A new crystalline form of an hiv drug intermediate and methods of making and using the same

Abstract

The application provides a new crystal form of an HIV drug intermediate and a preparation method and application thereof, and particularly relates to a compound isopropyl ether solvate of formula III, and the X-ray powder diffraction spectrum detected by using Cu-K alpha radiation has characteristic peaks at 6.8+ / -0.2, 13.9+ / -0.2 and 14.7+ / -0.2 degrees of 2 theta. Through extensive and in-depth research, the application accidentally finds that the compound isopropyl ether solvate of formula III has unique advantages in purity, stability, impurity removal effect, storage and process feasibility; and the method can simply and effectively remove the difficult-to-remove impurities or palladium residues generated in the preparation of GS6207 or GS-4182, significantly improves the purity of the GS6207 or GS-4182 intermediate, reduces the maximum single impurity content, and improves the efficiency of preparing the GS6207 or GS-4182 product.

Description

Technical Field

[0001] This invention relates to the field of chemical pharmaceuticals, and in particular to a novel crystal form of an HIV drug intermediate, its preparation method, and its uses. Background Technology

[0002] Lenapavir (also known as GS6207) is a human immunodeficiency virus type 1 (HIV-1) capsid inhibitor developed by Gilead for the treatment of HIV-1 infection in adult patients with multidrug-resistant HIV-1 who have received extensive treatment.

[0003] Lenapavir, a new generation of long-acting HIV prevention drugs, received marketing approval in China on December 25, 2024, in both tablet and injectable formulations. This breakthrough marks a significant step forward in the field of HIV prevention. The drug's unique administration method and long-acting properties will significantly improve patient adherence, providing a better solution for HIV prevention.

[0004] GS-4182, another novel HIV capsid inhibitor developed by Gilead, is an oral linapavir prodrug with the potential for long-acting administration and is currently in early development. Its research progress suggests it may play an important role in the future treatment of HIV and hepatitis C virus (HCV), particularly in combination with other long-acting drugs, potentially providing patients with more convenient treatment options. The structures of Lenacapavir and GS-4182 are shown below:

[0005]

[0006] The key intermediate of lenapavir, compound of formula III, is shown below:

[0007]

[0008] The preparation route of compound III is disclosed in patent WO2019161280A1 as shown below:

[0009]

[0010] This method requires the intermediate 2MsOH·n-PrOH, followed by hydrolysis with sodium hydroxide in a MeTHF / water solution to obtain compound III. Specifically, an aqueous sodium hydroxide solution (0.2 M; 2.2 equivalents; 9.2 g) is added to a reactor containing the intermediate 2MsOH·n-PrOH (1.0 g) in MeTHF (8.3 g). The two-phase mixture is stirred for approximately 15 minutes, and the aqueous layer is removed. The organic layer is washed four times with a 2.0 wt% aqueous sodium chloride solution (9.8 g) and concentrated to obtain compound III.

[0011] Regarding the study of the solid form of compound III, the journal article Organic Process Research & Development (2024), 28(8), 3382-3395 reported that under the conditions of isopropyl acetate and methyl tert-butyl ether, the slow addition of n-heptane yielded an amorphous compound III with a purity of only 90.2% and a palladium residue of 392 ppm. The reaction formula is shown below.

[0012]

[0013] Its purification is very difficult and there is excessive palladium residue, resulting in low yield, low purity, high cost and low economic efficiency of GS6207, making it difficult to industrialize and thus causing the low popularity of GS6207 and GS-4182.

[0014] Therefore, there is an urgent need to provide a simple purification method during the preparation of GS6207. Summary of the Invention

[0015] In view of the above technical background, the present invention provides a new crystal form of HIV drug intermediate, its preparation method and uses.

[0016] To achieve the above technical objectives, the present invention adopts the following technical solution:

[0017] The first aspect of this invention provides an isopropyl ether solvate of a compound of formula III, the structure of which is shown below:

[0018]

[0019] A second aspect of the present invention provides an isopropyl ether solvate of compound of formula III, the structure of which is shown below: the X-ray powder diffraction pattern detected by Cu-Kα radiation shows characteristic peaks of 2θ at 6.8±0.2°, 13.9±0.2°, and 14.7±0.2°.

