 9.29 (dd, J=5.53, 2.2 Hz, 1H) 9.91 (d, J=5.53 Hz, 1H) 10.25 (d, J=1.8 Hz, 1H)

##STR00081##

[0288] 7D can be converted to 7E by telescoping general procedures 5 and 6 in 92% yield without isolation of 7B.

Preparation of 3-(4-pyrimidin-2-yl-6-thioxo-pyridazin-1-yl)propanenitrile (6C)

[0289] ##STR00082##

[0290] Compound 6C was prepared according to the general sulfurization procedure 2.

[0291] 6C: .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 3.17 (t, J=6.79 Hz, 2H) 4.99 (t, J=6.79 Hz, 2H) 7.40 (t, J=4.95 Hz, 1H) 8.75 (d, J=1.83 Hz, 1H) 8.90 (d, J=5.14 Hz, 2H) 9.11 (d, J=2.20 Hz, 1H)

3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanenitrile hydrogen sulfate 7C

[0292] ##STR00083##

[0293] Compound 7C was prepared in 42% yield from 6C via general desulfurization procedure 4.

[0294] 7C: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm 3.40 (t, J=6.24 Hz, 2H) 5.22 (t, J=6.24 Hz, 2H) 7.67 (t, J=4.95 Hz, 1H) 9.02 (d, J=4.77 Hz, 2H) 9.17 (dd, J=5.87, 1.83 Hz, 1H) 9.91 (d, J=6.24 Hz, 1H) 10.26 (bs, 1H)

3-(4-pyrimidin-2-yl-6-thioxo-pyridazin-1-yl)propanoic acid 6B

[0295] ##STR00084##

[0296] General Procedure 9—HCl Hydrolysis

[0297] To a solution or tert-butyl 3-(4-pyrimidin-2-yl-6-thioxo-pyridazin-1-yl)propanoate (0.105 g, 0.33 mmol) in dioxane (1.65 mL) was added HCl 2M (6.59 mL, 7.85 g, 13.2 mmol). The reaction mixture was heated to reflux for 15 mins and then concentrated in vacuo to afford 3-(4-pyrimidin-2-yl-6-thioxo-pyridazin yl)propanoic acid 6B (0.083 g, 0.32 mmol, 96% yield).

[0298] 1H NMR (400 MHz, CD.sub.3OD) δ=9.08 (d, J=2.2 Hz, 1H), 8.94 (d, J=4.9 Hz, 2H), 8.61 (d, J=2.2 Hz, 1H), 7.52 (t, J=4.9 Hz, 1H), 4.89 (t, J=7.2 Hz, 2H), 2.99 (t, J=7.2 Hz, 2H)

Preparation of Ethyl 3-(6-oxo-4-pyridazin-3-yl-pyridazin-1-yl)propanoate (15A)

[0299] ##STR00085##

[0300] To a three neck round bottom flask (250 mL), charge 2-methyltetrahydrofuran (100 mL) at 24° C. under N.sub.2 atmosphere. Start stirring at 400 rpm. Charge 4-pyridazin-3-yl-1H-pyridazin-6-one 14A (10.00 g, 52.91 mmol). Charge K.sub.2CO.sub.3 (0.40 eq., 10.58 mmol) followed by tetrabutylammonium bromide (0.05 eq., 2.65 mmol). Heat the reaction mixture to 80° C. Charge ethyl prop-2-enoate (12.82 g, 2.40 eq., 127.0 mmol) dropwise with syringe pump over a period of 1 h. Continue the reaction at 80° C. for 420 min with monitoring the progress on UFLC. Cool the reaction to 24° C., add water (100 mL). Extract the aqueous with ethylacetate (2×100 mL) and separate the layers. Evaporate the combined ethylacetate layers to give pale violet solid (15.00 g). Triturate the pale violet solid in TBME (45 mL) to give the desired compound ethyl 3-(6-oxo-4-pyridazin-3-yl-pyridazin-1-yl)propanoate (15A) (13.50 g, 87% yield, 94% assay).

