Preparation method of oteconazole intermediate

Abstract

The invention discloses a preparation method of an oteconazole intermediate, and relates to the technical field of oteconazole preparation. According to the preparation method disclosed by the invention, an olefin intermediate B is prepared from a carbonyl intermediate C, and an intermediate A is obtained from the intermediate B under the action of ceric ammonium nitrate and sodium nitrite; the method has the advantages of cheap and easily available raw materials, simple reaction operation, mild reaction conditions, low requirements on equipment and easiness in industrial large-scale production. The target product conversion rate is high, the purification operation is simple, and the economic value is relatively high.

Description

Technical Field

[0001] The present invention relates to the technical field of the preparation of oteseconazole, and particularly relates to a preparation method of an oteseconazole intermediate. Background Art

[0002] Oteseconazole was developed by the American company Mycovia Pharmaceuticals. Oteseconazole is an antifungal drug, a azole metal enzyme inhibitor, which targets and inhibits fungal sterol 14α-demethylase (CYP51). On April 26, 2022, the U.S. Food and Drug Administration (FDA) approved Vivjoa capsules for reducing the incidence of recurrent vulvovaginal candidiasis (RVVC) in women with a history of RVVC and no reproductive potential.

[0003] The chemical name of oteseconazole is (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol, and its chemical structural formula is shown as follows:

[0004]

[0005] Nitro alcohol intermediate A is a key intermediate of oteseconazole.

[0006]

[0007] Currently, there are mainly the following two preparation processes for oteseconazole:

[0008] Method 1, epoxy intermediate route (CN103097374A)

[0009]

[0010] Method 2, nitro alcohol intermediate route (WO2017049196A1)

[0011]

[0012] In Method 1, the carbonyl intermediate C reacts under the action of diazomethane to obtain an epoxy intermediate, which is then prepared into the corresponding boric acid, and finally, through suzuki coupling, ring opening and chiral HPLC preparation, the oteseconazole finished product is obtained. First, diazomethane, which is explosive, is used in this route, posing a great safety hazard. Second, the separation of the finished product by chiral HPLC greatly limits the production capacity and is not conducive to industrial scale-up.

[0013] In Method 2, the carbonyl intermediate C first undergoes a chiral Henry reaction to obtain a nitrol intermediate with a certain chirality (ee = 80%). Then, through hydrogenation reduction, construction of tetrazole, chiral resolution, and Suzuki coupling, the finished product of ornidazole is obtained. In this route, a controlled and explosive-precursor chemical, nitromethane, is used. Therefore, higher requirements are also imposed during the procurement, transportation, warehousing, and use processes. Additionally, the ee value of the chiral nitrol intermediate in this route is only 80%, and subsequent chiral resolution is still required to improve the chirality of the product. Therefore, the advantages of this chiral Henry reaction are not obvious.

[0014] From the comparison of the above two routes, it can be seen that the nitrol intermediate A can be obtained as ornidazole through hydrogenation reduction, construction of tetrazole, chiral resolution, and Suzuki coupling, which is more conducive to industrial scale-up. Therefore, finding a safe, inexpensive, and easily scalable synthetic route for the nitrol intermediate A is a technical problem that urgently needs to be solved in the current field. Summary of the Invention

[0015] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a preparation method for an ornidazole intermediate, which has a simple process, low requirements for equipment, and simple operation. At the same time, the reagents used are inexpensive, the cost is low, and the yield is high.

[0016] The technical solution of the present invention to solve the above technical problems is as follows:

[0017] The present invention provides a preparation method for an ornidazole intermediate, and the ornidazole intermediate is ornidazole intermediate A, and the structural formula is: It includes the following steps: 1) Intermediate C:

[0018] is first converted into intermediate B: 2) Then, intermediate B is converted into intermediate A;

[0019] According to the preparation method of the present invention, intermediate B, an organic solvent, ammonium cerium nitrate, and sodium nitrite are mixed in a reaction kettle, and the temperature is controlled for the reaction. After the reaction is completed, it is refined by recrystallization with the organic solvent to obtain intermediate A.

[0020] According to the preparation method of the present invention, the organic solvent is selected from acetonitrile, tetrahydrofuran, and dichloromethane, and preferably anhydrous acetonitrile.

[0021] According to the preparation method of the present invention, the volume-weight ratio of the organic solvent to intermediate B is 5 - 15 v, and preferably 8 - 12 v.

[0022] According to the preparation method of the present invention, the molar ratio of ammonium cerium nitrate to intermediate B is 2.0 - 4.0:1, and preferably 2.5 - 3.5:1.

[0023] According to the preparation method of the present invention, the molar ratio of sodium nitrite to intermediate B is 2.0 - 4.0:1, preferably 2.5 - 3.5:1.

[0024] According to the preparation method of the present invention, the temperature of the temperature-controlled reaction is -10 to 10 °C, preferably -5 to 5 °C.

