EP4698521A1 - Process for the preparation of 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile and derivatives thereof - Google Patents
Process for the preparation of 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile and derivatives thereofInfo
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- EP4698521A1 EP4698521A1 EP24719164.6A EP24719164A EP4698521A1 EP 4698521 A1 EP4698521 A1 EP 4698521A1 EP 24719164 A EP24719164 A EP 24719164A EP 4698521 A1 EP4698521 A1 EP 4698521A1
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- carbonitrile
- dihydrothiazole
- hydroxy
- alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/14—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel process for the preparation of 4-hydroxy-4,5- dihydrothiazole-2-carbonitrile of the formula (I), (I). 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile is a versatile intermediate which can be used to prepare versatile precursor compounds of pharmaceutically active compounds, such as drugs and other chemical compounds used in medicine. Described is the further transformation of 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of the formula I into the thiazole-2-carbonitrile of the formula (III), (III), the thiazole-2-carboximidamide of formula (V), or of a salt thereof, Formula (V), (V) and the 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile derivatives of the formula (IV), (IV), -26- wherein R1 is C1-6-alkyl or phenyl and wherein the phenyl ring is optionally substituted with, halogen, C1-6-alkyl or C1-6-alkoxy.
Description
Process for the preparation of 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile and derivatives thereof
The invention relates to a novel process for the preparation of 4-hydroxy-4,5- dihydrothiazole-2-carbonitrile of the formula I
comprising, reacting cyanogen with l,4-dithiane-2,5-diol of the formula II
in a polar aprotic solvent in the presence of a tertiary organic amine.
The invention further relates to the transformation of the 4-hydroxy-4,5- dihydrothiazole-2-carbonitrile of the formula I into the versatile precursor compound thiazole-2-carbonitrile of the formula III
-hydroxy-4,5-dihydrothiazole-2-carbonitrile derivatives of the formula IV
thiazole-2-carboximidamide of formula V or of a salt thereof
Furthermore the invention comprises the novel thiazole precursor
4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of the formula I
and
4-hydroxy-4,5-dihydrothiazole-2-carbonitrile derivatives of the formula IV
wherein R1 is Ci-6-alkyl or phenyl, wherein the phenyl ring is optionally substituted with, halogen, Ci-6-alkyl or Ci-6-alkoxy.
Thiazole core structures form the scaffold of many lead compounds in drug discovery (A. Ayati et al, European Journal of Medicinal Chemistry 97 (2015), 699-718). For instance the PCT International Publication WO 2015/132276 Al discloses 6-fused heteroaryl dihydropyrimidines, which carry a thiazole moiety in the core structure and which have a potential to be used in the treatment and prophylaxis of Hepatitis B infections.
Object of the invention was to find a scalable processes for producing the precursor compound 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of the formula I from starting products available on a large scale and processes for the further transformation into the thiazole derivatives of formula III, IV and V as outlined above.
It was found that the object of the invention could be reached with the processes as outlined below.
The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term “Ci-6-alkyl” denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms. Typical examples include methyl, ethyl and propyl, butyl, pentyl or hexyl with its isomers, preferably Ci-4-alkyl, more preferably methyl or ethyl.
The term “Ci-6-alkoxy” denotes a Ci-6-alkyl group as defined above, which is attached to an oxygen atom. Typical examples include methoxy, ethoxy and propyloxy, butyloxy, pentyloxy or hexyloxy with its isomers, preferably Ci-4-alkyloxy, more preferably methoxy or ethoxy.
The term halogen stands for a halogen atom, which includes fluorine, chlorine, bromine and iodine, preferably chlorine.
The process for the preparation of 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of the formula I
HO comprises, reacting cyanogen with l,4-dithiane-2,5-diol of the formula II
II in a polar aprotic solvent in the presence of a tertiary organic amine as additive.
Cyanogen is a gas which is commercially available. For large scale applications it can be directly fed to the reaction mixture.
For lab scale synthesis, cyanogen can also be generated in situ by adding an aqueous solution of an alkali metal cyanide to an aqueous solution of a copper (II) salt having a temperature of 60°C to 100°C, preferably at about 80°C.
