CN118221606A - Cilastatin sodium intermediate compound and preparation method thereof - Google Patents

Cilastatin sodium intermediate compound and preparation method thereof Download PDF

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CN118221606A
CN118221606A CN202211639195.5A CN202211639195A CN118221606A CN 118221606 A CN118221606 A CN 118221606A CN 202211639195 A CN202211639195 A CN 202211639195A CN 118221606 A CN118221606 A CN 118221606A
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reaction
sodium
temperature
preparation
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刘忠
时江华
王新平
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Shandong New Time Pharmaceutical Co Ltd
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Shandong New Time Pharmaceutical Co Ltd
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Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a cilastatin sodium intermediate compound and a preparation method thereof. According to the invention, glycine methyl ester is used as a raw material to react with (S) -2, 2-dimethylcyclopropane-1-formic acid and 4-bromobutyraldehyde under the action of a catalyst to obtain a high purity, a new intermediate compound of cilastatin sodium with single configuration, namely (R, Z) -4- (5-bromopentanyl) -2- (2, 2-dimethylcyclopropyl) oxazol-5 (4H) -ketone, is subjected to vulcanization and salification to obtain cilastatin sodium, and the obtained final product has high purity and stable process, and is suitable for mass industrialized production.

Description

Cilastatin sodium intermediate compound and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a cilastatin sodium intermediate compound and a preparation method thereof.
Background
Cilastatin sodium (CILASTATIN SODIUM) is a renal dehydrogenase dipeptidase inhibitor developed in 1979 by Merck corporation of the united states under the chemical name: (+) - (Z) -7- [ (2R) - (2-amino-2-carboxyethyl) -thio ] -2- [ (1S) - (2, 2) -dimethylcyclopropylamido) I-2-eno heptanoic acid sodium salt having the structure shown below. Compound with carbapenem antibiotic imipenem in a ratio of 1:1 in clinic [ trade name: tenability (imipenem) is one of the antimicrobial drugs with high clinical evaluation. It protects the antibiotics such as imipenem which are easily hydrolyzed by the enzyme by inhibiting the activity of the renal dipeptide dehydrogenase.
At present, the synthesis process of cilastatin sodium is a mature process: document J.Med.chem.1987,30:1074-1090, xu Xiaoli (Xu Xiaoli, wang Haishan, wu Jianbo, et al, J. Chinese medical industry, 1994, 25 (2): 51-54) et al report that 7-bromo-2-oxoheptanoic acid is added to (S) - (+) -2, 2-dimethylcyclopropanecarboxylic acid amine, dehydrated to form an acrylic acid structure, L-cystine, decilastatin, is re-attached in sodium-liquid ammonia in a yield of only 19.7%, and the amidation step presents by-products of reaction with acid, and the use of sodium is dangerous:
U.S. Pat. No. 3, 20050119346, 03018544,WO 02094742 Chen Yang, synthesis of cilastatin sodium and its E isomer [ D ] Shanghai pharmaceutical industry institute, 2006, lang Fang, chen Pei, wang Jianwei, et al, J. Chinese J. Antibiotics 2008,33 (5): S1-S2 et al reported reacting L-cystine hydrochloride monohydrate with alkali metal salt (aqueous solution) of (Z) -7-chloro- ((S) -2, 2-dimethylcyclopropanecarboxylic acid amine) -2-heptenoic acid at room temperature, neutralizing to pH=5.0 with hydrochloric acid, reacting 30min at 85-90 ℃, E isomerization, resin chromatography, and removing sodium chloride to give cilastatin sodium with a total yield of 32.2%. However, when the amidation step is isomerized, E-type byproducts are easy to obtain, so that the reaction yield of the step is low, and the isomer byproducts are not easy to remove, which is not beneficial to industrial production:
Based on the problems of side reactions and isomer impurities in the preparation process of the cilastatin sodium in the above route, the development of a new preparation process of the cilastatin sodium, which is easy to operate, mild in reaction condition and beneficial to industrial production, is a problem which needs to be solved at present.
Disclosure of Invention
Based on the problems in the above route, the invention provides a novel cilastatin sodium intermediate compound, the E configuration and byproducts of the cilastatin sodium intermediate prepared by the intermediate are reduced, the operation is simple, the reaction condition is mild, and the industrial production is facilitated.