[0020] As a further improvement of the present invention, the isopropyl ether solvate of the aforementioned Formula III compound exhibits characteristic peaks at 6.8±0.2°, 13.9±0.2°, and 14.7±0.2° in its X-ray powder diffraction pattern detected by Cu-Kα radiation, and also possesses one or more of the following characteristic peaks: 6.1±0.2°, 8.6±0.2°, 9.5±0.2°, 10.2±0.2°, 10.4±0.2°, 12.5±0.2°, 13.1±0.2°. 14.5±0.2°, 15.2±0.2°, 16.5±0.2°, 17.2±0.2°, 18.2±0.2°, 18.9±0.2°, 19.5±0.2°, 20.2±0.2°, 20.6±0.2°, 20.8±0.2°, 22.1±0.2°, 23.2±0.2°, 23.8±0.2°, 24.3±0.2°, 25.3±0.2°, 30.7±0.2°, 33.7±0.2°.

[0021] Furthermore, the isopropyl ether solvate of the compound of formula III and... Figure 5 The XRPD diagrams shown are basically the same.

[0022] Furthermore, the residual solvent detected by the gas phase of the isopropyl ether solvate of Formula III of the present invention contains 33,000 to 45,000 ppm of isopropyl ether.

[0023] Furthermore, the differential scanning calorimetry (DSC) of the isopropyl ether solvate of Formula III compound has a characteristic endothermic peak at 111.1 ± 6 °C.

[0024] Furthermore, the differential scanning calorimetry (DSC) of the isopropyl ether solvate of compound III is compared with... Figure 6 The diagrams shown are basically the same.

[0025] Furthermore, the thermogravimetric analysis (TGA) of the isopropyl ether solvate of the formula III compound showed a weight loss of 3.0–4.0%, for example 3.6%, before reaching 140°C.

[0026] Furthermore, the thermogravimetric analysis (TGA) of the isopropyl ether solvate of compound III was compared with... Figure 7 Basically the same.

[0027] Furthermore, the NMR analysis of the polymorph and Figure 8 The diagrams shown are basically the same.

[0028] A third aspect of the present invention provides a method for preparing an isopropyl ether solvate of compound formula III, the method comprising the steps of:

[0029] Method 1:

[0030] Step (1) At a suitable temperature, the compound shown in Formula III is mixed with isopropyl ether or a mixed solvent containing isopropyl ether to obtain a suspension.

[0031] Step (2) involves filtering and separating the suspension, and drying it to obtain the isopropyl ether solvate of compound III.

[0032] Method 2:

[0033] Step (1) At a suitable temperature, the compound of formula III is dissolved in a nitrile solvent, and then isopropyl ether is added and stirred to obtain a suspension;

[0034] Step (2) The suspension is filtered and separated, and the resulting filter cake is dried to obtain the isopropyl ether solvate of Formula III.

[0035] Furthermore, the method one containing the isopropyl ether mixed solvent is obtained by mixing isopropyl ether with a nitrile solvent; preferably, the nitrile is acetonitrile.

[0036] Further, in step (1) of method one or method two, the weight-to-volume ratio of compound III to isopropyl ether is 1:(5-15) g / mL; preferably 1:(10-15); more preferably 1:10.

[0037] Further, in step (1) of method one or method two, the weight-to-volume ratio of compound III to acetonitrile (g / mL) is 1:(0-2); preferably 1:(0.5-1); more preferably 1:0.5.

[0038] Furthermore, the suitable temperature in step (1) of method one or method two is selected from 10 to 30°C, preferably 15 to 25°C.

[0039] Furthermore, step (1) of method one or method two also includes a stirring operation, in which the compound shown in formula III and isopropyl ether or a suspension containing isopropyl ether are stirred to obtain a suspension.

[0040] Furthermore, the stirring time in step (1) of method one or method two is 8 to 15 hours, preferably 10 to 12 hours.

[0041] Furthermore, the stirring temperature in step (1) of method one or method two is room temperature, preferably 15 to 25°C.

[0042] Furthermore, the drying temperature in step (2) of method one or method two is 40-75°C, preferably 55-65°C, and more preferably 60-65°C.