Suitable copper (II) salt is copper (II) sulfate and a suitable alkali metal cyanide is sodium- or potassium cyanide, preferably sodium cyanide.
The generated cyanogen can be directly delivered to the mixture of l,4-dithiane-2,5- diol of the formula II, tertiary organic amine and polar aprotic solvent having a temperature of 20°C to 80°C, preferably 30°C to 70°C.
Expediently the cyanogen is applied of 1.0 equivalents to 10.0 equivalents, preferably of 3.0 equivalents to 5.0 equivalents related to 1.0 equivalent of l,4-dithiane-2,5-diol.
The aprotic solvent can be selected from Ci-4-alkyl acetates such as ethyl acetate or isopropyl acetate, but preferably is ethyl acetate.
The tertiary organic amine typically is a tri-Ci-4-alkylamine such as diisopropylethyl amine or triethylamine.
The resulting 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of the formula I can be isolated, but in a preferred embodiment is kept in the reaction solution and further transformed, without its isolation in the subsequent process variants a) or b).
The 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of the formula I
HO is a compound which has not been described before and therefore constitutes a preferred embodiment of the present invention.
In a process variant a) the 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of the formula I can be transformed by way of a dehydration into the thiazole-2-carbonitrile of the formula III.
Suitable dehydrating agents are selected from tri-Cm- alkyl silyl halogenides, such as trimethylsilyl chloride, mineral acids such as hydrochloric acid or sulfuric acid, organic acids and its halogenides, such as acetic acid, -toluene sulfonic acid or methanesulfonyl chloride or phosphoric acid derivatives such as phosphorous oxychloride or phosphorous pentoxide. Preferred dehydrating agents are methanesulfonyl chloride or trimethylsilyl chloride, more preferably trimethylsilyl chloride.
The dehydrating agent can be applied in a range of 0.2 equivalents to 5.0 equivalents, preferably 0.5 equivalents to 1.5 equivalents related to 1.0 equivalent of 4-hydroxy-4,5- dihydrothiazole-2-carbonitrile.
The reaction ideally takes place in the polar aprotic solvent of the previous reaction step which preferably is ethyl acetate. It is however possible to work in a suitable alternative solvent, such as in a lower aliphatic alcohol, like ethanol.
A reaction temperature between 20°C and 100°C, preferably between 30°C and 70°C is usually chosen.
The thiazole-2-carbonitrile can be isolated by quenching the reaction mixture with water and recovering the product from the organic phase by methods well known to the skilled in the art. Further purification of the crude product can be achieved by sublimation.
In a preferred embodiment the crude thiazole-2-carbonitrile is, without further purification, further transformed into the thiazole-2-carboximidamide of formula V or of a salt thereof.
V
In a preferred embodiment a salt of the thiazole-2-carboximidamide of formula V is obtained.
The reaction involves in a first step a treatment with a base, which typically is an alkali alcoholate, preferably sodium methylate.
This reaction steps forms an intermediary iminoether, which, without isolation, is reacted further with the addition of ammonia or of an ammonium salt.
Preferably an ammonium salt is added, which can be selected from an ammonium salt of a mineral acid, such as e.g. from hydrochloric acid or from an organic acid such as e.g. from acetic acid or methane sulfonic acid. Preferred ammonium salts therefore are ammonium chloride, ammonium acetate or ammonium mesylate, but more preferably is ammonium chloride.
The reaction can be carried out at a reaction temperature between -10°C and 10°C, preferably at about 0°C in a polar protic solvent, such as in an aliphatic alcohols, preferably in methanol.
The product can be recovered from the reaction mixture by removing the solids by filtration and subsequently by distilling off the polar protic solvent and crystallizing the crude with a polar aprotic solvent such as MeCN and water
In a process variant b) the 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of the formula I is acylated with an acyl halide R ’COX or an acid anhydride R1C-(O)O(O)C-R1 , wherein R1 is Ci-6-alkyl or phenyl, wherein the phenyl ring is optionally substituted with, halogen, Ci-6-alkyl or Ci-6-alkoxy, to form 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile derivatives of the formula IV
wherein R1 is as above.
