Preparation method of cyclic conjugated acid ester

Abstract

The invention discloses a preparation method of cyclic conjugated carboxylic ester, and belongs to the technical field of medicine synthesis. The method comprises the following three steps: A, adding N, N '-dicyclohexylcarbodiimide and cuprous chloride into tert-butyl alcohol, and reacting to generate tert-butyl alcohol isourea; b, adding tert-butyl alcohol isourea into the N-protected 7-ACA, and reacting to obtain an intermediate 3a; and C, selectively hydrolyzing the acetic ester, so as to obtain the tert-butyl (6R, 7R)-3-hydroxymethyl-8-oxo-7-(2-phenylacetamide)-5-sulfo-1-azacyclo [4.2. 0] oct-2-ene-2-carboxylic ester. The process can effectively avoid displacement of intracyclic double bonds during carboxyl esterification, the adopted reaction reagent is relatively safe, the operation requirement is low, the equipment requirement is low, operation is easy, and large-scale industrial production is facilitated.

Description

Technical Field

[0001] The invention relates to a preparation process of a cyclic conjugated acid ester, belonging to the technical field of drug synthesis. Background Art

[0002] Cephalosporin is the abbreviation of cephalosporin antibiotics. Cephalosporins are a class of antibiotics obtained by semi-synthetically modifying the side chains of natural cephalosporin C obtained by culturing Cephalosporin. There are about 30 commonly used cephalosporins, which are divided into the first, second, third, fourth and fifth generations according to their generation order and antibacterial properties.

[0003] In the antibiotic market, cephalosporin antibiotics occupy a large share, and their related intermediates also show considerable market potential. The best-selling varieties of cephalosporin antibiotics are ceftriaxone sodium, cefazolin sodium, ceftriaxone, ceftriaxone, cefoperazone and cefuroxime / axetil, etc. These drugs are prepared from 7-aminocephalosporic acid (7-ACA), 7-aminodeacetoxycephalosporanic acid (7-ADCA) and other starting materials to obtain key intermediates. Among them: 7-ACA is subjected to amidation, esterification and selective ester hydrolysis to obtain the key intermediate 1 of cephalosporin API, and the reaction equation is expressed as follows:

[0004]

[0005] The common problems of the above reaction route include: when the intermediate 2 is carboxylic acid esterified, it is easy to cause the position of the double bond on the ring to be isomerized, forming the isomer impurity 3-isomer, which is difficult to separate and purify. When the side chain acetyl ester is hydrolyzed, if the carboxyl protecting group is unstable, it is easy to be hydrolyzed together, and when the acidic environment is adjusted, a lactonization byproduct 4 will be formed.

[0006] There are many reports on the research of protecting groups for the esterification of carboxyl groups on the cephalosporin ring. Typical synthetic routes are:

[0007] 1) Patent US6656917 B1, and the literature The Journal of Antibiotics, 1981, 1300 and 1985, 1738 use diazonium diphenylmethane as a reagent to generate diphenylmethyl carboxylate 1b. Although this method can inhibit double bond displacement, it is costly and uses a highly dangerous diazonium diphenylmethane reagent, which increases the process safety risk.

[0008]

[0009] 2) Patent US2016 / 139135A1 uses allyl to protect the carboxyl group, such as using 3-bromopropylene to protect the carboxyl group of cephalothin sodium, but the removal of propylene ester requires a precious metal catalyst, and the production cost is relatively high.

[0010] 3) Tert-butyl carboxylate is the most economical protecting group for carboxyl, but the preparation of tert-butyl ester of cephalosporin fragment is difficult. For example, Eur. J. Org. Chem. 2001, 2529 reported that carboxyl condensed with tert-butyl alcohol under the action of DCC condensation agent with a yield of 88%, but all double bonds in the ring were displaced. If the acetate of the side chain is first hydrolyzed by enzymatic method and then tert-butyl carboxylate is prepared with tert-butyl alcohol isourea, the double bond can be maintained, but the yield is only 61%. The document Bioorg. Med. Chem. Lett. 2016, 2068 uses boron trifluoride ether as catalysis, and 7-ACA carboxyl and tert-butyl acetate can be transesterified, but the esterification yield is only 52%. J. Org. Chem. 2010, 1289 uses p-toluenesulfonic acid / concentrated sulfuric acid as catalysis and tert-butyl acetate for transesterification, but it is necessary to use a sealed tube reaction, which is obviously not suitable for process scale-up.