The first aspect of the invention provides a novel cilastatin sodium intermediate compound, which has a structure as shown in a formula I-1:
The invention provides a preparation method of a cilastatin sodium intermediate compound I-1, which comprises the following steps of adding a compound SM-1, a compound SM-2 and an organic solvent A into a reaction bottle for temperature-controlled reflux reaction, adding alkali and acetic anhydride into a reaction liquid after the reaction is finished, reacting at room temperature, adding a compound SM-3, heating the reaction liquid until T 1 reaches the end of the reaction, and carrying out post-treatment to obtain the compound I-1, wherein the following steps are adopted:
Preferably, the organic solvent A is selected from one of toluene, 1, 4-dioxane, acetonitrile and N, N-dimethylformamide, wherein toluene is particularly preferred.
Preferably, the base is selected from one of sodium acetate, sodium carbonate, sodium hydride, sodium tert-butoxide, sodium acetate being particularly preferred.
Preferably, the reaction temperature T 1 is from 40℃to 80℃and, of these, 60℃is particularly preferred.
Preferably, the feeding mole ratio of the compound SM-1, the compound SM-2, the alkali and the compound SM-3 is as follows: 1.0:1.0 to 1.5:1.0 to 1.8:1.0 to 1.8, particularly preferably 1:1.05:1.05:1.1.
In a preferred embodiment, a post-treatment operation is performed after the reaction is completed, specifically, after the reaction is completed, the reaction is cooled to room temperature to obtain a suspension. To the suspension was added water, stirred at room temperature, insoluble matter was removed by filtration, and the organic phase was separated and washed with water. The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate to give compound I-1 as a white solid.
The invention provides an application of a compound I-1 in preparing cilastatin sodium, which comprises the following steps: under the protection of inert gas, adding a compound I-1, a compound SM-4 and an aqueous solution of alkali into a reaction device at a temperature of T 2, adding an organic solvent B, continuously stirring at a constant temperature for reaction, adding an aqueous solution of hydrochloric acid for regulating pH to be neutral, concentrating under reduced pressure at a temperature lower than room temperature, and removing water to obtain the compound I, wherein the synthetic route is as follows:
preferably, the alkali solution is selected from any one of aqueous sodium hydroxide solution, aqueous sodium hydride solution, aqueous sodium carbonate solution, aqueous sodium methoxide solution, and particularly preferably aqueous sodium hydroxide solution.
Preferably, the concentration of the alkali solution is 0.5mol/L to 2.0mol/L, and particularly preferably 1.0mol/L.
Preferably, the organic solvent B is selected from one or a combination of alcohol-free, tetrahydrofuran, ethanol, acetonitrile, wherein anhydrous methanol is particularly preferred
Preferably, the temperature T 2 is from-10℃to 0℃and of these, particularly preferably-3 ℃.
Preferably, the molar ratio of the compound I-1, the compound SM-4 and the base is 1:1.0-2.0:2.0-3.5, particularly preferably 1:1.05:2.25.
In a preferred embodiment, after the reaction is completed, a post-treatment operation is performed, specifically: adding methanol for dissolving, filtering to remove precipitate in the solution, concentrating the filtrate to obtain pale yellow solid, pulping with acetone water, cooling to-20deg.C for crystallization, and rapidly filtering at low temperature to obtain white powder I.
Compared with the prior art, the invention has the following effects
1. Provides a novel intermediate compound I-1 of cilastatin sodium, and provides a novel method for simply and efficiently preparing cilastatin sodium by using the compound, wherein the novel intermediate realizes the synthesis of a high-efficiency single configuration through a high-efficiency catalyst, the side reaction is reduced, and the configuration purity is improved;
2. The new intermediate compound I-1 is subjected to simple vulcanization and salifying to obtain cilastatin sodium, and the obtained product has high yield and high purity.