Suitable acyl halides RxCOX are those with R1 is Ci-4-alkyl, particularly methyl or phenyl and with X is chlorine. Preferred acyl halides are acetyl chloride or benzoyl chloride.
Suitable acid anhydride R1C-(O)O(O)-CR1 are those with R1 is Cw-alkyl, particularly methyl or phenyl. Preferred acid anhydride is acetic anhydride.
The reaction is preferably carried out in the presence of a tertiary organic amine, typically a tri-Ci-4-alkylamine such as tri ethylamine.
The reaction can take place at a reaction temperature between -10°C and 100°C, preferably at about 50°C in the polar aprotic solvent of the previous reaction step.
The 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile derivatives of the formula IV
wherein R1 is Ci-6-alkyl or phenyl and wherein the phenyl ring is optionally substituted with, halogen, Ci-6-alkyl or C i-6-alkoxy are novel compounds and therefore constitute a preferred embodiment of the present invention.
Preferred 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile derivatives of the formula IV are those with R1 is Ci-4-alkyl. Even more preferred is the 2-cyano-4,5-dihydrothiazol-5-yl acetate (R1 = methyl) and the 2-cyano-4,5-dihydrothiazol-5-yl benzoate (R1 = phenyl).
Examples
Overview:
Materials and Methods
HPLC analysis were carried out on a Shimadzu instrument using a Cl 8 reversed-phase analytical column (150 mm x 4.6 mm, particle size 5 pm) using mobile phases A (H2O/MeCN 90:10 (v/v) + 0.1 % CF3COOH) and B (MeCN + 0.1 % CF3COOH) at a flow rate of 1.5 mL/min. Retention times: 2.74 min (2), 7.72 min (3), 10.71 min (4), 4.54 min (5), 1.07 min (6) - applying the following gradient program for mobile phase B in A (% v/v):
GC-FID Analysis was performed on a Shimadzu GC FID 230 with a flame ionization detector, using an RTX-5MS column (30 m x 0.25 mm ID x 0.25 pm) and helium as carrier gas (40 cm sec -1 linear velocity). The injector temperature was set to 280°C. After 1 min at 50°C, the temperature was increased by 25°C/min to 300°C and kept constant at 300°C for 4 min. The detector gases used for flame ionization were hydrogen and synthetic air (5.0 quality). Retention times: 5.94 min (2), 4.53 min (5)
1H and 13C NMR spectra were recorded on a Bruker Avance III 300 MHz instrument at ambient temperature, in CDCh or DMSO-de as solvent, at 300 MHz and 75 MHz, respectively. Chemical shifts (6) are reported in ppm using TMS as internal standard. Coupling constants are given in Hz units. The letters s, d, t, q, and m are used to indicate singlet, doublet, triplet, quadruplet, and multiplet, respectively.
Abbreviations:
AcCl acetyl chloride
BzCl benzoyl chloride
DABCO l,4-diazabicyclo[2.2.2]octane
DBO l,8-Diazabicyclo(5.4.0)undec-7-ene
DIPEA diisopropylethyl amine
EtsN triethylamine
EtOAc ethyl acetate equiv equivalent
HPLC high pressure liquid chromatography iPrOAc isopropyl acetate
MeCN acetonitrile
MeOH methanol
MsCl mesityl chloride
NaOMe sodium methanolate
NMR nuclear magnetic resonance pTSA para-toluenesulfonic acid
TMG 1,1,3,3-tetramethylguanidine
TMSC1 trimethylsilyl chloride tR retention time
rt room temperature
Preparation of 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile (2)
Example 1
NEt
A solution of 9.80 g (200 mmol) NaCN in 50 mL water was added dropwise within 5 minutes to a blue hot (80°C) solution of 19.97 g CuSC>4 (80 mmol) in water (40 mL) and the evolved gas (cyanogen) was directly transferred via cannula (closed system) to a hot (60°C) suspension of l,4-dithiane-2,5-diol (1) (1.52 g, 10 mmol) and triethylamine (139 pL, 1 mmol, 0.1 equiv) in EtOAc (100 ml). After the addition of NaCN was complete (theoretical (CN)2 quantity: 40 mmol, 4 equiv) a colorless product solution was formed. The title compound 2 was obtained in 90% yield (HPLC, assay yield) as a solution in EtOAc and was used as such in the next step. Partial decomposition was observed when concentrating samples under vacuum at 40°C.
