Method for preparing 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile and its derivatives

Abstract

The present invention relates to a novel method for preparing 4-hydroxy-4,5-dihydrothiazole-2-carbonitride of formula (I). 4-hydroxy-4,5-dihydrothiazole-2-carbonitride is a versatile intermediate that can be used to prepare versatile precursor compounds of pharmaceutically active compounds such as drugs and other chemical compounds used in pharmaceuticals. These include 4-hydroxy-4,5-dihydrothiazole-2-carbonitride of formula (I), thiazole-2-carbonitride of formula (III), thiazole-2-carboxyimidoamide of formula (V) or salts thereof, and formula (IV) (wherein R 1 C 1~6 - Alkyl or phenyl, the phenyl ring is a halogen, C 1~6 -Alkyl or C 1~6 Further conversions of (which may be substituted with alkoxy) to 4-hydroxy-4,5-dihydrothiazole-2-carbonitride derivatives are described. TIFF2026513556000042.tif91128

Description

[Technical Field]

[0001] This invention relates to formula I A novel method for preparing 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of TIFF2026513556000002.tif31128, wherein cyanide is dissolved in a polar aprotic solvent in the presence of a tertiary organic amine, and formula II The present invention relates to a method, which involves reacting with 1,4-dithian-2,5-diol from TIFF2026513556000003.tif29128.

[0002] The present invention further uses 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of formula I as a general-purpose precursor compound. Formula III Thiazole-2-carbonilicate of TIFF2026513556000004.tif28128 Formula IV TIFF2026513556000005.tif29128's 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile derivative, and Formula V Thiazole-2-carboxyimamide or its salt from TIFF2026513556000006.tif33128 Regarding the conversion to [a specific format].

[0003] Furthermore, the present invention relates to a novel thiazole precursor. Equation I TIFF2026513556000007.tif31128's 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile and Formula IV TIFF2026513556000008.tif29128 (in the formula, R 1 is C 1~6 - Alkyl or phenyl, the phenyl ring is a halogen, C 1~6 -Alkyl or C 1~6 - May be substituted with alkoxy) 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile derivatives including

Background Art

[0004] The thiazole core structure forms a scaffold for many lead compounds in drug discovery (A. Ayati et al, European Journal of Medicinal Chemistry, 97 (2015), 699 - 718 (Non-Patent Document 1)). For example, International Publication No. 2015 / 132276 (Patent Document 1) discloses 6-condensed heteroaryldihydropyrimidines having a thiazole moiety in the core structure and having the potential to be used for the treatment and prevention of hepatitis B infection.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Non-Patent Documents

[0006]

Non-Patent Document 1

Summary of the Invention

[0007] An object of the present invention was to find a scalable process for producing the precursor compound 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of formula I from a large-scale available starting product, and a process for further conversion to thiazole derivatives of formula III, IV and V as outlined above.

[0008] It has been found that the object of the present invention can be achieved by the method outlined below.

Mode for Carrying Out the Invention

[0009] The following definitions are set forth to illustrate and define the meaning and scope of various terms used to describe the present invention in this specification.

[0010] The term "C 1~6 -alkyl" refers to a monovalent straight-chain or branched-chain saturated hydrocarbon group having 1 to 6 carbon atoms. Typical examples include methyl, ethyl, and propyl, butyl, pentyl or hexyl and their isomers, preferably C 1~4 -alkyl, more preferably methyl or ethyl.

[0011] The term "C 1~6 -alkoxy" refers to a C 1~6 -alkyl group as defined above bonded to an oxygen atom. Typical examples include methoxy, ethoxy, and propyloxy, butyloxy, pentyloxy or hexyloxy and their isomers, preferably C 1~4 -alkyloxy, more preferably methoxy or ethoxy.

[0012] The term halogen represents a halogen atom and includes fluorine, chlorine, bromine and iodine, preferably chlorine.

[0013] Formula I The method for preparing 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of TIFF2026513556000009.tif31128 involves reacting cyanide with 1,4-dithiane-2,5-diol of TIFF2026513556000010.tif29128 in a polar aprotic solvent in the presence of a tertiary organic amine as an additive. TIFF2026513556000010.tif29128.

