A caspofungin intermediate and a synthesis method thereof

Abstract

The present invention belongs to the field of pharmaceutical technology, and specifically relates to a caspofungin intermediate and a synthesis method thereof. The intermediate synthesis method comprises the following steps: mixing a compound as shown in formula II with thionyl chloride dissolved in solvent A to obtain a compound as shown in formula III. The present invention uses thionyl chloride to replace highly toxic, foul-smelling, irritating thiol or thiophenol compounds, avoids the use of highly corrosive acids, and the formed cyclic sulfite is conducive to maintaining the configuration of the reactants; at the same time, by utilizing its properties of easy departure and not changing the chiral configuration of the reactants, the ethylenediamine group is directly introduced without purification, shortening the reaction steps, reducing the number of preparation and purification times, and improving the yield and purity.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a caspofungin intermediate and a synthesis method thereof. Background Art

[0002] Caspofungin acetate is an echinocandin compound with a unique site of action, broad spectrum and low toxicity, and has been widely used as an antifungal agent for treatment or prevention.

[0003] The chemical structural formula of caspofungin acetate is shown in Formula I:

[0004]

[0005] William R. Leonard, Jr., the Journal of Organic Chemistry, 2007, 7, vol72, 2335-2343, used Pneumocandin B 0 Caspofungin is synthesized with thiophenol. As a stereoselective agent, thiophenol can carry out selective monosubstitution. However, thiophenol is highly toxic, has a foul odor, and is irritating, making it unsuitable for industrial production, especially batch drug production.

[0006] CN101648994A reports the synthesis of caspofungin using a mercapto aromatic compound R-SH as a stereoselective agent, wherein R is phenyl, 4-methoxyphenyl, methylimidazolyl, benzimidazolyl, etc. CN 102367267A describes the synthesis of caspofungin using an aromatic ring mercapto compound R'-SH substituted with hydroxyl, benzyloxy, phenoxy, substituted phenoxy, or substituted benzyloxy as a strong leaving group, preferably p-hydroxythiophenol, but it is difficult to avoid its toxicity and odor. CN102219833A reports the synthesis of caspofungin using a stereoselective agent 2-mercaptobenzothiazole or 1-phenyl-5-mercapto-tetrazolyl, but the actual yield is not high.

[0007] CN102112487A reports the use of nitrogen-containing nucleophiles to replace thiol or thiophenol compounds as strong leaving groups, and X is an auxiliary group selected from the following group, the group includes 5-membered and 6-membered heterocyclic aromatic rings and their derivatives with at least one N-atom as part of an imine group, wherein the N-atom constitutes a connection to a cyclohexapeptide; and ii) tetrazole and its derivatives, wherein one nitrogen atom constitutes a connection to a cyclohexapeptide. Although the use of malodorous and highly toxic thiol or thiophenol compounds is avoided, highly toxic and pungent solvents such as pyridine are introduced.

[0008] EP620232 and WO94 / 21677 use the starting material pneumocandin B 0The sulfone intermediate is obtained by reacting with alkylthiol or arylthiol, and then reacting with an amine compound in an anhydrous aprotic solvent, and then being separated by chromatography.

[0009] Most of the previously reported or published methods for synthesizing caspofungin using thiol or thiophenol compounds as stereoselective agents or strong leaving groups are to convert pneumocandin B 0 Or the caspofungin intermediate is mixed with a thiol or thiophenol compound dissolved in an acid, the selected acid is mainly a strong acid such as methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid, and the mixing temperature requirement is strict, and some temperatures require -50°C.

[0010] The disclosed methods for synthesizing caspofungin are not suitable for large-scale industrial production in terms of yield, stability, purity and three wastes. The synthesis steps in some methods must be carried out in a strictly anhydrous environment (using molecular sieves or dehydrating agents for dehydration); most methods require the use of highly toxic, foul-smelling, pungent thiol or thiophenol compounds, which seriously damage the health of operators and seriously pollute the environment; in some existing synthesis methods, the introduction of cyano groups inevitably leads to the formation of isomers, and the yield and stereoselectivity are not high, and expensive metals are used as catalysts, which increases the cost of industrialization; preparative chromatography is used multiple times, which increases the cost of industrialization and generates a large amount of three wastes. In view of this, it is urgent to further study methods for synthesizing caspofungin suitable for industrial production. Summary of the invention

[0011] In view of the shortcomings of the existing synthesis methods, the present invention provides a novel method for synthesizing a caspofungin intermediate. The method has short steps, less preparation and purification times, and is easy to scale up and suitable for industrial production.