[0301] 15A: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.16 (t, J=7.06 Hz, 3H), 2.82 (t, J=6.98 Hz, 2H), 4.06 (q, J=7.14 Hz, 2H), 4.35 (t, J=6.90 Hz, 2H), 7.67 (d, J=2.06 Hz, 1H), 7.89 (dd, J=8.64, 5.00 Hz, 1H), 8.41 (dd, J=8.64, 1.51 Hz, 1H), 8.70 (d, J=2.22 Hz, 1H), 9.34 (dd, J=4.92, 1.43 Hz, 1H).

Preparation of Ethyl 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl) propanoate (16A)

[0302] ##STR00086##

[0303] To a four neck round bottom flask (100 mL), charge pyridine (10.00 mL, 120.00 mmol) at 24° C. under N.sub.2 atmosphere. Start stirring at 250 rpm. Charge P.sub.2S.sub.5 (1.96 g, 0.50 eq., 8.75 mmol) at 24° C. Heat the reaction mixture to 115° C. Charge solution of ethyl 3-(6-oxo-4-pyridazin-3-yl-pyridazin-1-yl)propanoate 15A (5.00 g, 17.5 mmol) in Pyridine (15.10 mL, 190.00 mmol) dropwise over a period of 1 h at 115° C. Distilled out pyridine (15.00 mL, 190.00 mmol) and continue stirring at 115° C. for 240 min. Monitor the progress on HPLC, recharge distilled pyridine (15.00 mL, 190.0 mmol) and cooled the reaction mixture to 60° C., reaction mass quenched by water (37.50 mL) at 24° C., resultant suspension cooled to 20-25° C. Continue stirring at 20-25° C., 60 min. Filtration to give ethyl 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl) propanoate (16A) as orange solid (4.70 g, 89.00% yield, 97% assay).

[0304] 16A: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.16-1.19 (t, J=4.0 Hz, 3H), 2.96-2.99 (t, J=4.0 Hz, 2H), 4.06-4.11 (q, J=4.0 Hz, 2H), 4.78-4.82 (t, J=4.0 Hz, 2H), 7.89-7.92 (dd, J=8.0, 4.0 Hz, 1H), 8.46-8.52 (m, 2H), 9.11 (m, 1H), 9.35-9.37 (m, 1H)

Preparation of Ethyl 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoate hydrogen sulfate (17A)

[0305] ##STR00087##

[0306] To a four neck round bottom flask (100 mL), charge ethyl acetate/Water/Formic acid (4:2:1) (35.00 mL) at 24° C. under N.sub.2 atmosphere. Start stirring at 275 rpm. Charge ethyl 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl)propanoate (16A) (5.00 g, 16.00 mmol) at 24° C. Charge H.sub.2O.sub.2 (5.70 g, 5.10 mL, 3.06 eq., 50.00 mmol, 30% in H.sub.2O) dropwise in 240 min at 20-25° C. under N.sub.2 atmosphere. Continue the reaction at 20-25° C. for another 120 min and monitor the progress on UFLC. Charge Water (40 mL) and separate the organic layer. Extract the aqueous layer with ethyl acetate (4×15 mL) and separate the layers. Treat the aqueous layer with activated charcoal (500.00 mg, 10% w/w) and continue stirring overnight at 20-25° C. Filter the aqueous solution through Celite® bed to give a clear solution of ethyl 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoate hydrogen sulfate (17A) (49.00 g, 12.70 mmol, 78% yield, 9.2% w/w in H.sub.2O) and 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid hydrogen sulfate (17B) (49.0 g, 3.6 mmol, 3.6%, 2.4 w/w in H.sub.2O %). The aqueous solution was used as such for next step.