Detailed Description
The invention is further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
The structure of the compound obtained by the invention is confirmed:
HPLC peak area normalization method:
Chromatographic column: YMC-Triart C 18 column (4.6 mm. Times.250 mm,5 μm);
Mobile phase: acetonitrile/water (80:20);
Column temperature: 30 ℃;
Detection wavelength: 230nm;
flow rate: 1.0ml/min;
Sample injection amount: 10 μl;
Retention time: 20.6min
High resolution mass spectrometry of compound I ：ESI-HRMS:m/z＝300.0520[M+H]+;mp217～219℃;1H-NMR(400MHz,CDCl3)δ:6.77(t,1H),3.52(t,2H),2.16(dt,2H),1.82(m,2H),1.29(m,2H),1.00(d,1H),0.89(d,6H),0.75(d,1H),0.25(d,1H);13C-NMR(100MHz,CDCl3)δ:165.9,157.4,141.1,133.7,33.8,32.4,32.3,27.8,27.3,25.8,23.5,18.9,4.1.
HPLC peak area normalization method:
Chromatographic column: YMC-Triart C 18 column (4.6 mm. Times.250 mm,5 μm);
mobile phase: the mobile phase A is buffer solution (0.01 mol/L potassium dihydrogen phosphate solution), B is acetonitrile, and the gradient elution is carried out (0-40 min: B90-10%, 40-60min: B50-50%, 60-90min: B30-70%);
Column temperature: 50 ℃;
detection wavelength: 210nm;
Flow rate: 2.0ml/min;
Sample injection amount: 20 μl;
Retention time: 48.8min
ESI-HRMS(m/z):403.1380[M+Na]+;1H-NMR(400MHz,CDCl3)δ:12.39(br,1H),9.30(br,1H),8.36(br,2H),6.16(t,1H),3.77(t,1H),3.06(d,1H),2.81(d,1H),2.60(t,2H),2.16(dt,2H),1.57(m,2H),1.51(t,1H),1.29(m,2H),1.06(d,1H),0.89(s,6H),0.81(d,1H);13C-NMR(100MHz,CDCl3)δ:174.5,169.7,149.6,136.7,125.3,61.4,54.1,52.2,37.2,32.2,29.3,28.7,27.3,27.1,22.5,20.6,18.7,14.2.
Preparation of Compound I
Example 1
To a two-necked flask, compound SM-1 (16.02 g,0.20 mol), compound SM-2 (23.95 g,0.21 mol) and anhydrous toluene (100 mL) were added, the mixture was refluxed at a controlled temperature for 5 hours, the reaction solution was cooled to room temperature, sodium acetate (17.23 g,0.21 mol) and acetic anhydride (100 mL) were reacted at room temperature for 4 hours, after the completion of the reaction, compound SM-3 (32.99 g,0.22 mol) was added to the reaction solution, the reaction was carried out at 60℃for 5 hours after the completion of the reaction at room temperature, and the reaction solution was cooled to room temperature to obtain a suspension. To the suspension was added water (200 mL), and the mixture was stirred at room temperature for half an hour, insoluble matter was removed by filtration, and the organic phase was separated and washed with water (200 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give a white solid with a yield of 95.6% and an HPLC purity of 99.91%.
Example 2
To a two-necked flask, compound SM-1 (16.02 g,0.20 mol), compound SM-2 (22.81 g,0.20 mol) and 1, 4-dioxane (100 mL) were added, the temperature was refluxed for 5 hours, the reaction solution was cooled to room temperature, sodium carbonate (22.56 g,0.21 mol) and acetic anhydride (100 mL) were added to the reaction solution, the reaction was carried out for 4 hours at room temperature, after the completion of the reaction, compound SM-3 (32.99 g,0.22 mol) was added to the reaction solution, the reaction was carried out for 5 hours at 60℃after the completion of the reaction at room temperature, and the reaction solution was cooled to room temperature to obtain a suspension. To the suspension was added water (200 mL), and the mixture was stirred at room temperature for half an hour, insoluble matter was removed by filtration, and the organic phase was separated and washed with water (200 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give a white solid with a yield of 92.5% and HPLC purity of 99.72%.
Example 3
To a two-port flask, compound SM-1 (16.02 g,0.20 mol), compound SM-2 (34.22 g,0.30 mol) and acetonitrile (100 mL) were added, the mixture was refluxed at a controlled temperature for 5 hours, the reaction mixture was cooled to room temperature, sodium hydride (5.04 g,0.21 mol) and acetic anhydride (100 mL) were reacted at room temperature for 4 hours, after the completion of the reaction, compound SM-3 (32.99 g,0.22 mol) was added to the reaction mixture, the reaction mixture was reacted at 60℃for 5 hours after the completion of the reaction at room temperature, and the reaction mixture was cooled to room temperature to give a suspension. To the suspension was added water (200 mL), and the mixture was stirred at room temperature for half an hour, insoluble matter was removed by filtration, and the organic phase was separated and washed with water (200 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give a white solid with a yield of 93.1% and an HPLC purity of 99.54%.