Analytical data for 2
HPLC: 94.0 % area (tR = 2.74 min). ’H NMR (300 MHz, DMSO-d6) 8 6.99 (d, J= 7.0 Hz, 1H), 6.14 (dd, J= 13.0, 5.3 Hz, 1H), 3.78 (dd, J= 12.0, 7.4 Hz, 2H), 3.34 (dd, J= 12.1, 5.5 Hz, 1H).
Examples 1.1 - 1.3
In analogy to Example 1, 1 (0.076 g, 0.5 mmol) was converted within 0.25 h into 2, employing DIPEA instead of EtsN as base under the reaction conditions as listed in Table 1.
Table 1
1 Yield determined via GC employing biphenyl as internal standard
Examples 1.4 - 1.7
In analogy to Example 1, 1 (0.076 g, 0.5 mmol) was converted within 1 h in EtOAc at 30°C into 2 employing the additives as listed in Table 2.
Table 2
1 Yield determined via GC employing biphenyl as internal standard
Examples 1.8 - 1.11
In analogy to Example 1, 1 (0.152 g, 1.0 mmol) was converted within 0.5 h in EtOAc into 2 employing DIPEA (1 equiv) as additive under the reaction conditions as listed in Table 3.
Table 3
1 Yield determined via HPLC employing biphenyl as internal standard
Example 1.12 - 1.16
In analogy to Example 1, 1 (0.076 g, 0.5 mmol) was converted within 5 min in EtOAc at 60°C into 2 employing variable amounts of DIPEA, resp. EtsN as additives as listed in Table 4.
Table 4
1 Yield determined via HPLC employing biphenyl as internal standard
Preparation of 2-cvano-4.5-dihvdrothiazol-5-yl acetate (3)
Example 2 N
2 3
To the crude solution of 2 (as obtained according to Example 7) was added at 50°C triethylamine (2.79 mL, 20 mmol, 1.0 equiv) to obtain a colorless suspension. Acetyl chloride (1.71 mL, 24 mmol, 1.2 equiv) was added and the resulting mixture was stirred at 50°C for 1 h. The reaction was quenched with water (100 mL) and the organic layer was separated and washed with aqueous 5% NaHCCL (2x100 mL). The combined aqueous layers were extracted with EtOAc (2x50 mL). The combined organic layers were dried over Na2SO4 and filtered. From the filtrate, the solvent was evaporated under reduced pressure to dryness to afford 3. 14 g (93%) of the crude title compound 3 as a yellow to brownish oil with a purity of 84% (NMR assay), corresponding to an overall yield of Tl% (over 2 steps).
Analytical data for 3
HPLC: 92.3% area (fa = 7.72 min). ’H NMR (500 MHz, DMSO-de) 8 7.02 (dd, J= 7.9, 4.5 Hz, 1H), 3.99 (dd, J= 12.9, 7.9 Hz, 1H), 3.65 (dd, J= 12.9, 4.5 Hz, 1H), 2.08 (s, 3H). 13C NMR (75 MHz, DMSO-de) 8 168.7, 147.7, 111.8, 96.8, 38.4, 20.6.
Examples 2.1 - 2.4
In analogy to Example 2, 2 (0.026 g, 0.2 mmol) was converted within 1 h in EtOAc at 50°C into 3 employing variable amounts of AcCI, resp. EtsN as listed in Table 5.