[0307] 17A: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.12-10.13 (m, 1H), 9.92-9.90 (m, 1H), 9.36-9.34 (m, 1H), 9.15-9.11 (m, 1H), 8.57-8.54 (m, 1H), 8.06-8.02 (m, 1H), 5.18-5.13 (m, 2H), 4.07 (q, J=8.0 Hz, 2H), 3.27 (t, J=8.0 Hz, 2H), 1.12 (t, J=8.0 Hz, 3H).

[0308] 17A was Also Prepared According to the Following Procedure:

[0309] To a four neck round bottom flask (100 mL), charge acetic acid (21 mL, 1.5 M) at 24° C. under N.sub.2 atmosphere. Start stirring at 300-400 rpm. Charge ethyl 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl)propanoate (16 A) (1.00 g, 3.20 mmol, 1.00 eq., 93.00 mass %) at 24° C. and stir for 10 min. Dose H.sub.2O.sub.2 (1.20 mL, 11.00 mmol, 3.30 eq., 27.00 mass %) over the period of 120 min. Stir the reaction for 60 min and monitor the progress on HPLC. Quench the unreacted H.sub.2O.sub.2 into the reaction with saturated Na.sub.2SO.sub.3 (0.12 g, 0.96 mmol, 0.30 eq., 98.00 mass % in water) solution and stir for 30 min at 24° C. Concentrate the reaction mass under rota vapour to get crude gummy liquid (1.87 g, 67.00% ethyl 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoate hydrogen sulfate (17 A), 41.00 mass %).

Preparation of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid hydrogen sulfate (17B)

[0310] ##STR00088##

[0311] To a four neck round bottom flask (100 mL) installed with Dean-Stark and water condenser, charge ethyl 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoate;hydrogen sulfate 17A (49.00 g, 12.70 mmol, 9.2% w/w in H.sub.2O) at 24° C. Start stirring at 275 rpm. Charge conc. hydrogen chloride (0.662 g, 0.50 eq., 6.35 mmol, 35% in H.sub.2O) at 24° C. Heat the reaction mixture to 100° C. Continue the reaction at 100° C. for 3 h and monitor the progress on UFLC. Cool the reaction mixture to 24° C. Evaporate (˜10 mL) the aqueous layer to give ethyl 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoate hydrogen sulfate (17B) (47.00 g, 11.10 mmol, 67% yield from 16A, 7.66% w/w in H.sub.2O). The aqueous solution was used as such for next step.

[0312] 17B: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 3.30 (t, J=4 Hz, 2H), 5.17 (t, J=4.0 Hz, 2H), 8.09 (dd, J=8.0, 4.0 Hz, 1H), 8.59 (dd, J=8.0, 4.0 Hz, 1H), 9.14-9.16 (m, 1H), 9.39-9.40 (m, 1H), 9.93 (d, J=8.0 Hz, 1H), 10.16 (d, J=8.0 Hz, 1H).

3-(4-Pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid chloride (17E)

[0313] ##STR00089##

[0314] To a four neck round bottom flask (100 mL), charge ethyl 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoate hydrogen sulfate (17B) (47.00 g, 11.10 mmol, 7.66% w/w in H.sub.2O). Start stirring at 275 rpm. Charge Amberlite IRN78 hydroxide form (38.00 g, 69.40 mmol) over a period of 60 min until pH becomes 7-8 at 24° C. Filter the resulting suspension on sintered funnel. Wash the resin bed with water (2×15 mL) and combine the aqueous layers. Add conc. HCl (1.14 g, 1.00 eq., 11.00 mmol, 35% in H.sub.2O) to the aqueous layer and stir for 30 min at 24° C. Concentrate the acidic solution at 50° C. under reduced pressure to afford crude 17E (3.10 g, 62% yield from 16A, 86% assay). Crystallization in water/iPrOH/acetone (1:4:3, 21.2 mL) to afford 17E (1.76 g, 39% yield from 16A, 98% assay).