Example 4
To a two-necked flask, compound SM-1 (16.02 g,0.20 mol), compound SM-2 (23.95 g,0.21 mol) N, N-dimethylformamide (100 mL) and reflux at a controlled temperature were added, and after the reaction was completed, compound SM-3 (32.99 g,0.22 mol) was added to the reaction mixture after the completion of the reaction, the reaction was allowed to proceed to room temperature for 5 hours at 40℃and after the completion of the reaction, the reaction was allowed to cool to room temperature to give a suspension. To the suspension was added water (200 mL), and the mixture was stirred at room temperature for half an hour, insoluble matter was removed by filtration, and the organic phase was separated and washed with water (200 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give a white solid with a yield of 93.6% and an HPLC purity of 99.71%.
Example 5
To a two-necked flask, compound SM-1 (16.02 g,0.20 mol), compound SM-2 (23.95 g,0.21 mol) N, N-dimethylformamide (100 mL) and reflux at a controlled temperature were added, and after the reaction was completed, compound SM-3 (32.99 g,0.22 mol) was added to the reaction mixture after the completion of the reaction, the reaction was allowed to proceed to room temperature for 5 hours at 80℃and after the completion of the reaction, the reaction was allowed to cool to room temperature to give a suspension. To the suspension was added water (200 mL), and the mixture was stirred at room temperature for half an hour, insoluble matter was removed by filtration, and the organic phase was separated and washed with water (200 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give a white solid with a yield of 94.3% and an HPLC purity of 99.61%.
Example 6
To a two-necked flask, compound SM-1 (16.02 g,0.20 mol), compound SM-2 (23.95 g,0.21 mol) and anhydrous toluene (100 mL) were added, the mixture was refluxed at a controlled temperature for 5 hours, the reaction solution was cooled to room temperature, sodium tert-butoxide (20.18 g,0.21 mol) and acetic anhydride (100 mL) were added, the reaction solution was reacted at room temperature for 4 hours, after the completion of the reaction, compound SM-3 (29.99 g,0.20 mol) was added to the reaction solution, the reaction was carried out at 50℃for 5 hours after the completion of the reaction at room temperature, and the reaction solution was cooled to room temperature to obtain a suspension. To the suspension was added water (200 mL), and the mixture was stirred at room temperature for half an hour, insoluble matter was removed by filtration, and the organic phase was separated and washed with water (200 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give a white solid with a yield of 92.6% and an HPLC purity of 99.65%.
Example 7
To a two-necked flask, compound SM-1 (16.02 g,0.20 mol), compound SM-2 (23.95 g,0.21 mol) and anhydrous toluene (100 mL) were added, the mixture was refluxed at a controlled temperature for 5 hours, the reaction solution was cooled to room temperature, sodium tert-butoxide (20.18 g,0.21 mol) and acetic anhydride (100 mL) were added, the reaction solution was reacted at room temperature for 4 hours, after the completion of the reaction, compound SM-3 (53.99 g,0.36 mol) was added to the reaction solution, the reaction was carried out at 70℃for 5 hours at room temperature for 1 hour, and after the completion of the reaction, the reaction solution was cooled to room temperature, a suspension was obtained. To the suspension was added water (200 mL), and the mixture was stirred at room temperature for half an hour, insoluble matter was removed by filtration, and the organic phase was separated and washed with water (200 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give a white solid with a yield of 93.8% and an HPLC purity of 99.55%.