Table 5
1 HPLC area-%
Preparation of 2-cyano-4,5-dihydrothiazol-5-yl benzoate (4)
Example 3
2 4
To 1/10 of the crude solution of 2 (as obtained according to Example 7) was added at 50°C tri ethylamine (279 pL, 2 mmol, 1.0 equiv). A colorless suspension was formed. Benzoyl chloride (461pL, 2.4 mmol, 1.2 equiv) was added subsequently. After stirring for 1 h at 50°C the reaction was quenched with water (10 mL) and the organic layer was separated and washed with aqueous 5% NaHCCti (2xl0mL). The combined aqueous layers were extracted with EtOAc (2x5 mL). The combined organic layers were dried over Na2SC>4 and filtered. From the filtrate, the solvent was evaporated under reduced pressure to dryness to afford 475 mg (104%) of crude 4 as a brown oil with 58% purity (60% yield of pure compound). After column chromatography (EtOAc/cyclohexane) 110 mg (24%) of the title compound 4 was obtained as a white solid with >95% purity (by NMR assay).
Analytical data for 4
HPLC: 88.6 % area (tR = 10.71 min). ’H NMR (300 MHz, DMSO-d6) 8 7.99 (d, J = 7.2 Hz, 2H), 7.71 (t, J= 7.4 Hz, 1H), 7.55 (t, J= 7.7 Hz, 2H), 7.29 (dd, J= 7.9, 4.7 Hz, 1H), 4.11 (dd,
J= 12.9, 7.9 Hz, 1H), 3.88 (dd, J= 12.9, 4.6 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) 8 164.0, 148.1, 134.0, 129.6, 128.9, 128.6, 111.9, 97.7, 38.5.
Examples 3.1 - 3.4
In analogy to Example 3, 2 (0.026 g, 0.2 mmol) was converted within 1 h in EtOAc at 50°C into 3 employing variable amounts of BzCl and EtsN as listed in Table 6.
Table 6
1 HPLC area-%
Preparation of thiazole-2-carbonitrile (5)
Example 4
2 5
To the crude solution of 2 (obtained according to Example /) was added at 50°C trimethylsilyl chloride (2.54 mL, 20 mmol, 1 equiv) as dehydrating agent. After stirring for 1 h at 50°C, the reaction was quenched with water (100 mL) and the organic layer was separated and washed with aqueous 5% NaHCOs (2x100 mL). The combined aqueous layers were extracted with EtOAc (2x50 mL). The combined organic layers were dried over Na2SO4 and filtered. The solution was concentrated under reduced pressure to approx. 5% of its original volume. The desired product (5) was quantified as 67.5% NMR assay yield using
1,3, 5 -trimethoxy benzene as internal standard. The crude title compound 5 was purified by sublimation (60°C/15 mbar) to afford 835 mg (37% yield) product as colorless crystals.
Analytical data for 5
HPLC: 97.8 % area (tR = 4.54 min). 'H NMR (300 MHz, DMSO-d6) 8 8.34 (d, J= 3.1 Hz, 1H), 8.24 (d, J= 3.1 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) 8 145.4, 135.8, 128.5, 113.4.
Examples 4.1 - 4.6
In analogy to Example 4, 2 (0.026 g, 0.2 mmol) was converted at 100°C into 5 employing instead of trimethylsilyl chloride as dehydrating agent, the acids as listed in Table 7.
Table 7
1 Yield determined via GC employing biphenyl as internal standard
Examples 4.7 - 4.10
In analogy to Example 4, 2 (0.026 g, 0.2 mmol) was converted within 1 h in EtOAc at 100°C into 5 employing the dehydrating agents as listed in Table 8.
Table 8
1 Yield determined via GC employing biphenyl as internal standard
Examples 4.11 - 4.14
In analogy to Example 4, 2 (0.026 g, 0.2 mmol) was converted within Ih in EtOAc at 100°C into 5 employing instead of trimethylsilyl chloride other dehydrating agents as listed in Table 9.
Table 9
1 Yield determined via HPLC employing biphenyl as internal standard
Examples 4.15 - 4.26
In analogy to Example 4, 2 (0.026 g, 0.2 mmol) was converted within Ih in EtOAc into 5 employing different amounts of trimethyl silyl chloride as dehydrating agent at the reaction temperatures as listed in Table 10.
Table 10
1 Yield determined via HPLC or GC employing biphenyl as internal standard
Examples 4.27 - 4.30
In analogy to Example 4, 2 (0.026 g, 0.2 mmol) was converted within 1 h in EtOAc and at various temperatures into 5 employing instead of trimethylsilyl chloride other dehydrating agents as listed in Table 11.