[0043] Furthermore, the drying time in step (2) of method one or method two is 8 to 15 hours, preferably 10 to 12 hours.

[0044] The fourth aspect of the present invention provides the use of a compound of formula III, an isopropyl ether solvate, in the preparation of HIV drugs, comprising the preparation method of the compound of formula III, an isopropyl ether solvate, as described in the first and second aspects above or the method of preparing the compound of formula III, an isopropyl ether solvate, as described in the third aspect; preferably, the present invention provides the use of a compound of formula III, an isopropyl ether solvate, in the preparation of GS6207 or GS-4182.

[0045] The beneficial technical effects of the present invention are as follows:

[0046] I. Through extensive and in-depth research, this invention unexpectedly discovered that isopropyl ether solvates of Formula III have unique advantages in terms of purity, stability, impurity removal effect, storage, and process feasibility.

[0047] 1. When isopropyl ether is used as a single solvent, the inventors have observed superior impurity removal capabilities, effectively removing most impurities. In contrast, other solvents with slightly higher polarity (such as methyl ether, ethanol, isopropanol, ethyl acetate, etc.) cannot precipitate solids due to the high solubility of free bases within them. This invention, by controlling the production of a novel crystalline form of the isopropyl ether solvate of Formula III, not only solves the problem of difficult discharge of the original amorphous material in existing technologies, but also addresses the issue that the original amorphous material, in the later stages of concentration, slowly foams from a viscous oily state to a foamed solid as the encapsulating solvent evaporates. As an intermediate, this state of material cannot be discharged normally. The novel crystalline form of the isopropyl ether solvate of Formula III obtained by this invention allows for normal discharge, centrifugation, and drying, and further preparation of lenapvir and its salts meets ICH quality requirements.

[0048] This invention enhances impurity removal by adding an appropriate amount of acetonitrile as a benign solvent, particularly for stubborn impurities that cannot be removed by isopropyl ether alone. The synergistic effect of this mixed solvent system significantly improves the purity of the final product, meeting the requirements for high-purity pharmaceutical raw materials or intermediates.

[0049] 2. Crystal form stability—The crystal form formed by the isopropyl ether solvate exhibits good physical and chemical stability and is not prone to crystal transformation or degradation during storage and subsequent processing. This crystal form demonstrates high stability under normal conditions (such as room temperature and humidity), making it suitable for long-term storage and transportation.

[0050] 3. The preparation process of isopropyl ether solvates is simple, with mild operating conditions (e.g., room temperature or low temperature), making it suitable for large-scale production. By optimizing the solvent ratio (e.g., mixing isopropyl ether with acetonitrile), efficient crystallization and impurity removal can be achieved, reducing subsequent purification steps and lowering production costs. Compared to other solvent systems (e.g., DMF-water, acetone-water, ethanol-water, etc.), the isopropyl ether system can stably precipitate solids, avoiding dissolution or oiling problems caused by excessive solvent polarity. The process has good feasibility and is conducive to scale-up production.

[0051] 4. Isopropyl ether, as a low-polarity solvent, is relatively inexpensive and easy to recycle and reuse, reducing production costs. Compared with some highly toxic or high-boiling-point solvents (such as DMF), isopropyl ether has less toxicity and environmental impact, making it an economical and environmentally friendly solvent choice that meets the requirements of green chemistry.

[0052] 5. Advantages compared to other solvent systems: n-Heptane and n-Butyl Ether: While they can precipitate solids, their impurity removal effect is poor, failing to meet high purity requirements. Polar solvents (such as ethanol, isopropanol, ethyl acetate, etc.): Due to the high solubility of free alkali in these systems, it is difficult to precipitate solids, resulting in ineffective product separation. Mixed solvent systems (such as DMF-water, acetone-water, ethanol-water, etc.): Normal solids cannot be obtained, leading to poor process feasibility. Isopropyl ether-acetonitrile mixed system: Shows significant advantages in impurity removal, crystal stability, and process feasibility, making it the superior choice.

[0053] 6. Compatibility with downstream processes: Isopropyl ether solvates can be directly used in subsequent reactions or formulation processes without additional crystallization or purification steps, simplifying the process flow. This crystal form exhibits good solubility and reactivity in subsequent processing, making it suitable for various drug synthesis routes.