Example 8
To a two-port flask, compound SM-1 (16.02 g,0.20 mol), compound SM-2 (38.78 g,0.34 mol) and anhydrous toluene (100 mL) were added, the mixture was refluxed at a controlled temperature for 5 hours, the reaction solution was cooled to room temperature, sodium acetate (32.81 g,0.40 mol) and acetic anhydride (100 mL) were added, the reaction solution was reacted at room temperature for 4 hours, after the completion of the reaction, compound SM-3 (59.99 g,0.40 mol) was added to the reaction solution, the reaction was carried out at room temperature for 5 hours at 85℃after the completion of the reaction, and the reaction solution was cooled to room temperature to give a suspension. To the suspension was added water (200 mL), and the mixture was stirred at room temperature for half an hour, insoluble matter was removed by filtration, and the organic phase was separated and washed with water (200 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was evaporated by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give a white solid with a yield of 86.9% and an HPLC purity of 98.92%.
Preparation of Compound I
Example 9
Under the protection of nitrogen, adding a compound I-1 (6.01 g,0.02 mol), a compound SM-4 (8.19 g,0.02 mol) and a 1.0mol/L aqueous solution of sodium hydroxide (45 mL) into a double-mouth bottle at the temperature of minus 3 ℃ to react with methanol (200 mL) at constant temperature for 3 hours, adding a 1mol/L aqueous solution of hydrochloric acid to adjust pH to neutral, concentrating under reduced pressure at the temperature lower than room temperature to remove water to obtain a yellow solid, adding methanol (200 mL) to dissolve, filtering to remove sediment in the solution, concentrating filtrate to obtain a light yellow solid, pulping with acetone water, cooling and crystallizing at the temperature of minus 20 ℃, filtering rapidly at low temperature to obtain white powder I, wherein the yield is 98.8%, and the HPLC purity is 99.98%.
Example 10
Under the protection of nitrogen, compound I-1 (6.01 g,0.02 mol), compound SM-4 (8.19 g,0.02 mol) and 0.5mol/L aqueous sodium hydroxide solution (90 mL) are added into a double-mouth bottle under the protection of nitrogen, the mixture is reacted for 3 hours at constant temperature, 1mol/L aqueous hydrochloric acid solution is added to adjust pH to neutral, water is removed under reduced pressure at the temperature lower than room temperature to obtain yellow solid, methanol (200 mL) is added for dissolution, sediment in the solution is removed by filtration, filtrate is concentrated to obtain light yellow solid, the light yellow solid is pulped by acetone water, the mixture is cooled and crystallized at the temperature of minus 20 ℃, the mixture is rapidly filtered at low temperature to obtain white powder I, the yield is 93.0 percent, and the HPLC purity is 99.72 percent.
Example 11
Under the protection of nitrogen, compound I-1 (6.01 g,0.02 mol), compound SM-4 (4.85 g,0.04 mol) and 2.0mol/L aqueous solution of sodium hydride (23 mL) are added into a double-mouth bottle at the temperature of minus 3 ℃ to react with methanol (200 mL) at constant temperature for 3 hours, 1mol/L aqueous solution of hydrochloric acid is added to adjust pH to neutral, water is removed by decompression concentration at the temperature lower than room temperature to obtain yellow solid, methanol (200 mL) is added to dissolve, sediment in the solution is removed by filtration, filtrate is concentrated to obtain light yellow solid, the light yellow solid is pulped by acetone water, the mixture is cooled and crystallized at minus 20 ℃, the mixture is rapidly filtered at low temperature to obtain white powder I, the yield is 93.4%, and the HPLC purity is 99.60%.
Example 12
Under the protection of nitrogen, adding a compound I-1 (6.01 g,0.02 mol), a compound SM-4 (8.19 g,0.02 mol), 1mol/L aqueous solution of sodium carbonate (20 mL) and tetrahydrofuran (200 mL) into a double-mouth bottle at the temperature of minus 10 ℃ for reaction for 3 hours at constant temperature, adding 1mol/L aqueous solution of hydrochloric acid for regulating pH to be neutral, concentrating under reduced pressure at the temperature lower than room temperature to remove water to obtain yellow solid, adding methanol (200 mL) for dissolving, filtering to remove sediment in the solution, concentrating filtrate to obtain light yellow solid, pulping with acetone water, cooling and crystallizing at the temperature of minus 20 ℃, rapidly filtering at low temperature to obtain white powder I with the yield of 93.2% and the HPLC purity of 99.72%.