Table 11
1 Yield determined via HPLC employing biphenyl as internal standard
Preparation of thiazole-2-carboximidamide hydrochloride (6)
Example 5
Crude thiazole-2-carbonitrile 5 (6.4 mmol, 1.1 g crude 5 with 62% purity, 1 equiv; obtained according to Example 4) was dissolved in 6 mL of MeOH andNaOMe (25 % w/w in MeOH soln.; 0.5 mmol, 114 pL, 0.078 equiv) was added at 0°C. The brown suspension was stirred for ~3 h at 0°C and the temperature was increased to room temperature. Ammonium chloride (11 mmol, 588 mg, 1.72 equiv) was added and the resulting mixture was stirred for ~18 h at room temperature. Solids were filtered off over celite and washed with MeOH. From the filtrate, MeOH was distilled off and replaced by MeCN. Water (500 pL) was added to the suspension (~10 mL) and the mixture heated to 85°C and stirred at this temperature for 1 h.
The dark brown solution was cooled to 0°C within 3 h and stirred at this temperature for at least 1 h. The crystals were isolated by filtration, washed with MeCN and dried for 16 h at 50°C under reduced pressure to afford compound 6 (898 mg, 88%, 95% NMR assay, 83% pure yield over two steps) as a brown crystalline solid.
Analytical data for 6
HPLC: 99.3 % area (tR = 1.07 min). ’H NMR (300 MHz, DMSO-d6) 8 9.62 (bs, 3H), 8.38 (d, J= 3.0 Hz, 1H), 8.24 (d, J= 3.0 Hz, 1H), 7.86 (bs, 1H). 13C NMR (75 MHz, DMSO-d6) 8 157.0, 154.0, 144.8, 128.8.
Example 6
Telescoped process for the preparation of thiazole-2-carboximidamide hydrochloride (6)
(
N
50°C 1 h 0 °C - rt, 18h
From crude EtOAc solution of thiazole-2-carbonitrile 5 (20.0 mmol 5 with 94.3 area-% HPLC purity, 1 equiv; obtained according to Example 4 without evaporation to dryness), the solvent was distilled off and replaced by methanol. The solution (10 mL) was cooled to 0°C and NaOMe (25 %w/w in MeOH soln.) was added (1.0 mmol, 229 pL, 0.05 equiv). The resulting brown suspension was stirred for 3 h at 0°C and the temperature was increased to room temperature. Ammonium chloride was added (22 mmol, 1.18 mg, 1.1 equiv) and the resulting mixture was stirred for 18 h at room temperature. Solids were filtered off, washed with MeOH and disposed off. From the filtrate, MeOH was replaced by MeCN (four times, 5 mL of MeCN added, evaporation to ~10 mL volume). Solid formation was observed when MeCN was added to the mixture. 1 mL of water was added to the suspension. The slight brown solid was isolated by filtration and washed with MeCN and petrol ether to afford after drying 1.40 g of the title compound 6. The mother liquor was reduced in volume until more of the title compound 6 precipitated. The solid was isolated by filtration and washed with MeCN and petrol ether and dried to afford additional 400 mg of compound 6 as a brown solid. In total, 1.80 g (55% over 4 steps, 99% NMR assay, 99.8 HPLC area-%) of compound 6 were obtained as a brown crystalline solid.
Claims
1. Process for the preparation of 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of the formula I
HO comprising, reacting cyanogen with l,4-dithiane-2,5-diol of the formula II
in a polar aprotic solvent in the presence of a tertiary organic amine.
2. Process of claim 1, wherein the cyanogen is delivered to the mixture of 1,4- dithiane-2,5-diol of the formula II, tertiary organic amine and polar aprotic solvent having a temperature of 20°C and 80°C.
3. Process of any one of claims 1 or 2, wherein the polar aprotic solvent is selected from a Ci4-alkyl acetate and the tertiary organic amine is selected from atri-Ci-4-alkylamine.