[0025] According to the preparation method of the present invention, the recrystallization solvent is selected from n-heptane, n-hexane, ethyl acetate or a combination of two of them, preferably a mixed solvent of n-heptane and ethyl acetate.

[0026] On the other hand, the preparation of intermediate A further includes intermediate C:

[0027]

[0028] being converted into intermediate B.

[0029] According to the preparation method of the present invention, it includes mixing organic solvent 1, methyltriphenylphosphonium iodide, and a base in a reaction kettle, after keeping warm and stirring for a period of time, dissolving intermediate C in organic solvent 2 and dropping it into the reaction system under temperature control, and after the reaction is completed, removing impurities by slurrying with an organic solvent and concentrating to obtain intermediate B.

[0030] According to the preparation method of the present invention, both organic solvent 1 and organic solvent 2 are selected from acetonitrile, tetrahydrofuran, dichloromethane, toluene or a combination of two of them, and both organic solvent 1 and organic solvent 2 are preferably tetrahydrofuran.

[0031] According to the preparation method of the present invention, the base is selected from potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, and N,N-diisopropylethylamine, preferably potassium tert-butoxide.

[0032] According to the preparation method of the present invention, the volume-weight ratio of organic solvent 1 to intermediate C is 3 - 8 v, preferably 4 - 6 v.

[0033] According to the preparation method of the present invention, the volume-weight ratio of organic solvent 2 to intermediate C is 1 - 5 v, preferably 2.5 - 3.5 v.

[0034] According to the preparation method of the present invention, the molar ratio of methyltriphenylphosphonium iodide to intermediate C is 1.0 - 3.0:1, preferably 1.1 - 1.3:1. The molar ratio of the base to intermediate C is 1.0 - 3.0:1, preferably 1.1 - 1.3:1.

[0035] According to the preparation method of the present invention, the temperature of its heat preservation and stirring is -10 to 10 °C, preferably -5 to 5 °C.

[0036] According to the preparation method of the present invention, the dropping temperature is -10 to 30 °C, preferably 5 to 15 °C.

[0037] According to the preparation method of the present invention, the impurity-removing organic solvent is selected from n-heptane, n-hexane or a combination of both, preferably n-hexane.

[0038] In the present invention, if there is a conflict between the Chinese name and the structural formula of the compound, the structural formula shall prevail, except when the structural formula has obvious errors.

[0039] The beneficial effects of the present invention are as follows: The raw materials of this route are cheap and easily available, the reaction operation is simple, the reaction conditions are mild, the requirements for equipment are low, and it is easy to scale up for industrial production. The conversion rate of the target product is high, the purification operation is simple, and it has high economic value. Description of the Drawings

[0040] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention, and therefore should not be regarded as limiting the scope. For those of ordinary skill in the art, without creative efforts, other related drawings can also be obtained based on these drawings.

[0041] Figure 1 1H-NMR spectrum of intermediate B obtained in Example 1 of the present invention 1 ;

[0042] Figure 2 1H-NMR spectrum of intermediate A obtained in Example 2 of the present invention 1 ; Detailed Embodiments

[0043] The following examples illustrate the present invention, but do not limit the present invention. In the art, simple substitutions or improvements made by those skilled in the art to the present invention fall within the scope of the technical solutions protected by the present invention.

[0044] Example 1:

[0045] Preparation of Intermediate B

[0046] In a 1 L three-necked flask, add 69.7 g of methyltriphenylphosphonium iodide (1.2 eq.) and 250 mL of tetrahydrofuran. Stir for 5 minutes at room temperature and then cool to 0 °C. Add 19.3 g of potassium tert-butoxide (1.2 eq.), and continue to stir at 0 °C for 60 minutes. Dropwise add a tetrahydrofuran solution of Intermediate C (50 g of Intermediate C dissolved in 150 mL of tetrahydrofuran), controlling the internal temperature not to exceed 10 °C. After the addition is complete, naturally restore to room temperature and react for 3 h. After monitoring by TLC that the raw materials have disappeared, pour the reaction solution into 800 mL of water to quench the reaction, add ethyl acetate for extraction twice, 200 mL each time, and retain the organic layer. Add 200 mL of 15% brine to the organic layer for washing once, and then add an appropriate amount of anhydrous sodium sulfate for drying. Filter off the sodium sulfate, concentrate the organic layer to dryness, and obtain a pale yellow crude product. Add 250 mL of n-hexane to the above crude product, stir at room temperature for 2 h, filter off the insoluble matter, concentrate the filtrate to dryness, and obtain 49.2 g of a white solid, namely Intermediate B, with a molar yield of 99.0% and a purity of 98.2%.