[0315] 17E: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm 10.15 (m, 1H), 9.93 (d, J=8.0 Hz, 1H), 9.37-9.35 (m, 1H), 9.15-9.13 (m, 1H), 8.57-8.54 (m, 1H), 8.06-8.02 (m, 1H), 5.17 (t, J=8.0 Hz, 2H), 3.30 (t, J=8.0 Hz, 2H).

[0316] 17E was Also Prepared from 17B Via the Following Procedure:

[0317] To a three neck round bottom flask (250 mL) assemble with dean-stark and water condenser. Start stirring at 400 rpm. A mixture of ethyl 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoate hydrogen sulfate (17A) (1.00 eq., 139.00 g, 36.50 mmol, 9.36% w/w in H.sub.2O) and 3-(4-pyridazin-3-ylpyridazin ium-1-yl)propanoic acid hydrogen sulfate 17B (139.00 g, 2.60 mmol, 0.61% w/w in H.sub.2O) was charged. The mixture was stirred for 5 min. Charge aqueous solution of BaCl.sub.2.2H.sub.2O (41.00 mL, 1.05 eq., 41.00 mmol, 1M solution in water) dropwise over a period of 10 min at room temperature. Continue the reaction at room temperature for 20 min and monitor the progress using BaCl.sub.2 test. Heat the reaction mixture to 100° C. Continue the reaction at 100° C. for 180 min and monitor the progress on UFLC. Cool the reaction to 24° C. Filter the aqueous solution through the Celite® bed and wash the Celite® bed with water (3×45 mL). Evaporate aqueous solution to give 17E crude as brown solid (12.70 g). Crystallization in water/iPrOH (1:4, 100 mL) to afford 17E as an off-white solid (7.80 g, 69% yield from 16A, 94% assay).

[0318] 17E: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm 10.15 (m, 1H), 9.93 (d, J=8.0 Hz, 1H), 9.37-9.35 (m, 1H), 9.15-9.13 (m, 1H), 8.57-8.54 (m, 1H), 8.06-8.02 (m, 1H), 5.17 (t, J=4.0 Hz, 2H), 3.30 (t, J=4.0 Hz, 2H).

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

[0319] ##STR00090##

[0320] To a three neck round bottom flask (25 mL), charge acetonitrile (8 mL) at 24° C. under N.sub.2 atmosphere. Start stirring at 400 rpm. Charge 4-pyridazin-3-yl-1H-pyridazin-6-one 14A (1.00 g, 5.45 mmol) and stir for 5 min. Charge K.sub.2CO.sub.3 (1.20 eq. 6.55 mmol), followed by tetrabutylammonium bromide (0.05 eq., 0.27 mmol). Heat the reaction mixture to 80° C. Charge tert-butyl prop-2-enoate (0.85 g, 1.20 eq., 6.55 mmol) dropwise in 5 min. Continue the reaction at 80° C. for 240 min with monitoring the progress on UFLC. Cool the reaction to 24° C., concentrate the acetonitrile and add water (10 mL). Extract the aqueous with ethylacetate (2×10 mL) and separate the layers. Evaporate the combined ethylacetate layers to give pale violet solid (1.38 g). Triturate the pale violet solid in TBME (5 mL) to give the desired compound tert-butyl 3-(6-oxo-4-pyridazin-3-yl-pyridazin-1-yl)propanoate (15D) (1.27 g, 74% yield, 96% assay).

[0321] 15D: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.36 (s, 9H), 2.73 (t, J=6.85 Hz, 2H), 4.31 (t, J=6.91 Hz, 2H), 7.67 (d, J=2.20 Hz, 1H), 7.90 (dd, J=8.68, 5.01 Hz, 1H), 8.41 (dd, J=8.62, 1.41 Hz, 1H), 8.70 (d, J=2.20 Hz, 1H), 9.34 (dd, J=4.95, 1.41 Hz, 1H).

tert-butyl 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl)propanoate 16D

[0322] ##STR00091##

[0323] 16D was prepared from 15D in 32% yield according to General Procedure 2.