4. Process of anyone of claims 1 to 3, wherein the 4-hydroxy-4,5-dihydrothiazole-2- carbonitrile of the formula I is further transformed, without isolation, in accordance with process variant a) by dehydration to form the thiazole-2-carbonitrile of the formula III.
b) by acylation with an acyl halide R ’COX or an acid anhydride R1C(O)O(O)-CR1, wherein R1 is Ci-6-alkyl or phenyl and wherein the phenyl ring is optionally substituted with, halogen, Ci-6-alkyl or Ci-6-alkoxy, to form 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile derivatives of the formula IV
wherein R1 is as above.
5. Process of claim 4, wherein the dehydrating agent in step a) is selected from tri-Cm- alkyl silyl halogenides, mineral acids, organic acids and its halogenides or phosphoric acid derivatives.
6. Process of claim 4 or 5, wherein the dehydration in step a) takes place at a reaction temperature between 20°C and 100°C in a polar aprotic solvent.
7. Process of any one of claims 4 to 6, wherein the thiazole-2-carbonitrile of the formula III is not isolated, but further transformed into the thiazole-2-carboximidamide salt of formula V
V
8. Process of claim 7, wherein the transformation in a first step takes place with a base and in a subsequent step with ammonia or an ammonium salt.
9. Process of claim 8, wherein the transformation in a first step takes place with an alkali alcoholate and in a subsequent step with an ammonium salt of a mineral acid or of an organic acid.
10. Process of anyone of claims 7 to 9, wherein the reaction takes place at a reaction temperature between -10°C and 10°C, in a polar protic solvent.
11. Process of claim 4, wherein the acylation reaction in step b) is performed with an acyl halide R COX or an acid anhydride R1C-(O)O(O)-CR1, wherein R1 is Ci4-alkyl or phenyl and X is chlorine in the presence of a tertiary organic amine.
12. Process of claim 4 or 11, wherein the reaction in step b) takes place at a reaction temperature between -10°C and 100°C in a polar aprotic solvent.
13. 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile derivatives of the formula IV
wherein R1 is Ci-6-alkyl or phenyl and wherein the phenyl ring is optionally substituted with, halogen, Ci-6-alkyl or Ci-6-alkoxy.
14. 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile derivatives of the formula IV wherein R1 is Ci-4-alkyl, preferably methyl, or phenyl.
15. 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of the formula I
HO
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP23168155 | 2023-04-17 | ||
| PCT/EP2024/060118 WO2024218026A1 (en) | 2023-04-17 | 2024-04-15 | Process for the preparation of 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile and derivatives thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP4698521A1 true EP4698521A1 (en) | 2026-02-25 |
Family
ID=86051965
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP24719164.6A Pending EP4698521A1 (en) | 2023-04-17 | 2024-04-15 | Process for the preparation of 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile and derivatives thereof |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP4698521A1 (en) |
| CN (1) | CN120858090A (en) |
| TW (1) | TW202506652A (en) |
| WO (1) | WO2024218026A1 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003273055A1 (en) * | 2002-10-21 | 2004-05-04 | Ihara Chemical Industry Co., Ltd. | Process for producing aromatic nitrile compound |
| WO2013060744A2 (en) * | 2011-10-25 | 2013-05-02 | Universite De Droit Et De La Sante De Lille 2 | Compounds having an ethr inhibiting activity - use of said compounds as drugs - pharmaceutical composition and product containing said compounds |
| AU2015226206B2 (en) | 2014-03-07 | 2017-03-16 | F. Hoffmann-La Roche Ag | Novel 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of Hepatitis B virus infection |
-
2024
- 2024-04-15 WO PCT/EP2024/060118 patent/WO2024218026A1/en not_active Ceased
- 2024-04-15 CN CN202480021607.XA patent/CN120858090A/en active Pending
- 2024-04-15 EP EP24719164.6A patent/EP4698521A1/en active Pending
- 2024-04-16 TW TW113114123A patent/TW202506652A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| TW202506652A (en) | 2025-02-16 |
| WO2024218026A1 (en) | 2024-10-24 |
| CN120858090A (en) | 2025-10-28 |
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