[0012] The specific technical solutions of the present invention are as follows:

[0013] A compound as shown in formula III, whose structural formula is as follows:

[0014]

[0015] A method for synthesizing a compound as shown in formula III comprises the following steps:

[0016] The compound shown in formula II is mixed with thionyl chloride dissolved in solvent A to obtain a compound shown in formula III.

[0017]

[0018] Preferably, the solvent A is selected from one or more of dichloromethane, chloroform, acetonitrile, pyridine, ether, toluene, xylene, chlorobenzene and dichlorobenzene.

[0019] Preferably, the temperature at which the compound of formula II is mixed with thionyl chloride is -5 to -30°C, preferably -25 to -20°C.

[0020] Preferably, the molar ratio of the compound of formula II to thionyl chloride is 3:1.

[0021] The compound III can be used to synthesize the intermediate compound IV.

[0022] A method for synthesizing a compound as shown in formula IV comprises the following steps: without purification, mixing the compound as shown in formula III with ethylenediamine dissolved in solvent B to obtain the compound as shown in formula IV.

[0023]

[0024] Preferably, the solvent B is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, trifluoroethanol, ether, acetonitrile, dichloromethane and chloroform.

[0025] Preferably, the mixing temperature of the compound of formula III and ethylenediamine is 0 to 45°C, preferably 35°C.

[0026] Preferably, the method for synthesizing the compound as shown in formula IV comprises the following steps:

[0027] Slowly dropwise under nitrogen protection, the compound of formula II and thionyl chloride dissolved in solvent A are mixed, and the reaction progress is tracked by high performance liquid chromatography. The reaction time is 1-3 hours, preferably 1.5 hours. After the mixed reaction, a cold saturated aqueous solution of potassium carbonate is added dropwise to the reaction solution to absorb unreacted thionyl chloride and hydrogen chloride generated by the reaction, and the reaction solution is washed with cold pure water until it is nearly neutral. After extraction and separation and reduced pressure distillation, a light yellow solid compound of formula III is obtained, and then the compound of formula III is mixed with ethylenediamine dissolved in solvent B without purification to obtain a compound of formula IV;

[0028] The invention uses thionyl chloride to replace thiol or thiophenol compounds with highly toxic, foul smell and irritating odor, avoids the use of strong corrosive acid, and the formed cyclic sulfite is conducive to maintaining the configuration of the reactant; at the same time, by utilizing the property of easy departure and no change in the chiral configuration of the reactant, the ethylenediamine group is directly introduced without purification, the reaction steps are shortened, the number of preparation and purification times is reduced, and the yield is improved. The yield of the intermediate IV is above 89%, and the purity is about 89%. DETAILED DESCRIPTION

[0029] The beneficial effects of the present invention are further described by the following examples. The examples are only for illustrative purposes and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by ordinary technicians in the field according to the present invention are also included in the scope of the present invention.

[0030] Example 1

[0031] The compound of formula II (10.00 g, 9.4 mmol) and chloroform (200 mL) were placed in a 500 mL three-necked flask, placed in a low-temperature bath under nitrogen protection, cooled to -30°C, and dichlorothionyl (SOCl) was slowly added dropwise at this temperature. 2 , 0.37g, 3.1mmol) in chloroform (20mL), after the addition was complete, the reaction began, and the reaction progress was monitored by HPLC tracking, and the reaction time was 1h. Cold potassium carbonate saturated aqueous solution was added to the reaction solution until no more bubbles were generated, the organic layer was separated, the water layer was extracted with chloroform (50mL×2), the organic layers were combined, washed with cold pure water until nearly neutral, and dried with anhydrous sodium sulfate overnight, filtered, distilled under reduced pressure, and then vacuum dried to obtain a light yellow solid of the compound of formula III. The yield was 90.6%.