[0011]

[0012] Therefore, the industry urgently needs an efficient and stable carboxyl protecting group strategy, which will not produce double bond position isomerism problems during the carboxylic acid esterification process. The protecting group is relatively stable in alkaline hydrolysis and can ultimately prepare key intermediates with high quality. Summary of the invention

[0013] In order to solve the above problems, the present invention provides a new process for preparing cyclic conjugated acid esters. A three-step method is adopted: A. N, N'-dicyclohexylcarbodiimide and cuprous chloride are added to tert-butyl alcohol to react to generate tert-butyl isourea; B. Tert-butyl isourea is added to 7-ACA protected by phenylacetyl to react to obtain a crude product of tert-butyl carboxylate; the crude product is recrystallized using an ester solvent and an aliphatic hydrocarbon solvent to obtain a pure product. C. The ester is selectively hydrolyzed to obtain the product. The reaction reagents used in the present invention are safe, have low operating requirements, low equipment requirements, are easy to operate, and are conducive to large-scale industrial production. Tert-butyl ester has good alkali stability, and the intermediate 3a can be selectively hydrolyzed to remove acetate using conventional chemical methods, and the tert-butyl ester itself is also easy to remove under acidic conditions.

[0014] The novel process for preparing a cyclic conjugated acid ester of the present invention comprises the following steps:

[0015] A. Tert-butyl alcohol reacts with N,N'-dicyclohexylcarbodiimide in the presence of cuprous chloride to generate tert-butyl isourea;

[0016] B. Compound 2a reacts with tert-butyl isourea to obtain a crude compound 3a, which is then recrystallized from an ester solvent and an alkane solvent to obtain compound 3a;

[0017] C. Compound 3a was selectively hydrolyzed in a methanol-base system to obtain tert-butyl (6R, 7R)-3-hydroxymethyl-8-oxo-7-(2-phenylacetamide)-5-thio-1-azacyclo[4.2.0]oct-2-ene-2-carboxylate.

[0018] The chemical reaction equation is expressed as follows:

[0019]

[0020] Furthermore, in step A of the above technical solution, the molar ratio of N,N'-dicyclohexylcarbodiimide to tert-butanol is 1:1-8; the weight ratio of N,N'-dicyclohexylcarbodiimide to cuprous chloride is 1:0.02-0.05.

[0021] Furthermore, in step B of the above technical solution, the ester solvent is selected from ethyl formate, methyl acetate, ethyl acetate or isopropyl acetate; the alkane solvent is selected from n-hexane, cyclohexane, n-heptane or petroleum ether.

[0022] Furthermore, in step B of the above technical solution, the recrystallization is carried out by first adding ethyl acetate to heat and dissolve, and then adding petroleum ether to cool and crystallize; the weight ratio of ethyl acetate to petroleum ether is 1:1-8.

[0023] Furthermore, in step C of the above technical solution, the base is selected from sodium hydroxide or potassium hydroxide.

[0024] Furthermore, in the above technical scheme, step C is performed by dissolving the tert-butyl ester intermediate in methanol, adding an aqueous alkali solution at low temperature, and selectively hydrolyzing the acetate. After the reaction is complete, the pH is adjusted to neutral, and conventional post-treatment is performed to obtain the target product 1a.