[0014] Cyanide is a commercially available gas. In large-scale applications, it can be fed directly into the reaction mixture.

[0015] In laboratory-scale synthesis, cyanide can also be produced in situ by adding an aqueous solution of alkali metal cyanide to an aqueous solution of copper(II) salt at a temperature of 60°C to 100°C, preferably about 80°C.

[0016] A suitable copper(II) salt is copper(II) sulfate, and a suitable alkali metal cyanide is sodium cyanide or potassium cyanide, preferably sodium cyanide.

[0017] The generated cyanide can be directly added to a mixture of 1,4-dithian-2,5-diol of formula II, a tertiary organic amine, and a polar aprotic solvent at a temperature of 20°C to 80°C, preferably 30°C to 70°C.

[0018] Appropriately, cyanide is applied in an amount of 1.0 to 10.0 equivalents, preferably 3.0 to 5.0 equivalents, per 1.0 equivalent of 1,4-dithian-2,5-diol.

[0019] Aprotic solvents include C(ethyl acetate) or isopropyl acetate. 1~4 -It can be selected from alkyl acetates, but ethyl acetate is preferred.

[0020] Tertiary organic amines are typically tri-C amines such as diisopropylethylamine or triethylamine. 1~4 -It is an alkylamine.

[0021] The resulting 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of formula I can be isolated, but in preferred embodiments, it is retained in the reaction solution and further converted in subsequent method variations (a) or (b) without isolation.

[0022] Equation I 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of TIFF2026513556000011.tif31128 is a previously unreported compound and therefore constitutes a preferred embodiment of the present invention.

[0023] In method variation (a), 4-hydroxy-4,5-dihydrothiazole-2-carbonitride of formula I is converted to formula III by dehydration. It can be converted to thiazole-2-carbonitride, TIFF2026513556000012.tif28128.

[0024] The appropriate dehydrating agent is Tri-C 1~4 -Selected from alkylsilyl halides, such as trimethylsilyl chloride, mineral acids, such as hydrochloric acid or sulfuric acid, organic acids and their halides, such as acetic acid, p-toluenesulfonic acid or methanesulfonyl chloride, or phosphoric acid derivatives, such as phosphorus oxychloride or phosphorus pentoxide. Preferred dehydrating agents are methanesulfonyl chloride or trimethylsilyl chloride, more preferably trimethylsilyl chloride.

[0025] The dehydrating agent can be applied in an amount of 0.2 to 5.0 equivalents, preferably 0.5 to 1.5 equivalents, per 1.0 equivalent of 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile.

[0026] This reaction ideally takes place in a polar aprotic solvent, preferably ethyl acetate, as in the previous reaction step. However, the reaction may also work well in a suitable alternative solvent, such as a lower aliphatic alcohol like ethanol.

[0027] A reaction temperature of 20°C to 100°C, preferably 30°C to 70°C, is typically selected.

[0028] Thiazole-2-carbonitride can be isolated by quenching the reaction mixture with water and recovering the product from the organic phase by a method well known to those skilled in the art. Further purification of the crude product can be achieved by sublimation.

[0029] In a preferred embodiment, crude thiazole-2-carbonitrile is further converted without further purification to thiazole-2-carboxyimidoamide of formula V or a salt thereof. TIFF2026513556000013.tif33128

[0030] In a preferred embodiment, a salt of thiazole-2-carboxyimidoamide of formula V is obtained.

[0031] This reaction involves a first step of treatment with a base, typically an alkaline alcoholate, preferably a sodium methylate.

[0032] This reaction step forms an intermediate iminoether, which can be further reacted by adding ammonia or an ammonium salt without isolation.

[0033] Preferably, an ammonium salt is added, which can be selected from an ammonium salt of a mineral acid, such as hydrochloric acid, or from an organic acid, such as acetic acid or methanesulfonic acid. Therefore, preferred ammonium salts are ammonium chloride, ammonium acetate, or ammonium mesylate, but ammonium chloride is more preferred.