[0032] Under nitrogen protection, the compound of formula III was dissolved in methanol (10 mL), then mixed with ethylenediamine (50 mL) at 0°C for reaction, and HPLC was performed until the raw material was basically exhausted (about 2 h). After reduced pressure distillation, 100 mL of methanol and 200 mL of ethyl acetate were added, and the crystal product was separated by filtration. The crystal product was vacuum dried to obtain a compound of formula IV (yield 89.9%). The purity was 90.1%.

[0033] Example 2

[0034] The compound of formula II (10.00 g, 9.4 mmol) and dichloromethane (200 mL) were placed in a 500 mL three-necked flask, placed in a low-temperature bath under nitrogen protection, cooled to -5°C, and thionyl chloride (SOCl) was slowly added dropwise at this temperature. 2 , 0.37g, 3.1mmol) in dichloromethane (20mL), after the addition was complete, the reaction began, and the reaction progress was monitored by HPLC tracking, and the reaction time was 3h. Cold saturated aqueous solution of potassium carbonate was added to the reaction solution until no more bubbles were generated, the organic layer was separated, the water layer was extracted with dichloromethane (50mL×2), the organic layers were combined, washed with cold pure water until nearly neutral, and dried over anhydrous sodium sulfate overnight, filtered, distilled under reduced pressure, and then dried in vacuum to obtain a light yellow solid of the compound of formula III. Yield 90.2%

[0035] Under nitrogen protection, the compound of formula III was dissolved in ethanol (10 mL), then mixed with ethylenediamine (50 mL) at 45°C for reaction, and HPLC was used to detect until the raw material was basically exhausted (about 2 h). After reduced pressure distillation, 100 mL of ethanol and 200 mL of ethyl acetate were added, and the crystal product was separated by filtration. The crystal product was vacuum dried to obtain a compound of formula IV (yield 89.8%). Purity 89.9%.

[0036] Example 3

[0037] The compound of formula II (10.00 g, 9.4 mmol) and chloroform (200 mL) were placed in a 500 mL three-necked flask, placed in a low-temperature bath under nitrogen protection, and cooled to -25°C. At this temperature, thionyl chloride (SOCl 2 , 0.37g, 3.1mmol) in chloroform (20mL), after the addition was complete, the reaction began, and the reaction progress was monitored by HPLC, and the reaction time was 1.5h. Cold saturated aqueous solution of potassium carbonate was added to the reaction solution until no more bubbles were generated, the organic layer was separated, the water layer was extracted with chloroform (50mL×2), the organic layers were combined, washed with cold pure water until nearly neutral, and dried with anhydrous sodium sulfate overnight, filtered, distilled under reduced pressure, and then vacuum dried to obtain a light yellow solid of the compound of formula III. The yield was 90.1%.

[0038] Under nitrogen protection, the compound of formula III was dissolved in methanol (10 mL), and then mixed with ethylenediamine (50 mL) at 35°C for reaction, and HPLC was performed until the raw material was basically exhausted (about 2 h). After reduced pressure distillation, 100 mL of methanol and 200 mL of ethyl acetate were added, and the crystal product was separated by filtration. The crystal product was vacuum dried to obtain a compound of formula IV (yield 89.9%). Purity 90.1%.

[0039] Example 4

[0040] The compound of formula II (10.00 g, 9.4 mmol) and chloroform (200 mL) were placed in a 500 mL three-necked flask, placed in a low-temperature bath under nitrogen protection, cooled to -20°C, and dichlorothionyl (SOCl) was slowly added dropwise at this temperature. 2 , 0.37g, 3.1mmol) in chloroform (20mL), after the addition was complete, the reaction began, and the reaction progress was monitored by HPLC, and the reaction time was 1.5h. Cold potassium carbonate saturated aqueous solution was added to the reaction solution until no more bubbles were generated, the organic layer was separated, the water layer was extracted with chloroform (50mL×2), the organic layers were combined, washed with cold pure water until nearly neutral, and dried with anhydrous sodium sulfate overnight, filtered, distilled under reduced pressure, and then vacuum dried to obtain a light yellow solid of the compound of formula III. The yield was 89.8%.