[0054] In summary, isopropyl ether solvates and their crystal forms exhibit significant advantages in terms of impurity removal efficiency, crystal stability, process feasibility, and economy. Further optimization of the solvent system by adding acetonitrile can significantly improve impurity removal efficiency, yielding high-purity free alkaline solvates. This is an efficient, environmentally friendly process option suitable for large-scale production.

[0055] II. This invention provides a simple and effective method for removing difficult-to-remove impurities or palladium residues generated during the preparation of GS6207 or GS-4182, significantly improving the purity of GS6207 or GS-4182 intermediates, reducing the maximum single impurity content, and improving the efficiency of preparing GS6207 or GS-4182 products. Attached Figure Description

[0056] The accompanying drawings, which are provided to further illustrate the invention and constitute a part of this invention, are illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention.

[0057] Figure 1 XRPD spectrum of compound III;

[0058] Figure 2 DSC spectrum of compound III;

[0059] Figure 3TGA spectra of compound III;

[0060] Figure 4 HPLC chromatogram of compound III;

[0061] Figure 5 XRPD spectrum of the isopropyl ether solvate of compound III;

[0062] Figure 6 DSC spectrum of the isopropyl ether solvate of compound III;

[0063] Figure 7 TGA spectrum of the isopropyl ether solvate of compound III;

[0064] Figure 8 HNMR spectrum of the isopropyl ether solvate of compound III;

[0065] Figure 9 HPLC chromatogram of isopropyl ether solvate of compound III. Detailed Implementation

[0066] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. Obviously, the described embodiments are merely some embodiments of this invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this invention are within the scope of protection of this invention.

[0067] Unless otherwise specified, the reagents described are used directly without purification. All solvents were purchased from commercial suppliers and are ready for use without treatment.

[0068] Methods for determining X-ray powder diffraction of crystals are known in the art. For example, a D8 Advance X-ray powder diffractometer was used with the following parameters: X-ray reflection parameters: Cu, Kα; tube voltage: 40 kV; tube current: 40 mA; slits: #2 scattering slit: 1°, #3 anti-scattering slit: 1°, #4 receiving slit: 0.3 mm; scanning mode: stepping; step angle: 0.02°; sampling time: 0.1 s; scanning range: from 3.0 to 40.0 degrees.

[0069] DSC measurement methods are known in the art. For example, a scanning calorimetry (DSC) plot can be acquired on a DSC250 with the following method parameters: scan rate: 10 °C / min, heating rate from 10 °C to 300 °C; protective gas: nitrogen.

[0070] Thermogravimetric analysis (TGA) methods are known in the art. For example, the thermogravimetric analysis (TGA) chromatogram described in this invention was acquired using Discovery 55, with the following method parameters: scan rate: 10 °C / min, heating rate from room temperature to 300 °C; protective gas: nitrogen.

[0071] Example 1: Preparation of Compound III

[0072]

[0073] 1400g of compound IV, 874g of compound V, 582g of KHCO3, 11.2L of 2-MeTHF, and 2.8L of H2O were added to a 20L reactor. The reactor was purged with nitrogen for protection. 6.9g of palladium chloride and 20.82g of diphenylcyclohexylphosphine were added. The reactor was heated to 70℃ and reacted for 8-12 hours. The reaction mixture was then cooled to 20-30℃, and 2.8L of water was added. After stirring for 10 minutes, the mixture was separated. The organic phase was washed with 10% sodium bisulfate solution. The organic phase was concentrated, dissolved in 5.6L of ethanol, and transferred to a 20L reactor. 429g of methanesulfonic acid was prepared with 12.6L of n-butyl ether solution and added dropwise to the reactor. The mixture was stirred at 20-30℃ for 1 hour and then filtered. The obtained solid was dissolved in 14 L of 2-MeTHF, and the pH was adjusted to 8-9 with 20% sodium carbonate solution. After stirring for 10 min, the mixture was separated. The organic phase was washed once with 1.4 L of water, and 1400 g of activated carbon was added and stirred at room temperature for 1 h. The mixture was then filtered. The filtrate was concentrated until no liquid flowed out to obtain the crude product of Formula III (yellowish-brown solid), whose XRPD is as follows: Figure 1 DSC, for example Figure 2 TGA, for example Figure 3 HPLC, such as Figure 4 (Purity 97.2%).