[0324] 16D: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.39 (s, 9H), 2.89 (t, J=6.74 Hz, 2H), 4.76 (t, J=6.82 Hz, 2H), 7.90 (dd, J=8.64, 5.00 Hz, 1H), 8.47 (d, J=2.22 Hz, 1H), 8.52 (dd, J=8.64, 1.51 Hz, 1H), 9.11 (d, J=2.22 Hz, 1H), 9.36 (dd, J=4.92, 1.43 Hz, 1H)

tert-butyl 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoate hydrogen sulfate 17D

[0325] ##STR00092##

[0326] 17D was prepared from 16D in 56% yield according to general desulfurization procedure 4:

[0327] 17D: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm 1.35 (s, 9H), 3.21 (t, J=6.11 Hz, 2H), 5.15 (t, J=6.03 Hz, 2H), 8.04 (dd, J=8.64, 5.15 Hz, 1H), 8.55 (dd, J=8.72, 1.43 Hz, 1H), 9.16 (dd, J=6.34, 2.54 Hz, 1H), 9.36 (dd, J=5.15, 1.51 Hz, 1H), 9.91 (d, J=6.34 Hz, 1H), 10.17 (d, J=2.06 Hz, 1H)

3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid hydrogen sulfate 17B

[0328] ##STR00093##

[0329] To a four neck round bottom flask (5.0 L), charge solution of tert-butyl 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoate;methane (17D) (870 g, 1358 mmol, 60.00 mass %) in water. Start stirring at 275 rpm. Dose conc. HCl (180.0 g, 1630 mmol, 33 mass %) at temperature 22-25° C. Heat the reaction mass at 50° C. and stir for 3 h. Monitor the progress on HPLC. After completion of reaction, the reaction mixture was concentrated to give crude 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid hydrogen sulfate (17 B) (517 g, 1181 mmol, 86%, 75.00 mass %). The aq. solution was used as such without further purification.

[0330] 17B: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 3.30 (t, J=4 Hz, 2H), 5.17 (t, J=4.0 Hz, 2H), 8.09 (dd, J=8.0, 4.0 Hz, 1H), 8.59 (dd, J=8.0, 4.0 Hz, 1H), 9.14-9.16 (m, 1H), 9.39-9.40 (m, 1H), 9.93 (d, J=8.0 Hz, 1H), 10.16 (d, J=8.0 Hz, 1H).

3-(4-Pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid chloride (17E)

[0331] ##STR00094##

[0332] 17D can be converted to 17E by telescoping general procedures 5 and 6 in 90% yield (90% assay) without isolation of 17B.

Preparation of 4-pyridazin-3-yl-1H-pyridazine-6-thione (15E)

[0333] ##STR00095##

[0334] 4-pyridazin-3-yl-1H-pyridazin-6-one (14A) (2.00 g) was mixed with dry pyridine (16 ml) and the reaction mixture was heated to 90° C. under stirring. Phosphorus pentasulfide (1.27 g) was added in portions and the reaction mixture was stirred at 90° C. for 6 h and for additional 2 h at 110° C. The reaction was cooled to 5° C. and ice cold water (100 ml) was added under cooling. The suspension was heated to 60° C. and slowly cooled to RT. The solid was filtered, washed twice with ice cold water, and dried under reduced pressure providing 4-pyridazin-3-yl-1H-pyridazine-6-thione 15E (2.08 g) as a yellow solid. 15E: .sup.1H NMR (DMSO-d.sub.6) δ=14.98 (br s, 1H), 9.37 (dd, J=4.77, 1.47 Hz, 1H), 9.07 (d, J=2.20 Hz, 1H), 8.50 (dd, J=8.44, 1.47 Hz, 1H), 8.32 (d, J=2.20 Hz, 1H), 7.91 (dd, J=8.62, 4.95 Hz, 1H) LC-MS RT (Standard Method): 0.28 min; MS (ES-pos) calcd for [C8H6N4S]+H.sup.+: 191, found 191.

