Refining method of Bittegravir intermediate and hydrate prepared by refining method

Abstract

The invention discloses a refining method of a Bittegravir intermediate ((1S, 3R)-3-hydroxycyclopentyl) tert-butyl carbamate and a hydrate prepared by the refining method. According to the method, the ((1S, 3R)-3-hydroxycyclopentyl) tert-butyl carbamate crude product is crystallized in a manner of preparing the hydrate (compound 1) in a specific solvent, so that the operation is simplified, impurities are effectively removed, the purification is efficient, and the quality control of downstream prepared raw material medicines and preparations is more facilitated. Meanwhile, a crystallization solvent system is mainly composed of water and can be recycled, so that the use amount of an organic solvent is reduced, and the method is more environment-friendly. Besides, the hydrate solid product with good characters is prepared by the method, the storage and transportation stability of the intermediate is improved, the industrial production cycle arrangement is more flexible, and the feeding and metering are more convenient. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a method for refining a Bittegravir intermediate ((1S, 3R)-3-hydroxycyclopentyl)carbamic acid tert-butyl ester and a hydrate obtained therefrom, and in particular to a method for refining a Bittegravir intermediate ((1S, 3R)-3-hydroxycyclopentyl)carbamic acid tert-butyl ester suitable for industrialization and a hydrate obtained therefrom that is easy to use. Background Art

[0002] Biktarvy is a new combination drug for the treatment of human immunodeficiency virus type 1 (HIV-I) infection. It consists of the HIV nucleoside reverse transcriptase inhibitor emtricitabine, the nucleotide reverse transcriptase inhibitor tenofovir alafenamide fumarate, and the HIV integrase strand transfer inhibitor bictegravir. It is used to treat pediatric and adult HIV-I infection.

[0003]

[0004] Compound 2 is an important material for the preparation of Bitegvir sodium, and its quality will affect the quality, safety and effectiveness of the raw material. CN106470975 discloses a method for preparing compound 2, and the specific process is as follows: ((1S, 3R)-3-acetylcyclopentyl)carbamic acid tert-butyl ester is oxidized by m-chloroperbenzoic acid and hydrolyzed under alkaline conditions to obtain a crude product of ((1S, 3R)-3-hydroxycyclopentyl)carbamic acid tert-butyl ester. The crude product is purified by reducing the reaction treated filtrate to a theoretical amount of 1.5 to 1.6 V / m at <45°C, and the resulting mixture is stirred at 30 to 35°C for 30 to 60 minutes. Then, n-heptane is added within 1 to 2 hours, and the seed crystals of compound 2 are stirred for 2 to 3 hours. Then, n-heptane is slowly added and stirred for 2 to 3 hours, and the resulting mixture is cooled to 10 to 15°C and stirred for 3 to 5 hours. Finally, the product was collected by filtration and washed with n-heptane at 10-15°C, and dried under reduced pressure at 35-45°C to obtain a refined product.

[0005]

[0006] When purifying the crude product obtained by the above method, a large amount of toluene (about 5.8 m / m) is required to reduce the moisture content of the entire system to KF≤0.05%. It is also necessary to add 7% m / m activated carbon decolorization and 7% m / m diatomaceous earth to assist filtration. The resulting filtrate needs to be further concentrated, and crystal seeds need to be added during the crystallization process to induce crystallization. The overall operation of this method is cumbersome, time-consuming and energy-consuming, and it also produces a large amount of waste, which is not conducive to industrial production. In addition, the appearance of the refined product obtained by the above method will soften and become sticky during the placement process, and it is not convenient for transportation, storage, and weighing. Summary of the invention

[0007] Purpose of the invention: The present invention aims to provide a method for refining the intermediate ((1S, 3R)-3-hydroxycyclopentyl)carbamic acid tert-butyl ester of Bittegravir with effective impurity removal, convenient operation, economy, environmental protection and stable product, and its obtained hydrate with excellent properties.

[0008] Technical solution: The method for refining the Bittegravir intermediate ((1S, 3R)-3-hydroxycyclopentyl)carbamic acid tert-butyl ester of the present invention is to heat and dissolve the crude product of ((1S, 3R)-3-hydroxycyclopentyl)carbamic acid tert-butyl ester in a mixed solvent, and then cool and crystallize, perform solid-liquid separation, and perform post-treatment to obtain the refined product compound 1 of the intermediate.

[0009]

[0010] The mixed solvent is a mixed solvent of at least two of water, toluene and n-heptane.