[0041] Under nitrogen protection, the compound of formula III was dissolved in methanol (10 mL), and then mixed with ethylenediamine (50 mL) at 35°C for reaction, and HPLC was used to detect until the raw material was basically exhausted (about 2 h). After reduced pressure distillation, 100 mL of methanol and 200 mL of ethyl acetate were added, and the crystal product was separated by filtration. The crystal product was vacuum dried to obtain a compound of formula IV (yield 89.6%). The purity was 90.2%.

[0042] Example 5

[0043] Compound II (10.00 g, 9.4 mmol) and chloroform (200 mL) were placed in a 500 mL three-necked flask and placed in a low-temperature bath under nitrogen protection, cooled to -20°C, and thionyl chloride (SOCl) was slowly added dropwise at this temperature. 2 , 0.74g, 6.2mmol) in chloroform (20mL), after the addition was complete, the reaction began, and the reaction progress was monitored by HPLC, and the reaction time was 1.5h. Cold saturated aqueous solution of potassium carbonate was added to the reaction solution until no more bubbles were generated, the organic layer was separated, the water layer was extracted with chloroform (50mL×2), the organic layers were combined, washed with cold pure water until nearly neutral, and dried with anhydrous sodium sulfate overnight, filtered, distilled under reduced pressure, and then dried in vacuum to obtain a light yellow solid of the compound of formula III. The yield was 58.4%.

[0044] Under nitrogen protection, the compound of formula III was dissolved in methanol (10 mL), then mixed with ethylenediamine (50 mL) at 35°C for reaction, and reacted at room temperature after the addition was complete. HPLC detection was performed until the raw material was basically exhausted (about 2 hours). After reduced pressure distillation, 100 mL of methanol and 200 mL of ethyl acetate were added, and the crystal product was separated by filtration. The crystal product was vacuum dried to obtain a compound of formula IV (yield 71.3%). Purity 82.2%.

[0045] Example 6

[0046] Compound II (10.00 g, 9.4 mmol) and chloroform (200 mL) were placed in a 500 mL three-necked flask. Under nitrogen protection, the flask was placed in a low-temperature bath and cooled to -20°C. At this temperature, thionyl chloride (SOCl 2 , 1.11, 9.4mmol) in chloroform (20mL), after the addition was complete, the reaction began, and the reaction progress was monitored by HPLC, and the reaction time was 1.5h. Cold potassium carbonate saturated aqueous solution was added to the reaction solution until no more bubbles were generated, the organic layer was separated, the water layer was extracted with chloroform (50mL×2), the organic layers were combined, washed with cold pure water until nearly neutral, and dried with anhydrous sodium sulfate overnight, filtered, distilled under reduced pressure, and then vacuum dried to obtain a light yellow solid of the compound of formula III. The yield was 21.2%.

[0047] Under nitrogen protection, the compound of formula III was dissolved in methanol (10 mL), then mixed with ethylenediamine (50 mL) at 35°C for reaction, and reacted at room temperature after the dropwise addition was completed. HPLC detection was performed until the raw material was basically exhausted (about 2 hours). After reduced pressure distillation, 100 mL of methanol and 200 mL of ethyl acetate were added, and the crystal product was separated by filtration. The crystal product was vacuum dried to obtain a compound of formula IV (yield 59.3%). Purity 75.4%.

[0048] Example 7

[0049] Compound II (10.00 g, 9.4 mmol) and chloroform (200 mL) were placed in a 500 mL three-necked flask. Under nitrogen protection, the flask was placed in a low-temperature bath and cooled to -20°C. At this temperature, thionyl chloride (SOCl 2 , 0.19g, 1.6mmol) in chloroform (20mL), after the addition was complete, the reaction began, and the reaction progress was monitored by HPLC, and the reaction time was 1.5h. Cold saturated aqueous solution of potassium carbonate was added to the reaction solution until no more bubbles were generated, the organic layer was separated, the water layer was extracted with chloroform (50mL×2), the organic layers were combined, washed with cold pure water until nearly neutral, and dried with anhydrous sodium sulfate overnight, filtered, distilled under reduced pressure, and then dried in vacuum to obtain a light yellow solid of the compound of formula III. The yield was 76.6%.