[0025] Beneficial effects of the present invention

[0026] The invention solves the technical difficulties of the existing 7-aminocephalosporic acid carboxyl protection (low yield, use of dangerous reagents, high production cost, not suitable for process amplification and the like), the new process esterification reaction has high specificity, the double bond in the ring does not shift, and the product yield is high; the ester is selectively hydrolyzed, the tert-butyl ester is stable, no lactone ring by-product is generated, the hydrolysis product can exist stably, and is suitable for substrate structure modification; the production cost is low, the reaction conditions are mild, the process safety is high, and it is suitable for industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the liquid chromatogram of pure product 3a in Example 1;

[0028] Figure 2 This is the NMR spectrum of pure 3a in Example 1;

[0029] Figure 3 It is the liquid chromatogram of 3a isomer in Comparative Example 1;

[0030] Figure 4 This is the LC-MS spectrum of sample 1a in Example 5; DETAILED DESCRIPTION

[0031] In order to deepen the understanding of the present invention, the present invention will be further described in detail below in conjunction with embodiments and drawings. The embodiments are only used to explain the present invention and do not constitute a limitation on the protection scope of the present invention.

[0032] Example 1

[0033] 1) Add N,N'-dicyclohexylcarbodiimide (20.6g, 0.10mol) to 11.1g tert-butyl alcohol, add 0.8g cuprous chloride, replace with nitrogen three times, and stir at room temperature overnight. Filter, the filtrate contains 17.4g of product O-tert-butyl-N,N'-dicyclohexylisourea, with a yield of 62%, and it is used directly without purification;

[0034] 2) Add cefoperazone intermediate 2a (5.0 g, 0.012 mol) to a 100 mL reaction bottle, add 20 mL of dichloromethane, and add O-tert-butyl-N,N'-dicyclohexylisourea (17.4 g, 0.062 mol) solution dropwise while controlling the temperature to not higher than 0°C. After the addition is completed, the internal temperature is raised to 40°C and reacted for 16 hours. The reaction is monitored by TLC, and the reaction is completed. Filter and dry with silica gel pad to obtain 6.2 g of crude product, and crystallize with ethyl acetate / petroleum ether = 1 / 8 to obtain 4.28 g of pure product 3a, with a yield of 75%.

[0035] Example 2

[0036] 1) Add N,N'-dicyclohexylcarbodiimide (20.6g, 0.10mol) to 44g tert-butyl alcohol, add 1.0g cuprous chloride, replace with nitrogen three times, and stir at room temperature overnight. Filter, the filtrate contains 18.1g of product O-tert-butyl-N,N'-dicyclohexylisourea, with a yield of 64%, and it is used directly without purification;

[0037] 2) Add cefoperazone intermediate 2a (5.0 g, 0.012 mol) to a 100 mL reaction bottle, add 25.0 mL of dichloromethane, control the temperature not to exceed 10 ° C, add O-tert-butyl-N, N'-dicyclohexyl isourea (16.8 g, 0.06 mol), add the temperature to 20 ° C, react for 16 hours, and monitor the reaction by TLC. Filter and spin dry to obtain 6.0 g of crude product, and crystallize with ethyl acetate / n-heptane = 1 / 5 to obtain 4.56 g of pure product 3a, with a yield of 80%, and the purity is consistent with Example 1.

[0038] Example 3

[0039] 1) Add N,N'-dicyclohexylcarbodiimide (82.5g, 0.40mol) to 59g tert-butyl alcohol, add 3.2g cuprous chloride, replace with nitrogen three times, and stir at room temperature overnight. Filter, the filtrate contains 77g of product O-tert-butyl-N,N'-dicyclohexylisourea, with a yield of 69%, and it is used directly without purification;

[0040] 2) Add cefuroxime intermediate 2a (20.0g, 0.05mol) to a 500mL reaction bottle, add 80mL tetrahydrofuran, control the temperature not to exceed 0°C, add O-tert-butyl-N,N'-dicyclohexylisourea (56.0g, 0.20mol) solution dropwise, raise the internal temperature to 30°C and react for 16 hours, and monitor the reaction by TLC. Filter and spin dry to obtain 22g crude product, and crystallize from ethyl acetate / n-heptane = 1 / 8 to obtain 17.2g pure product 3a, with a yield of 75%. The purity is consistent with Example 1.