[0011] Preferably, in the mixed solvent, the mass ratio of water, toluene and n-heptane is (0.5-10):(0-2):(0-2).

[0012] More preferably, in the mixed solvent, the mass ratio of water to the crude product is (0.5-10):1, the mass ratio of toluene to the crude product is (0-2):1, and the mass ratio of n-heptane to the crude product is (0-2):1.

[0013] Preferably, the mixed solvent is a mixed solvent of water-toluene-n-heptane, water-toluene, or water-n-heptane.

[0014] Further preferably, in the water-toluene-n-heptane mixed solvent, the mass ratio of water, toluene and n-heptane is 40:9:9.

[0015] More preferably, in the water-toluene or water-n-heptane mixed solvent, the mass ratio of water to toluene or n-heptane is 40:9.

[0016] Further preferably, in the mixed solvent, the mass ratio of water to the crude product is 2.5:1.

[0017] Further preferably, in the mixed solvent, the mass ratio of toluene or n-heptane to the crude product is 9:16.

[0018] Preferably, the temperature of the heating and dissolving is 30 to 80°C.

[0019] More preferably, the temperature of the heating and dissolving is 50°C.

[0020] Preferably, the temperature of the cooling crystallization is 0-20°C.

[0021] More preferably, the temperature of the cooling crystallization is 0-15°C.

[0022] More preferably, the temperature of the cooling crystallization is 0-5°C.

[0023] Preferably, the solid-liquid separation includes sedimentation, vacuum filtration, filter press, centrifugation, etc.

[0024] Preferably, the post-treatment is to remove the residual solvent, which specifically includes normal pressure drying, reduced pressure drying, boiling drying, freeze drying, etc.

[0025] The crystal structure of compound 1 obtained by the purification method of the present invention is monoclinic, P21 space group; the unit cell parameters are α=90°, β=93.545(1)°, γ=90°.

[0026] Preferably, the crystals of compound 1 are represented by a diffraction angle of 2θ±0.2°, and have characteristic diffraction peaks at 8.26°, 14.95°, 16.53°, 16.65°, 18.94°, 21.36°, 21.97°, 25.75°, and 33.23°.

[0027] Preferably, the crystals of Compound 1 have characteristic melting peaks at 50.75±0.3°C and 110.26±0.3°C.

[0028] Preferably, the crystals of Compound 1 have a weight loss of 31.1%±0.2% between 25°C and 130°C.

[0029] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0030] The present invention optimizes the crystallization system and parameters, and crystallizes the crude product of ((1S, 3R)-3-hydroxycyclopentyl)carbamate in a specific solvent in the form of a hydrate. Crystallization can be performed without adding seed crystals, which simplifies the operation, effectively removes ((1S, 3S)-3-hydroxycyclopentyl)carbamate and other impurities, and has high purification efficiency. The quality requirements can be met by refining once, which is more conducive to the quality control of the raw materials and preparations prepared downstream. At the same time, the crystallization solvent system is mainly water, and can be recycled, reducing the amount of organic solvents, which is more environmentally friendly. In addition, a hydrate solid product with good properties is obtained by this method, the stability of intermediate storage and transportation is improved, the problem of non-hydrate becoming sticky when placed is avoided, and the industrial production cycle is more flexible and the feeding and metering are more convenient. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The single crystal diffraction pattern SC-XRD spectrum of compound 1 prepared in Example 2;

[0032] Figure 2 is the X-ray diffraction XRD pattern of compound 1 prepared in Example 2;

[0033] Figure 3 is the TGA spectrum of compound 1 prepared in Example 2;

[0034] Figure 4 is the DSC spectrum of compound 1 obtained in Example 2;

[0035] Figure 5 This is the HPLC detection spectrum of the crude product obtained in Example 1;

[0036] Figure 6 This is the HPLC detection spectrum of compound 1 prepared in Example 2. DETAILED DESCRIPTION

[0037] The technical solution of the present invention is further described below in conjunction with embodiments.