[0034] This reaction can be carried out in a polar protic solvent such as an aliphatic alcohol, preferably methanol, at a reaction temperature of -10°C to 10°C, preferably about 0°C.

[0035] The product can be recovered from the reaction mixture by removing the solid by filtration, then distilling off the polar protic solvent, and crystallizing the crude product in a polar aprotic solvent such as MeCN or water.

[0036] In method variant (b), 4-hydroxy-4,5-dihydrothiazole-2-carbonitride of formula I is replaced with acyl halogenated R 1 COX or acid anhydride R 1 C-(O)O(O)CR 1(In the formula, R 1 is C 1~6 - Alkyl or phenyl, the phenyl ring is a halogen, C 1~6 -Alkyl or C 1~6 -Acylated using (which may be substituted with alkoxy), formula IV TIFF2026513556000014.tif29128 (in the formula, R 1 (As stated above) It forms a 4-hydroxy-4,5-dihydrothiazole-2-carbonitride derivative.

[0037] Appropriate halogenated acyl R 1 COX is R 1 C 1~4 -Alkyl, particularly methyl or phenyl, where X is chlorine. Preferred acyl halides are acetyl chloride or benzoyl chloride.

[0038] Appropriate acid anhydride R 1 C-(O)O(O)-CR 1 R 1 C 1~4 -It is an alkyl group, particularly methyl or phenyl. The preferred acid anhydride is acetic anhydride.

[0039] This reaction preferably involves a tertiary organic amine, typically tri-C such as triethylamine. 1~4 -This is carried out in the presence of alkylamines.

[0040] This reaction can be carried out in the polar aprotic solvent from the previous reaction step at a reaction temperature of -10°C to 100°C, preferably about 50°C.

[0041] Formula IV TIFF2026513556000015.tif29128 (in the formula, R 1 is C 1~6 - Alkyl or phenyl, the phenyl ring is a halogen, C 1~6 -Alkyl or C 1~6 - May be substituted with alkoxy) The 4-hydroxy-4,5-dihydrothiazole-2-carbonitride derivative is a novel compound and therefore constitutes a preferred embodiment of the present invention.

[0042] A preferred 4-hydroxy-4,5-dihydrothiazole-2-carbonitride derivative of formula IV is R 1 C 1~4 -It is alkyl. More preferably is 2-cyano-4,5-dihydrothiazole-5-yl acetate (R 1 =methyl) and 2-cyano-4,5-dihydrothiazole-5-ylbenzoate (R 1 =phenyl) [Examples]

[0043] overview: TIFF2026513556000016.tif77164

[0044] Materials and methods HPLC analysis was performed using a Shimadzu instrument with a C18 reversed-phase analysis column (150 mm × 4.6 mm, particle size 5 μm), with 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 and retention times of 2.74 min (2), 7.72 min (3), 10.71 min (4), 4.54 min (5), and 1.07 min (6). The following gradient program was applied to mobile phase B (%v / v) in A. TIFF2026513556000017.tif47128

[0045] GC-FID analysis was performed using a Shimadzu GC FID 230 equipped with a hydrogen flame ionization detector, employing an RTX-5MS column (30 m × 0.25 mm × ID × 0.25 μm) and helium as the carrier gas (40 cmsec-1 linear velocity). The injector temperature was set to 280°C. After 1 minute at 50°C, the temperature was increased to 300°C at a rate of 25°C / min and maintained at 300°C for 4 minutes. The detector gases used for flame ionization were hydrogen and synthetic air (quality 5.0). Retention times: 5.94 min (2), 4.53 min (5)

[0046] 1 1H NMR spectrum and 13 ¹³C NMR spectra were recorded at 300 MHz and 75 MHz, respectively, in CDCl3 or DMSO-d6 as solvent, at ambient temperature using a Bruker Avance III 300 MHz instrument. Chemical shifts (δ) were recorded in ppm using TMS as an internal standard. Coupling constants are given in Hz. The letters s, d, t, q, and m are used to indicate singlet, doublet, triplet, quadrant, and multiplet, respectively.