[0041] Example 4

[0042] 1) Add N,N'-dicyclohexylcarbodiimide (20.6g, 0.1mol) to 10.3g tert-butyl alcohol, add 0.8g cuprous chloride, replace with nitrogen three times, and stir at room temperature overnight. Filter, the filtrate contains 17.4g of product O-tert-butyl-N,N'-dicyclohexylisourea, and the yield is 62%;

[0043] 2) Cefdrolene intermediate 2a (20 g, 0.05 mol) was added into a 250 mL reaction bottle, and 80 mL of dichloromethane was added. The temperature was controlled not to exceed 0°C, and O-tert-butyl-N,N'-dicyclohexylisourea (17.4 g, 0.062 mol) solution was added dropwise. After the addition was completed, the temperature was raised to 30°C and the reaction was carried out for 16 hours. The reaction was not complete under HPLC monitoring, and the conversion rate was about 40%.

[0044] Example 5

[0045] Add tert-butyl carboxylate 3a (5.0 g, 0.011 mol) to a 500 mL reaction bottle, add 200 mL methanol, add sodium hydroxide (1.8 g, 0.045 mol) water (10 mL) solution dropwise with dry ice-ethanol at -30 °C, control the internal temperature at -30 °C to react for 1 hour after the addition is completed, monitor the reaction by LC-MS, control the internal temperature at -30 °C to adjust pH = 6-7, evaporate methanol, add 20 mL water, extract twice with 10 mL ethyl acetate, combine the organic phases, dry, filter, and spin dry to obtain a crude product, and recrystallize from petroleum ether / ethyl acetate = 3 / 1 to obtain 3.75 g of pure product 1a, with a yield of 83%. Comparative Example 1 Original esterification conditions, causing double bond shift:

[0046]

[0047] Cefuroxime 2a (5.0 g, 0.012 mol) was added to a 100 mL reaction bottle, dissolved with 20 ml of dichloromethane, replaced with nitrogen three times, cooled to an internal temperature of -30 ° C, 4-dimethylaminopyridine (0.5 g), N, N'-dicyclohexylcarbodiimide (2.7 g, 0.013 mol) and tert-butyl alcohol (2 g, 0.024 mol) were added respectively, and the temperature was raised to room temperature (30 ° C) and stirred for 3 hours. The reaction was monitored by TLC to complete, and the reaction solution was filtered, dried, and purified by a silica gel column to obtain 3.9 g of the product 3-acetoxymethyl-8-oxygen-7-phenylacetylamino-5-sulfur-1-nitrogen-bicyclo[4.2.0]oct-3-ene-2-carboxylic acid tert-butyl ester, with a yield of 68%. Comparative Example 1 NMR and liquid chromatograms show that the double bond shift byproduct obtained by this method is obtained.

[0048] According to the NMR data: if the double bond of 3a is not shifted, the sulfur-carbon methylene hydrogen peak will appear at the displacement of 3.35; if 3a is shifted, there will be no peak at the displacement of 3.35, and the hydrogen peak of the sulfur-carbon-carbon double bond will appear at 6.27.

[0049] Comparative Example 2

[0050] Cefuroxime 2a (5.0 g, 0.012 mol) was added into a 100 mL reaction bottle, dissolved with 20 ml of dichloromethane, replaced with nitrogen three times, cooled to an internal temperature of -30°C, N,N'-dicyclohexylcarbodiimide (2.7 g, 0.013 mol) and tert-butanol (2 g, 0.024 mol) were added respectively, and the temperature was raised to room temperature (30°C) and stirred for 3 hours. TLC monitoring showed that the reaction did not generate esterification products or isomers, but only active ester intermediates formed by cefuroxime 2a and N,N'-dicyclohexylcarbodiimide.