Preparation of 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl)propanenitrile (16C)

[0335] ##STR00096##

[0336] A flask was charged with 4-pyridazin-3-yl-1H-pyridazine-6-thione (15E) (6.20 g, 30 mmol, 1.00 eq) and dissolved in Me-THF (89 mL). Tetrabutylammonium hydroxide (1.20 g, 1M in MeOH, 1.5 mmol, 0.05 equiv.) and Acrylonitrile (1.7 g, 31 mmol, 1.00 eq) were added. The resulting mixture was stirred at 50° C. After 2 h, tetrabutylammonium hydroxide (0.25 g, 1M in MeOH, 1.5 mmol, 0.01 equiv.) and Acrylonitrile (1.7 g, 31 mmol, 1.00 eq) were again added and the mixture was stirred at 50° C. overnight.

[0337] The mixture was then filtered and the resulting solid was washed with 200 mL of TBME (200 mL).

[0338] The solid was dried in vacuum for 30 min to give 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl)propanenitrile 16C isolated as a brown solid (6.74 g, 86% purity, 80% yield).

[0339] 16C: .sup.1H NMR (DMSO-d.sub.6) δ=9.38 (br d, J=4.03 Hz, 1H), 9.19 (br d, J=1.47 Hz, 1H), 8.54 (br d, J=8.44 Hz, 1H), 8.50 (br d, J=1.47 Hz, 1H), 7.92 (br dd, J=8.44, 5.14 Hz, 1H), 4.87 (br t, J=6.24 Hz, 2H), 3.25 (br t, J=6.24 Hz, 2H)

[0340] LC-MS RT (Standard Method): 0.59 min; MS (ES-pos) calcd for [C11H9N5S]+H.sup.+: 244, found 244.

Preparation of 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl)propanoic acid (16B)

[0341] ##STR00097##

[0342] 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl)propanenitrile (16C) (0.5 g) was dissolved in hydrochloric acid (4 M, 4.8 ml). The reaction was stirred at 50° C. for 6 h, diluted with water and filtered. The solid was washed with water, and dried under reduced pressure providing 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl)propanoic acid 16B (0.39 g, 96% assay, 75% yield) as a brown solid.

[0343] 16B: .sup.1H NMR (DMSO-d.sub.6) δ=12.49 (br s, 1H), 9.37 (dd, J=4.77, 1.47 Hz, 1H), 9.13 (d, J=2.20 Hz, 1H), 8.51 (dd, J=8.80, 1.47 Hz, 1H), 8.47 (d, J=2.57 Hz, 1H), 7.91 (dd, J=8.80, 5.14 Hz, 1H), 4.78 (t, J=7.15 Hz, 2H), 2.92 (t, J=6.97 Hz, 2H)

[0344] LC-MS RT (STANDARD LONG Method): 1.49 min; MS (ES-pos) calcd for [C11H10N4O2S]+H.sup.+: 263, found 263.

Preparation of 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl)propanamide (16E)

[0345] ##STR00098##

[0346] 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl)propanenitrile (16C) (0.54 g) was dissolved in acetic acid (6.2 ml) and hydrochloric acid (4 M, 1.8 ml) was added. The reaction was stirred at RT for 3 h, diluted with water (18 ml) and filtered. The solid was washed with water, and dried under reduced pressure providing 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl)propanamide 16E (0.32 g) as a brown solid.

[0347] 16E: .sup.1H NMR (DMSO-d.sub.6) δ=9.36 (br d, J=5.14 Hz, 1H), 9.10 (d, J=1.83 Hz, 1H), 8.50 (br d, J=8.44 Hz, 1H), 8.44 (d, J=1.83 Hz, 1H), 7.90 (dd, J=8.62, 4.95 Hz, 1H), 7.50 (br s, 1H), 6.97 (br s, 1H), 4.78 (br t, J=7.34 Hz, 2H), 2.75 (br t, J=7.52 Hz, 2H)

[0348] LC-MS RT (STANDARD LONG Method): 1.32 min; MS (ES-pos) calcd for [C11H11N5OS]+H.sup.+: 262, found 262.