[0047] Abbreviation: AcCl (Acty chloride) BzCl Benzoyl Chloride DABCO 1,4-Diazabicyclo[2.2.2]octane DBO 1,8-Diazabicyclo(5.4.0)Undeca-7-En DIPEA Diisopropylethylamine Et3N triethylamine HCl ethyl acetate equiv equivalent HPLC (High-Pressure Liquid Chromatography) iPrOAc Isopropyl Acetate MeCN acetonitrile MeOH methanol MsCl Mesityl Chloride NaOMe (Sodium Methanelate) NMR nuclear magnetic resonance pTSA (para-toluenesulfonic acid) TMG 1,1,3,3-tetramethylguanidine TMSCl (Trimethylsilyl Chloride) t R retention time rt room temperature

[0048] Preparation of 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile (2) Example 1 A solution of 9.80 g (200 mmol) of NaCN dissolved in 50 mL of water was added dropwise within 5 minutes to a blue hot (80°C) solution of 19.97 g (80 mmol) of CuSO4 dissolved in 40 mL of water. The resulting gas (cyanide) was transferred directly to a hot (60°C) suspension of 1,4-dithian-2,5-diol (1) (1.52 g, 10 mmol) and triethylamine (139 μL, 1 mmol, 0.1 equivalent) suspended in 100 mL of siRNA via a cannula (closed system). After the addition of NaCN was complete (theoretical amount (CN)2: 40 mmol, 4 equivalents), a colorless product solution was formed. Title compound 2 was obtained as an siRNA solution in 90% yield (HPLC, assay yield) and used directly in the next step. When the sample was concentrated under vacuum at 40°C, partial decomposition was observed.

[0049] Analysis data 2 HPLC: 94.0% area (t R =2.74 minutes). 1 H NMR(300MHz,DMSO-d6)δ 6.99(d,J=7.0Hz,1H),6.14(dd,J=13.0,5.3Hz,1H),3.78(dd,J=12.0,7.4Hz,2H),3.34(dd,J=12.1,5.5Hz,1H).

[0050] Examples 1.1-1.3 Similar to Example 1, 1 (0.076 g, 0.5 mmol) was converted to 2 within 0.25 hours under the reaction conditions listed in Table 1, using DIPEA instead of Et3N as the base.

[0051] [Table 1] 1 Yield measured by GC using biphenyl as an internal standard.

[0052] Examples 1.4-1.7 Similar to Example 1, 1 (0.076 g, 0.5 mmol) was converted to 2 within 1 hour in butyl at 30°C using the additives listed in Table 2.

[0053] [Table 2] 1 Yield measured by GC using biphenyl as an internal standard.

[0054] Examples 1.8-1.11 Similar to Example 1, 1 (0.152 g, 1.0 mmol) was converted to 2 in butyl under the reaction conditions listed in Table 3, using DIPEA (1 equivalent) as an additive, within 0.5 hours.

[0055] [Table 3] 1 Yield measured by HPLC using biphenyl as an internal standard.

[0056] Examples 1.12-1.16 Similar to Example 1, 1 (0.076 g, 0.5 mmol) was converted to 2 within 5 minutes in ethyl acetate at 60°C using different amounts of DIPEA or Et3N as additives listed in Table 4.

[0057] [Table 4] 1 Yield measured by HPLC using biphenyl as an internal standard.

[0058] Preparation of 2-cyano-4,5-dihydrothiazole-5-yl acetate (3) Example 2 To a crude solution of compound 2 (obtained according to Example 1), triethylamine (2.79 mL, 20 mmol, 1.0 equivalent) was added at 50°C to obtain a colorless suspension. Acetyl chloride (1.71 mL, 24 mmol, 1.2 equivalents) was added, and the resulting mixture was stirred at 50°C for 1 hour. The reaction product was quenched with water (100 mL), the organic layer was separated, and washed with 5% NaHCO3 aqueous solution (2 × 100 mL). The combined aqueous layer was extracted with RINKAN (2 × 50 mL). The combined organic layer was dried over Na2SO4 and filtered. From the filtrate, the solvent was evaporated to dryness under reduced pressure to obtain 3.14 g (93%) of crude title compound 3 as a yellow to brownish oil with a purity of 84% (NMR assay), which corresponds to a total yield of 77% (2 steps).