[0051] Comparative Example 3

[0052] Protecting carboxyl groups using PMB

[0053]

[0054] Add intermediate 2a (5.0g, 12.8mmol) to a 100ml reaction bottle, add 50mL DMF, potassium carbonate (3.54g, 25.6mmol), replace with nitrogen three times, add p-methoxybenzyl chloride (2.21g, 13.0mmol), heat to 45℃ and react for 12 hours after the addition, and monitor the reaction by TLC. Add water, extract with ethyl acetate, spin dry and pass through a column to obtain 1.6g of a mixed product with a yield of 25%. This method has a low yield, and judging from the nuclear magnetic resonance, there are some double bond shift byproducts in the product.

[0055] The crude PMB protected product (1.0 g, 1.2 mmol) was added into a 100 mL reaction bottle, and 20 mL of methanol was added. A solution of sodium hydroxide (0.16 g, 4.0 mmol) in water (3 mL) was added dropwise under dry ice-ethanol at -30 °C. After the addition was completed, the internal temperature was controlled at -30 °C for 1 hour. The raw material disappeared under LC-MS monitoring, but the PMB group was also hydrolyzed.

[0056] The present invention uses 7-ACA, which is supplied in large quantities on the market, as an initial raw material, and reacts it with homemade O-tert-butyl-N,N'-dicyclohexylisourea to obtain an intermediate product with no double bond displacement. Compared with the prior art, the safety of the raw materials used in the present invention is greatly improved, the equipment cost is greatly reduced, thereby greatly reducing the production cost, and the reaction time is shortened compared with the prior art, the post-treatment method is simple and does not require column chromatography purification, and the total yield is improved.

Claims

1. A method for preparing a cyclic conjugate acid ester, characterized in that: The reaction route is as follows:

2. The method for preparing a cyclic conjugate acid ester according to claim 1, wherein: The steps include: A. Tert-butyl alcohol reacts with N,N'-dicyclohexylcarbodiimide in the presence of cuprous chloride to generate tert-butyl isourea; B. Compound 2a reacts with tert-butyl isourea to obtain a crude compound 3a, which is then recrystallized from an ester solvent and an alkane solvent to obtain compound 3a; C. Compound 3a was selectively hydrolyzed in a methanol-base system to obtain tert-butyl (6R, 7R)-3-hydroxymethyl-8-oxo-7-(2-phenylacetamide)-5-thio-1-azacyclo[4.2.0]oct-2-ene-2-carboxylate.

3. The method for preparing a cyclic conjugate acid ester according to claim 2, wherein: In step A, the molar ratio of N,N'-dicyclohexylcarbodiimide to tert-butyl alcohol is 1:1-8; the weight ratio of N,N'-dicyclohexylcarbodiimide to cuprous chloride is 1:0.02-0.

05.

4. The method for preparing a cyclic conjugate acid ester according to claim 2, wherein: In step B, the ester solvent is selected from ethyl formate, methyl acetate, ethyl acetate or isopropyl acetate; the alkane solvent is selected from n-hexane, cyclohexane, n-heptane or petroleum ether.

5. The method for preparing a cyclic conjugate acid ester according to claim 4, wherein: In step B, the recrystallization is carried out by first adding ethyl acetate to heat and dissolve, and then adding petroleum ether to cool and crystallize.

6. The method for preparing a cyclic conjugate acid ester according to claim 5, wherein: The weight ratio of ethyl acetate to petroleum ether is 1:3-8.

7. The method for preparing a cyclic conjugate acid ester according to claim 2, wherein: In step C, the base is selected from sodium hydroxide or potassium hydroxide.

8. The method for preparing a cyclic conjugate acid ester according to claim 2, wherein: Step C: dissolving the tert-butyl ester intermediate in methanol, adding an aqueous alkali solution at low temperature to selectively hydrolyze the acetate; After the reaction is complete, the pH is adjusted to neutral and conventional post-treatment is performed to obtain the target product 1a.

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