Preparation of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanamide hydrogensulfate (17E)

[0349] ##STR00099##

[0350] 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl)propanamide (16E) (30 mg) was dissolved in acetic acid (0.57 ml) and hydrochloric acid (4 M, 0.057 ml). Hydrogen peroxide (35% in water, 0.33 ml) was added. The reaction was stirred at RT for 0.5 h, diluted with 2-Propanol (4 ml) and filtered. The solid was washed with 2-Propanol, and dried under reduced pressure providing 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanamide hydrogensulfate 17F (18 mg).

[0351] 17F: .sup.1H NMR (D.sub.2O) δ=10.12 (d, J=1.83 Hz, 1H), 9.86 (d, J=6.24 Hz, 1H), 9.35 (dd, J=5.14, 1.47 Hz, 1H), 9.11 (dd, J=6.24, 2.57 Hz, 1H), 8.55 (dd, J=8.44, 1.47 Hz, 1H), 8.04 (dd, J=8.80, 5.14 Hz, 1H), 5.13 (t, J=6.24 Hz, 2H), 3.17 (t, J=6.24 Hz, 2H)

[0352] LC-MS RT (STANDARD LONG Method): 0.63 min; MS (ES-pos) calcd for [C11H12N5O].sup.+: 230, found 230.

Preparation of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid hydrogensulfate (17B)

[0353] ##STR00100##

[0354] 3-(4-pyridazin-3-yl-6-thioxo-pyridazin-1-yl)propanoic acid (16B) (0.30 g) was suspended in acetic acid (5 ml), cooled to 10° C., and hydrogen peroxide (35% in water, 0.32 ml) was added dropwise. After 50 min, the reaction was warmed to RT and Sodium metabisulfite was added until remaining peroxide was quenched. Isopropanol (5 ml) was added, the precipitate was filtered and dried to give 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid hydrogensulfate 17B (280 mg) as a beige solid.

Preparation of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid hydrogensulfate (17B)

[0355] ##STR00101##

[0356] 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanamide hydrogensulfate 17F (20 mg) was dissolved in hydrochloric acid (4M, 0.5 ml) and stirred at 50° C. for 17 h. The reaction was concentrated and the oily residue was triturated with 2-propanol (4 ml), filtered, and washed with 2-propanol (2×1 ml) to provide 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid hydrogensulfate 17B (8 mg) as solid.

Preparation of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid chloride salt (17E) from 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanenitrile chloride salt (17G)

[0357] ##STR00102##

[0358] 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanenitrile chloride salt 17G (17.9 g, 40.4 mmol, 55.8%) was stirred with hydrochloric acid (46.0 g, 0.404 mol, 10 eq, 32% w/w in H.sub.2O) at 80° C. for 2.5 h. Water (31 g) was added and volatiles (HCl/Water azeotrope) were removed by rotary evaporation at 55° C. To remove excessive HCl as well as water, propionic acid (15.5 g) was added to the residue and the resulting mixture was evaporated to dryness to result in crude product (17G) as a black amorphous (glass-like) solid in 96% yield (24.9 g, purity=41.4%, quantitative 1H NMR in D.sub.2O with 1-Methyl-2-pyridone as standard).

[0359] NMR data: .sup.1H NMR (400 MHz, D.sub.2O) 6 ppm: 10.13 (d, J=2.4 Hz, 1H), 9.95 (d, J=6.3 Hz, 1H), 9.34 (dd, J=5.1 Hz, 1.5 Hz, 1H), 9.15 (dd, J=6.3 Hz, 2.6 Hz, 1H), 8.57 (dd, J=8.7 Hz, 1.5 Hz, 1H), 8.04 (dd, J=8.7 Hz, 5.1 Hz, 1H), 5.18 (t, J=6.1 Hz, 2H), 3.29 (t, J=6.1 Hz, 2H).