[0050] Under nitrogen protection, the compound of formula III was dissolved in methanol (10 mL), then mixed with ethylenediamine (50 mL) at 35°C for reaction, and reacted at room temperature after the addition was complete. HPLC detection was performed until the raw material was basically exhausted (about 2 hours). After reduced pressure distillation, 100 mL of methanol and 200 mL of ethyl acetate were added, and the crystalline product was separated by filtration. The crystalline product was vacuum dried to obtain a compound of formula IV (yield 47.3%). Purity 70.5%.

[0051] Example 8

[0052] The compound of formula II (10.00 g, 9.4 mmol) and chloroform (200 mL) were placed in a 500 mL three-necked flask, placed in a low-temperature bath under nitrogen protection, and cooled to -35°C. At this temperature, thionyl chloride (SOCl 2 , 0.37g, 3.1mmol) in chloroform (20mL), after the addition was complete, the reaction began, and the reaction progress was monitored by HPLC tracking, and the reaction time was 1h. Cold saturated aqueous solution of potassium carbonate was added to the reaction solution until no more bubbles were generated, the organic layer was separated, the water layer was extracted with chloroform (50mL×2), the organic layers were combined, washed with cold pure water until nearly neutral, and dried with anhydrous sodium sulfate overnight, filtered, distilled under reduced pressure, and then vacuum dried to obtain a light yellow solid of the compound of formula III. The yield was 81.3%.

[0053] Under nitrogen protection, the compound of formula III was dissolved in methanol (10 mL), then mixed with ethylenediamine (50 mL) at 0°C for reaction, and HPLC was performed until the raw material was basically exhausted (about 2 h). After reduced pressure distillation, 100 mL of methanol and 200 mL of ethyl acetate were added, and the crystal product was separated by filtration. The crystal product was vacuum dried to obtain a compound of formula IV (yield 74.5%). The purity was 81.3%.

[0054] Example 9

[0055] The compound of formula II (10.00 g, 9.4 mmol) and chloroform (200 mL) were placed in a 500 mL three-necked flask, placed in a low-temperature bath under nitrogen protection, cooled to 0°C, and thionyl chloride (SOCl) was slowly added dropwise at this temperature. 2 , 0.37g, 3.1mmol) in chloroform (20mL), after the addition was complete, the reaction began, and the reaction progress was monitored by HPLC tracking, and the reaction time was 1h. Cold potassium carbonate saturated aqueous solution was added to the reaction solution until no more bubbles were generated, the organic layer was separated, the water layer was extracted with chloroform (50mL×2), the organic layers were combined, washed with cold pure water until nearly neutral, and dried with anhydrous sodium sulfate overnight, filtered, distilled under reduced pressure, and then vacuum dried to obtain a light yellow solid of the compound of formula III. The yield was 57.5%.

[0056] Under nitrogen protection, the compound of formula III was dissolved in methanol (10 mL), then mixed with ethylenediamine (50 mL) at 0°C for reaction, and HPLC was performed until the raw material was basically exhausted (about 2 h). After reduced pressure distillation, 100 mL of methanol and 200 mL of ethyl acetate were added, and the crystal product was separated by filtration. The crystal product was vacuum dried to obtain a compound of formula IV (yield 44.3%). The purity was 56.7%.

[0057] Example 10

[0058] Compound II (10.00 g, 9.4 mmol) and chloroform (200 mL) were placed in a 500 mL three-necked flask, and placed in a low-temperature bath under nitrogen protection, and the temperature was lowered to -35°C. At this temperature, a solution of thiophenol (0.34 g, 3.1 mmol) in chloroform (20 mL) was slowly added dropwise. After the addition was completed, the reaction began. The reaction process was monitored by HPLC tracking. The reaction time was 1 h. Cold potassium carbonate saturated aqueous solution was added to the reaction solution until no more bubbles were generated. The organic layer was separated, and the water layer was extracted with chloroform (50 mL × 2). The organic layers were combined, washed with cold pure water until nearly neutral, and dried with anhydrous sodium sulfate overnight. After filtration, the compound was distilled under reduced pressure and dried under vacuum to obtain a light yellow solid of the compound of formula III. The yield was 57.1%.