Example 11
Under the protection of nitrogen, compound I-1 (6.01 g,0.02 mol), compound SM-4 (8.19 g,0.02 mol), 1mol/L aqueous solution of sodium hydroxide (40 mL) and ethanol (200 mL) are added into a double-mouth bottle at the temperature of 0 ℃ for reaction for 3 hours at constant temperature, 1mol/L aqueous solution of hydrochloric acid is added for regulating pH to be neutral, water is removed by decompression concentration at the temperature lower than room temperature to obtain yellow solid, methanol (200 mL) is added for dissolution, sediment in the solution is removed by filtration, filtrate is concentrated to obtain light yellow solid, the light yellow solid is pulped by acetone water, the mixture is cooled and crystallized at the temperature of minus 20 ℃, the mixture is rapidly filtered at the low temperature to obtain white powder I, the yield is 93.3%, and the HPLC purity is 99.61%.
Example 12
Under the protection of nitrogen, compound I-1 (6.01 g,0.02 mol), compound SM-4 (8.19 g,0.02 mol), 3.0mol/L aqueous solution of sodium methoxide (15 mL) and acetonitrile (200 mL) are added into a double-mouth bottle at the temperature of 5 ℃ to react for 3 hours at constant temperature, 1mol/L aqueous solution of hydrochloric acid is added to adjust pH to neutral, water is removed by decompression concentration at the temperature lower than room temperature to obtain yellow solid, methanol (200 mL) is added to dissolve, precipitate in the solution is removed by filtration, filtrate is concentrated to obtain light yellow solid, the light yellow solid is pulped by acetone water, the mixture is cooled and crystallized at the temperature of minus 20 ℃, the white powder I is obtained by rapid filtration at the low temperature, and the yield is 87.4 percent and the HPLC purity is 98.90 percent.

Claims (10)

1. The cilastatin sodium intermediate compound is characterized by having a structure shown in a formula I-1:
2. A process for the preparation of cilastatin sodium intermediate compound I-1 as claimed in claim 1, characterized in that the process comprises the steps of: adding a compound SM-1, a compound SM-2 and an organic solvent A into a reaction bottle for temperature-controlled reflux reaction, adding alkali and acetic anhydride into a reaction liquid after the reaction is finished, reacting at room temperature, adding a compound SM-3, heating the reaction liquid to T 1 until the reaction is finished, and performing post-treatment to obtain the compound I-1, wherein the following steps are adopted:
3. the preparation method according to claim 2, wherein the base is one selected from sodium acetate, sodium carbonate, sodium hydride and sodium tert-butoxide.
4. The preparation method according to claim 2, wherein the organic solvent A is selected from one of toluene, 1, 4-dioxane, acetonitrile and N, N-dimethylformamide.
5. The process according to claim 2, wherein the reaction temperature T 1 is from 40 ℃ to 80 ℃.
6. The preparation method according to claim 2, wherein the compound SM-1, compound SM-2, alkali and compound SM-3 are added in the following molar ratios: 1.0:1.0 to 1.5:1.0 to 1.8:1.0 to 1.8.
7. Use of compound I-1 according to claim 1 for the preparation of cilastatin sodium.
8. Use of a cilastatin sodium intermediate compound I-1 as claimed in claim 1 for the preparation of cilastatin sodium, characterized in that the preparation process comprises the steps of:
adding a compound I-1, a compound SM-4 and an aqueous solution of alkali into a reaction device under the protection of inert gas and temperature control T 2, adding an organic solvent B, continuously stirring at constant temperature for reaction, adding an aqueous solution of hydrochloric acid to adjust pH to be neutral, and concentrating under reduced pressure at a temperature lower than room temperature to remove water to obtain a compound I;
The synthetic route is as follows:
9. The use according to claim 8, wherein the alkaline solution is selected from any one of aqueous sodium hydroxide, aqueous sodium hydride, aqueous sodium carbonate, aqueous sodium methoxide; the concentration of the alkali solution is 0.5 mol/L-2.0 mol/L.
10. The use according to claim 8, wherein the organic solvent B is selected from one of alcohol-free, tetrahydrofuran, ethanol, acetonitrile or a combination thereof; the temperature T 2 is-10-0 ℃; the feeding mole ratio of the compound I-1 to the compound SM-4 to the alkali is 1:1.0-2.0:2.0-3.5.
CN202211639195.5A 2022-12-19 2022-12-19 Cilastatin sodium intermediate compound and preparation method thereof Pending CN118221606A (en)

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