Preparation of 4-pyrimidin-2-yl-1H-pyridazine-6-thione (4C)

[0360] ##STR00103##

[0361] 3-chloro-5-pyrimidin-2-yl-pyridazine (4B) (1.00 eq., 0.200 g, 0.997 mmol) and Thiourea (2.00 eq., 0.153 g, 1.99 mmol) were suspended in MeOH (6 mL). The pale-yellow suspension was heated to 60° C. for 2 h. The reaction was after cooled down to room temperature to give a very thick yellow suspension. The solid was filtered off and was washed with a small amount of MeOH. The title compound was obtained after drying in vacuo as a yellow solid (0.167 g, 85% Yield, 97% purity).

[0362] 1H NMR (DMSO-d6, 400 MHz) 14.99 (br s, 1H), 9.04 (d, J=4.8 Hz, 2H), 9.00 (d, J=1.8 Hz, 1H), 8.30 (s, 1H), 7.67 (t, J=4.9 Hz, 1H)

Preparation of ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate hydrogen sulfate (7A)

[0363] ##STR00104##

[0364] O-ethyl 3-(4-pyrimidin-2-yl-6-thioxo-pyridazin-1-yl)propanethioate (18A) (0.500 g, 1.60 mmol) was slurried in Acetic acid (10.7 mL) at 22° C. Additional Acetic acid (3.3 mL) was added to give a clear solution. The resulting brown solution was cooled to 16-18° C. using an ice-water bath. H.sub.2O.sub.2 (30% wt in H.sub.2O) was added in portion via syringe at 16-18° C. as described below.

[0365] A first portion of H.sub.2O.sub.2 (30% wt in H.sub.2O, 1.10 eq., 0.2 mL) was added over the period of 1 min at 17-19° C. and stirred for 10 min. A second addition of H.sub.2O.sub.2 (30% wt in H.sub.2O, 0.55 eq., 0.1 mL) was added over the period of 1 min at 17-19° C. and stirred for 10 min. A third addition of H.sub.2O.sub.2 (30% wt in H.sub.2O, 1.65 eq., 0.4 mL) was added over the period of 1 min at 18° C. The cooling ice-water bath was removed and the reaction mixture allowed to gradually warm to 24° C. and stirred for 1 h. Analysis indicated incomplete reaction. The reaction mixture was cooled again to 18° C. with an ice water bath and a fourth portion of H.sub.2O.sub.2 (30% wt in H.sub.2O, 1.30 eq., 0.24 mL) was added over the period of 1 min at 18-20° C. The reaction mass was quenched with solid Sodium Metabisulfite (5.00 equiv., 8.00 mmol) at 24° C. under stirring. (solid sodium metabisulfite was added portionwise (0.2 eq. each), and after each addition of sodium metabisulfite, the suspension was stirred for 10 min). The presence of residual H.sub.2O.sub.2 by checked using a starch-iodine paper coloring test. c) Starch-iodine paper was made wet before addition of reaction mixture. Inorganic insoluble materials were removed by filtration on a sintered funnel. The collected solid was washed with CH.sub.2Cl.sub.2 (2×10 mL). The combined filtrate and washings were concentrated under reduced pressure to afford 1.453 g of solid crude material. The crude material was taken up in CH.sub.2Cl.sub.2 (25 mL) and stirred for 15 min at 24° C. The insoluble inorganic was again removed by filtration on sintered funnel and the filtrate was concentrated under reduced pressure till constant weight to afford of sticky yellow solid (0.25 g). This material was analyzed using quantitative 1HNMR in DMSO-d6 (using 1,3,5-trimethoxybenzene as an internal standard). The analysis indicated the title compound (7A, analytical data as reported above) had been formed in 29% Chemical yield.