[0047] 1 1H-NMR (400 MHz, d6-DMSO): δ 8.83 (d, J = 2.1 Hz, 1H), 8.23 (dd, J = 8.4, 2.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.31 - 7.17 (m, 2H), 7.06 (tdd, J = 8.5, 2.6, 1.0 Hz, 1H), 5.97 (t, J = 1.8 Hz, 1H), 5.74 (s, 1H).

[0048] Example 2:

[0049] Preparation of Intermediate A

[0050] Add 49.2 g of Intermediate B obtained in Example 1 (1.0 eq.) and 492 mL of anhydrous acetonitrile (10 v) to a 1 L three-necked flask, stir to dissolve, replace with nitrogen three times, cool the system to 0 °C, and add 233.8 g of ammonium cerium(IV) nitrate (3.0 eq.) at this temperature. After stirring evenly, add 29.4 g of sodium nitrite (3.0 eq.) in batches. After the addition is complete, continue to react at 0 °C for 3 - 4 h. After monitoring by TLC that the raw materials have disappeared, pour the reaction solution into 1500 mL of water to quench, and then extract with dichloromethane twice, 500 mL each time. After combining the organic layers, add 500 mL of saturated brine for washing once, and then dry with anhydrous sodium sulfate for 2 h. Filter off the sodium sulfate, concentrate under reduced pressure, and obtain a yellow oily crude product. Add 500 mL of n-heptane and 50 mL of ethyl acetate to the above crude product, heat to 50 °C to dissolve clearly, then naturally cool to room temperature for crystallization, filter by suction, and dry the obtained filter cake under reduced pressure at 50 °C to constant weight to obtain 44.5 g of a white solid, namely Intermediate A, with a molar yield of 76.5% and a purity of 99.1%.

[0051] 1 1H-NMR (400 MHz, d6-DMSO): δ 8.71 (d, J = 2.3 Hz, 1H), 8.21 (dd, J = 8.4, 2.4 Hz, 1H), 7.60 (s, 1H), 7.41 (dd, J = 8.9, 6.9 Hz, 2H), 7.24 (ddd, J = 12.1, 9.1, 2.6 Hz, 1H), 7.03 (td, J = 8.5, 2.6 Hz, 1H), 5.70 (d, J = 12.9 Hz, 1H), 5.14 (d, J = 12.3 Hz, 1H).

[0052] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the inventive concept of the present invention, several modifications and improvements can be made, and these all belong to the protection scope of the present invention.

Claims

1. A method for preparing an ornidazole intermediate, characterized in that, The ornidazole intermediate is ornidazole intermediate A, and the structural formula is: It includes the following steps: 1) Intermediate C: First, convert it into intermediate B: 2) Then, convert intermediate B into intermediate A.

2. The preparation method according to claim 1, characterized in that, Step 2) includes mixing intermediate B with an organic solvent, ammonium cerium(IV) nitrate, and sodium nitrite, controlling the temperature for reaction, and after the reaction is completed, obtaining intermediate A through recrystallization and purification.

3. The preparation method according to claim 2, characterized in that, The organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, and dichloromethane.

4. The preparation method according to claim 3, characterized in that, The volume-to-weight ratio of the organic solvent to intermediate B is 5 - 15 v.

5. The preparation method according to claim 2, characterized in that, The molar ratio of ammonium cerium(IV) nitrate to intermediate B is 2.0 - 4.0:1, and the molar ratio of sodium nitrite to intermediate B is 2.0 - 4.0:

1.

6. The preparation method according to claim 2, characterized in that, The temperature for the temperature-controlled reaction is -10 to 10 °C, and the recrystallization solvent is selected from n-heptane, n-hexane, ethyl acetate, or a combination of two of them.

7. The preparation method according to claim 1, characterized in that, Step 1) includes mixing organic solvent 1, methyltriphenylphosphonium iodide, and a base, stirring while keeping warm, dissolving intermediate C in organic solvent 2, and dropping it into the reaction system while controlling the temperature. After the reaction is completed, impurity removal is carried out by slurrying with an organic solvent and concentration to obtain intermediate B. The molar ratio of methyltriphenylphosphonium iodide to intermediate C is 1.0 - 3.0:1, the temperature for stirring while keeping warm is -10 to 10 °C, and the dropping temperature is -10 to 30 °C.

8. The preparation method according to claim 7, characterized in that, Both organic solvent 1 and organic solvent 2 are selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, toluene, or a combination of two of them, and the impurity-removing organic solvent is selected from n-heptane, n-hexane, or a combination of the two.

9. The preparation method according to claim 7, characterized in that, The base is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, and N,N-diisopropylethylamine, and the molar ratio of the base to intermediate C is 1.0 - 3.0:

1.

10. The preparation method according to claim 7, characterized in that, The volume-to-weight ratio of organic solvent 1 to intermediate C is 3 - 8 v, and the volume-to-weight ratio of organic solvent 2 to intermediate C is 1 - 5 v.

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