[0059] Analysis data 3 HPLC: 92.3% area (t R =7.72 minutes). 1 H NMR(500MHz,DMSO-d6)δ 7.02(dd,J=7.9,4.5Hz,1H),3.99(dd,J=12.9,7.9Hz,1H),3.65(dd,J=12.9,4.5Hz,1H),2.08(s,3H). 13 C NMR(75MHz,DMSO-d6)δ 168.7,147.7,111.8,96.8,38.4,20.6.

[0060] Examples 2.1-2.4 Similar to Example 2, 2 (0.026 g, 0.2 mmol) was converted to 3 within 1 hour in ethyl acetate at 50°C using different amounts of AcCl or Et3N as listed in Table 5.

[0061] [Table 5] 1 HPLC area-%

[0062] Preparation of 2-cyano-4,5-dihydrothiazole-5-ylbenzoate (4) Example 3 To the crude solution of TIFF2026513556000025.tif261281 / 10-2 (obtained according to Example 1), triethylamine (279 μL, 2 mmol, 1.0 equivalent) was added at 50°C. A colorless suspension was formed. Then, benzoyl chloride (461 μL, 2.4 mmol, 1.2 equivalents) was added. After stirring at 50°C for 1 hour, the reaction mixture was quenched with water (10 mL), the organic layer was separated and washed with 5% NaHCO3 aqueous solution (2 × 10 mL). The combined aqueous layer was extracted with RINKAN (2 × 5 mL). The combined organic layer was dried over Na2SO4 and filtered. From the filtrate, the solvent was evaporated to dryness under reduced pressure to obtain 475 mg (104%) of crude 4 as a brown oily substance with a purity of 58% (pure compound with a yield of 60%). After column chromatography (SiO2 / cyclohexane), 110 mg of the title compound 4 (24%) was obtained as a white solid with a purity of over 95% (by NMR assay).

[0063] Analysis data 4 HPLC: 88.6% area (t R =10.71 minutes). 1 H NMR(300MHz,DMSO-d6)δ 7.99(d,J=7.2Hz,2H),7.71(t,J=7.4Hz,1H),7.55(t,J=7.7Hz,2H),7.29(dd, J=7.9,4.7Hz,1H),4.11(dd,J=12.9,7.9Hz,1H),3.88(dd,J=12.9,4.6Hz,1H). 13 C NMR(75MHz,DMSO-d6)δ 164.0,148.1,134.0,129.6,128.9,128.6,111.9,97.7,38.5.

[0064] Examples 3.1-3.4 Similar to Example 3, 2 (0.026 g, 0.2 mmol) was converted to 3 within 1 hour in acetone at 50°C using different amounts of BzCl and Et3N listed in Table 6.

[0065] [Table 6] 1 HPLC area-%

[0066] Preparation of thiazole-2-carbonitride (5) Example 4 To the crude solution of compound 2 (obtained according to Example 1), trimethylsilyl chloride (2.54 mL, 20 mmol, 1 equivalent) was added as a dehydrating agent at 50°C. After stirring at 50°C for 1 hour, the reaction was quenched with water (100 mL), the organic layer was separated, and washed with 5% NaHCO3 aqueous solution (2 × 100 mL). The combined aqueous layer was extracted with Depositphotos (2 × 50 mL). The combined organic layer was dried over Na2SO4 and filtered. The solution was concentrated under reduced pressure to approximately 5% of its original volume. Using 1,3,5-trimethoxybenzene as an internal standard, the NMR assay yield of the desired product (5) was quantified at 67.5%. The crude title compound 5 was purified by sublimation (60°C / 15 mbar) to obtain 835 mg (yield 37%) of the product as colorless crystals.

[0067] 5 Analysis Data HPLC: 97.8% area (t R =4.54 minutes). 1 H NMR(300MHz,DMSO-d6)δ 8.34(d,J=3.1Hz,1H),8.24(d,J=3.1Hz,1H). 13 C NMR(75MHz,DMSO-d6)δ 145.4,135.8,128.5,113.4.