[0038] Example 1: Preparation of crude tert-butyl ((1S, 3R)-3-hydroxycyclopentyl)carbamate

[0039] Add 90g of tert-butyl ((1S, 3R)-3-acetylcyclopentyl)carbamate and 450g of toluene to a clean and dry 1L reaction bottle, and stir to dissolve. Divide meta-chloroperbenzoic acid (174g) into 5-8 portions at 25-30°C and add them to the reaction bottle within 4-6 hours. Stir the reaction at 25-30°C and monitor the reaction by HPLC until completion. After the reaction is completed, slowly add 20% sodium bisulfite aqueous solution (250g), keep the temperature in the reaction bottle below 30°C, and test negative with potassium iodide paper. Slowly add 10% sodium hydroxide (560g) and stir, keep the temperature below 20°C, separate the liquids, and wash with water. Add 90g of water, 180g of methanol, and 32g of sodium hydroxide to the organic phase, stir the reaction at 25-30°C, and monitor the reaction by HPLC until the reaction is completed. After the reaction is completed, the temperature is adjusted to below 15°C, and the pH is adjusted to 7-8 with 1N hydrochloric acid. The layers were separated, the aqueous phase was stripped with toluene, and the organic phases were combined and rotary evaporated to obtain the crude product of ((1S, 3R)-3-hydroxycyclopentyl)carbamic acid tert-butyl ester (HPLC detection spectrum see Figure 5 )spare.

[0040] Example 2: Refining crude product in water-toluene-n-heptane system

[0041] Take 1 part (theoretical amount: 79.7 g) of the crude product of ((1S, 3R)-3-hydroxycyclopentyl)carbamic acid tert-butyl ester prepared in Example 1, add 45 g of toluene, 45 g of n-heptane, and 200 g of water, heat to 50 ° C with stirring, then slowly cool to below 15 ° C, keep warm for 1 hour, filter with suction, and air dry to obtain 94 g of compound 1, with a yield of 81.7%, purity: 100%, EE = 100% (HPLC detection spectrum see Figure 6 ).

[0042] Example 3: Refining crude product in water-toluene system

[0043] Take 1 part (theoretical amount: 79.7 g) of the crude product of ((1S, 3R)-3-hydroxycyclopentyl)carbamic acid tert-butyl ester prepared in Example 1, add 45 g of toluene and 200 g of water, heat to 50°C with stirring, then slowly cool to below 5°C, keep warm for 1 hour, filter with suction, and dry with air to obtain 85 g of compound 1, with a yield of 73.9%, purity: 97.3%, EE=100%.

[0044] Example 4: Refining crude product with water-n-heptane

[0045] Take a portion of the crude product of tert-butyl ((1S, 3R)-3-hydroxycyclopentyl)carbamate of Example 1 (theoretical amount: 79.7 g), add 45 g of n-heptane and 200 g of water, heat to 50°C with stirring, then slowly cool to below 5°C, keep warm for 1 hour, filter with suction, and dry with air to obtain 100.8 g of compound 1, with a yield of 87.6%, purity: 95.7%, and EE=98.2%.

Claims

1. A method for refining a Bitegvir intermediate ((1S, 3R)-3-hydroxycyclopentyl)carbamic acid tert-butyl ester, characterized in that: The crude product of ((1S, 3R)-3-hydroxycyclopentyl)carbamic acid tert-butyl ester is heated and dissolved in a mixed solvent, and then cooled and crystallized, solid-liquid separated, and post-treated to obtain the refined product compound 1 of the intermediate; The mixed solvent is a mixed solvent of at least two of water, toluene and n-heptane.

2. The preparation method according to claim 1, characterized in that: In the mixed solvent, the mass ratio of water, toluene and n-heptane is (0.5-10):(0-2):(0-2).

3. The preparation method according to claim 2, characterized in that: In the mixed solvent, the mass ratio of water to the crude product is (0.5-10):1, the mass ratio of toluene to the crude product is (0-2):1, and the mass ratio of n-heptane to the crude product is (0-2):

1.

4. The preparation method according to claim 1, characterized in that: The mixed solvent is a mixed solvent of water-toluene-n-heptane, water-toluene, and water-n-heptane.

5. The preparation method according to claim 4, characterized in that: In the water-toluene-n-heptane mixed solvent, the mass ratio of water, toluene and n-heptane is 40:9:

9.

6. The preparation method according to claim 4, characterized in that: In the water-toluene or water-n-heptane mixed solvent, the mass ratio of water to toluene or n-heptane is 40:

9.

7. The preparation method according to claim 4, characterized in that: In the mixed solvent, the mass ratio of water to the crude product is 2.5:

1.

8. The preparation method according to claim 1, characterized in that: The temperature of the heating and dissolving is 30-80°C.

9. The preparation method according to claim 1, characterized in that: The temperature of the cooling and crystallization is 0-20°C.

10. A compound 1 obtained by the purification method according to claim 1, characterized in that: Its crystal structure is monoclinic, P21 space group; the unit cell parameters are α=90°, β=93.545(1)°, γ=90°.

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