[0059] Under nitrogen protection, the compound of formula III was dissolved in methanol (10 mL), then mixed with ethylenediamine (50 mL) at 0°C for reaction, and HPLC was performed until the raw material was basically exhausted (about 2 h). After reduced pressure distillation, 100 mL of methanol and 200 mL of ethyl acetate were added, and the crystal product was separated by filtration. The crystal product was vacuum dried to obtain a compound of formula IV (yield 56.1%). The purity was 62.4%.

[0060] The compound of formula IV was analyzed by 1H-NMR and MS mass spectrometry:

[0061] 1HNMR(600.13MHz,CD3OD):7.13(m,2H),6.71(m,2H),4.89(d,1H),4.85(d,1H ),4.60(d,1H),4.56(dd,1H),4.42-4.50(m,2H),4.43(dd,1H),4.23(m,3H),4 .14(dd,1H),4.11(d,1H),3.89(d,1H),3.69-3.72(m,3H),3.54(d,1H),3.25( d,1H),2.72-2.95(m,5H),2.48(dd,1H),2.37(dd,1H),2.11-2.15(m,3H),1.8 6-1.93(m,3H),1.75(s,6H),1.46(m,2H),1.20-1.35(m,15H),0.96(m,2H),0.86(m,1H),0.79(t,3H),0.75-0.78(m,6H);

[0062] MS (ESI): 1108.3215 (M+H+).

[0063] The compound of formula III was analyzed by 1H-NMR and MS mass spectrometry:

[0064] 1HNMR(600.13MHz,CD3OD):7.25(d,1H),7.13(m,2H),6.71(m,2H),5.76(m,1H),4.85(d,1H),4.60(d,1H ),4.56(dd,1H),4.42-4.50(m,2H),4.23(m,3H),4.14(dd,1H),4.11(d,1H),3.89(d,1H),3.69-3.72(m, 3H),3.54(d,1H),3.25(d,1H),2.72-2.95(m,1H),2.48(dd,1H),2.11-2.15(m,4H),1.86-1.93(m,3H),1 .75(s,6H),1.46(m,2H),1.20-1.35(m,15H),0.96(m,2H),0.86(m,1H),0.79(t,3H),0.75-0.78(m,6H);

[0065] MS (ESI): 1112.2795 (M+H + ).

[0066] Comparative Example 1

[0067] Compound 7 (3.0 g, 2.59 mmol) was dissolved in 6.5 ml of water and 6.5 ml of methanol, cooled to -10°C, and ethylenediamine (12.8 ml, 0.192 mol) was slowly added dropwise, and the temperature of the addition was controlled not to exceed 2°C. After the addition was completed, the mixture was reacted at 25°C for 6 hours, and acetic acid was added to terminate the reaction. The pH of the reaction solution was adjusted to between 5 and 6, and then separated and purified by reverse phase chromatography (C18) column (10%-60% acetonitrile / water gradient elution). The eluate was collected and freeze-dried to obtain compound 4 with a yield of 82.4% and a purity of 77.4%. The mass spectrum of compound 4: MS (ESI) 1108.3215 (M+H + ). The structural formula of compound 7 is as follows:

[0068]

Claims

1. A compound as shown in formula III, whose structural formula is as follows: 。 2. A method for synthesizing the compound of formula III as claimed in claim 1, characterized in that: The following steps are involved: Mixing the compound of formula II and thionyl chloride dissolved in solvent A, and reacting for 1-3 hours to obtain a compound of formula III; ， Solvent A is selected from one or more of dichloromethane, chloroform, acetonitrile, pyridine, ether, toluene, xylene, chlorobenzene, and dichlorobenzene; the temperature at which the compound of formula II and thionyl chloride are mixed is -5 to -30°C; and the molar ratio of the compound of formula II to thionyl chloride is 3:

1.

3. The synthesis method according to claim 2, characterized in that The temperature at which the compound of formula II is mixed with thionyl chloride is -25 to -20°C.

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