[0068] Examples 4.1-4.6 Similar to Example 4, 2 (0.026 g, 0.2 mmol) was converted to 5 at 100°C using the acids listed in Table 7 instead of trimethylsilyl chloride as the dehydrating agent.

[0069] [Table 7] 1Yield measured by GC using biphenyl as an internal standard.

[0070] Examples 4.7-4.10 Similar to Example 4, 2 (0.026 g, 0.2 mmol) was converted to 5 within 1 hour in siRNA at 100°C using the dehydrating agents listed in Table 8.

[0071] [Table 8] 1 Yield measured by GC using biphenyl as an internal standard.

[0072] Examples 4.11-4.14 Similar to Example 4, 2 (0.026 g, 0.2 mmol) was converted to 5 within 1 hour in siRNA at 100°C using other dehydrating agents listed in Table 9 instead of trimethylsilyl chloride.

[0073] [Table 9] 1 Yield measured by HPLC using biphenyl as an internal standard.

[0074] Examples 4.15-4.26 Similar to Example 4, 2 (0.026 g, 0.2 mmol) was converted to 5 in siRNA within 1 hour using different amounts of trimethylsilyl chloride as a dehydrating agent at the reaction temperatures listed in Table 10.

[0075] [Table 10] 1 Yield determined by HPLC or GC using biphenyl as an internal standard.

[0076] Examples 4.27-4.30 Similar to Example 4, 2 (0.026 g, 0.2 mmol) was converted to 5 within 1 hour at various temperatures in siRNA, using other dehydrating agents listed in Table 11 instead of trimethylsilyl chloride.

[0077] [Table 11] 1 Yield measured by HPLC using biphenyl as an internal standard.

[0078] Preparation of thiazole-2-carboximidoamide hydrochloride (6) Example 5 Crude thiazole-2-carbonitrile 5 (6.4 mmol, 1.1 g crude 5 (62% purity), 1 equivalent, obtained in Example 4) was dissolved in 6 mL of MeOH, and NaOMe (25% w / w in MeOH solvent, 0.5 mmol, 114 μL, 0.078 equivalents) was added at 0°C. The brown suspension was stirred at 0°C for about 3 hours, and the temperature was raised to room temperature. Ammonium chloride (11 mmol, 588 mg, 1.72 equivalents) was added, and the resulting mixture was stirred at room temperature for about 18 hours. The solid was filtered off with Celite and washed with MeOH. MeOH was removed from the filtrate and replaced with MeCN. Water (500 μL) was added to the suspension (about 10 mL), and the mixture was heated to 85°C and stirred at this temperature for 1 hour. The dark brown solution was cooled to 0°C within 3 hours and stirred at this temperature for at least 1 hour. The crystals were isolated by filtration, washed with MeCN, and dried under reduced pressure at 50°C for 16 hours to obtain compound 6 (898 mg, 88%, 95% NMR assay, 2-step net yield 83%) as a brown crystalline solid.

[0079] 6 Analysis Data HPLC: 99.3% area (t R =1.07 minutes). 1 H NMR(300MHz,DMSO-d6)δ 9.62(bs,3H),8.38(d,J=3.0Hz,1H),8.24(d,J=3.0Hz,1H),7.86(bs,1H). 13C NMR(75MHz,DMSO-d6)δ 157.0,154.0,144.8,128.8.

[0080] Example 6 Telescope process for preparing thiazole-2-carboxyimidoamide hydrochloride (6) TIFF2026513556000034.tif21169 The solvent was removed from a crude siRNA solution of thiazole-2-carbonitrile 5 (20.0 mmol 5, 94.3 area % HPLC purity, 1 equivalent, obtained according to Example 4 without evaporation to dryness) and replaced with methanol. The solution (10 mL) was cooled to 0°C and NaOMe (25% w / w in MeOH solvent) was added (1.0 mmol, 229 μL, 0.05 equivalents). The resulting brown suspension was stirred at 0°C for 3 hours and then the temperature was raised to room temperature. Ammonium chloride was added (22 mmol, 1.18 mg, 1.1 equivalents), and the resulting mixture was stirred at room temperature for 18 hours. The solid was filtered off, washed with MeOH, and discarded. From the filtrate, MeOH was replaced with MeCN (5 mL of MeCN was added four times, and evaporated to a volume of approximately 10 mL). When MeCN was added to the mixture, solid formation was observed. 1 mL of water was added to the suspension. A slightly brownish solid was isolated by filtration, washed with MeCN and petroleum ether, and dried to obtain 1.40 g of the title compound 6. The volume of the mother liquor was reduced until more title compound 6 precipitated. The solid was isolated by filtration, washed with MeCN and petroleum ether, and dried to obtain a further 400 mg of compound 6 as a brown solid. In total, 1.80 g (55% in 4 steps, 99% NMR assay, 99.8% HPLC area) of compound 6 was obtained as a brown crystalline solid.

Claims

1. Equation I A method for preparing 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile, wherein cyanide is dissolved in a polar aprotic solvent in the presence of a tertiary organic amine, and the formula II The method comprising reacting with 1,4-dithian-2,5-diol.

2. The method according to claim 1, wherein the cyanide is added to a mixture having temperatures of 20°C and 80°C, comprising 1,4-dithian-2,5-diol of formula II, a tertiary organic amine, and a polar aprotic solvent.

3. The aforementioned polar aprotic solvent is C １～４ - Selected from alkyl acetates, the tertiary organic amine is Tri-C １～４ - The method according to any one of claims 1 or 2, selected from alkylamines.

4. The 4-hydroxy-4,5-dihydrothiazole-2-carbonitride of formula I is not isolated, (a) Dehydration, Formula III Method variations that form thiazole-2-carbonitride, or (b) Acyl halide R １ COX or acid anhydride R １ C(O)O(O) - CR １ (wherein R １ is C １～６ -alkyl or phenyl, and the phenyl ring may be substituted with halogen, C １～６ -alkyl or C １～６ -alkoxy), acylation using the same gives formula IV (In the formula, R １ (As stated above) A modified method for forming a 4-hydroxy-4,5-dihydrothiazole-2-carbonitride derivative, The method according to any one of claims 1 to 3, further converted according to the following:

5. The dehydrating agent in step (a) is Tri-C １～４ - The method according to claim 4, selected from alkylsilyl halides, mineral acids, organic acids and their halides, or phosphoric acid derivatives.

6. The method according to claim 4 or 5, wherein the dehydration in step (a) is carried out in a polar aprotic solvent at a reaction temperature of 20°C to 100°C.

7. The thiazole-2-carbonnitrile of formula III was not isolated, and formula V The method according to any one of claims 4 to 6, further converted to a thiazole-2-carboxyimidoamide salt.

8. The method according to claim 7, wherein the conversion is carried out using a base in a first step and using ammonia or an ammonium salt in a subsequent step.

9. The method according to claim 8, wherein the conversion is carried out using an alkaline alcohol in a first step, and in a subsequent step using an ammonium salt of a mineral acid or organic acid.

10. The method according to any one of claims 7 to 9, wherein the reaction is carried out in a polar protic solvent at a reaction temperature of -10°C to 10°C.

11. The acylation reaction in step (b) is performed by acyl halogen R １ COX or acid anhydride R １ C-(O)O(O)-CR １ (In the formula, R １ is C １～４ The method according to claim 4, wherein the method is carried out using an alkyl or phenyl (where X is chlorine in the presence of a tertiary organic amine).

12. The method according to claim 4 or 11, wherein the reaction in step (b) is carried out in a polar aprotic solvent at a reaction temperature of -10°C to 100°C.

13. Formula IV (In the formula, R １ C １～６ - Alkyl or phenyl, the phenyl ring is a halogen, C １～６ - Alkyl or C １～６ (May be substituted with alkoxy) A 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile derivative.

14. R １ C １～４ - A 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile derivative of formula IV, preferably alkyl, methyl, or phenyl.

15. Equation I 4-hydroxy-4,5-dihydrothiazole-2-carbonitride.

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