[0074] Example 2:

[0075] At room temperature, 1400 g of crude compound III was dissolved in 700 mL of acetonitrile and transferred to a reaction vessel. 14 L of isopropyl ether was added and the mixture was stirred for 12 h. The mixture was filtered, and the filter cake was dried at 60 °C for 12 h to obtain an off-white solid with a yield of 84%. Its XRPD was as follows: Figure 5 DSC, for example Figure 6 TGA, for example Figure 7 HNMR such Figure 8 The HNMR spectrum of the isopropyl ether solvate of compound III showed characteristic chemical shift peaks of isopropyl ether at 3.59 ppm and 1.03 ppm, with hydrogen numbers of 0.61 and 3.45, respectively. HPLC data were as follows... Figure 9 (Purity 99.8%).

[0076] Example 3:

[0077] Following a method similar to Example 2, a single solvent was added, and the impurity removal effect of different solvents was examined.

[0078] At room temperature, add 10 mL of n-heptane or isopropyl ether and 1 g of crude compound of formula III, and stir for 12 h. Filter, and dry the filter cake at 60 °C for 12 h to obtain an off-white solid. The purity test results are shown in Table 1.

[0079] Table 1

[0080] Purity test results Crude compound of formula III before purification Purity 97.5%, maximum single impurity 1.02% The product after purification with n-heptane Purity 98%, maximum single impurity 1% Product purified with n-butyl ether Purity 98.4%, maximum single impurity 0.95% Product purified with isopropyl ether Purity 98.8%, maximum single impurity 0.42%

[0081] The crude compound of formula III before purification was prepared according to the method in Example 1. According to the purity test results, isopropyl ether has a significant purification effect, and isopropyl ether is preferred.

[0082] Example 4:

[0083] Following a similar method to Example 3 above, 50 mL of isopropyl ether was added to a reaction flask at room temperature, followed by 5 g of crude compound of formula III. The mixture was stirred for 12 h. After filtration, the filter cake was dried at 60 °C for 12 h to obtain an off-white solid with a purity of 98.68% and a yield of 93%.

[0084] Example 5:

[0085] At room temperature, 50 mL of isopropyl ether and 2.5 mL of acetonitrile were added to a reaction flask, followed by 5 g of crude compound of formula III. The mixture was stirred for 12 h. After filtration, the filter cake was dried at 60 °C for 12 h to give an off-white solid with a purity of 99.81% and a yield of 84%.

[0086] Example 6:

[0087] At room temperature, 50 mL of isopropyl ether and 5 mL of acetonitrile were added to a reaction flask, followed by 5 g of crude compound of formula III. The mixture was stirred for 12 h. After filtration, the filter cake was dried at 60 °C for 12 h to give an off-white solid with a purity of 99.84% and a yield of 72%.

[0088] Table 2: Statistical table of purification results in Examples 4-6:

[0089]

[0090] In Examples 4-6, the crude compounds of Formula III were prepared using a similar method to that in Example 1 and were derived from different batches. Based on the removal of impurities and the yield, the system of Example 5 was preferred for purification.

[0091] Example 7:

[0092] At room temperature, 1 mL of acetone and 1 g of crude compound III were added and stirred until dissolved. Then, 1 mL of water was added dropwise. An oily substance precipitated in the system, and the product could not be separated normally.

[0093] Example 8:

[0094] At room temperature, 1 mL of DMF and 1 g of crude compound III were added and stirred until dissolved. Then, 1 mL of water was added dropwise. An oily substance precipitated out of the system and adhered severely to the walls, making it impossible to separate the product normally.

[0095] Example 9:

[0096] At room temperature, 1 mL of ethanol and 1 g of crude compound III were added and stirred until dissolved. Then, 1 mL of water was added dropwise. An oily substance precipitated in the system, and the product could not be separated normally.

[0097] The above embodiments are only for illustrating the technical concept and features of the present invention and should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be included within the scope of protection of the present invention.

Claims

1. An isopropyl ether solvate of a compound of formula III, the structure of which is shown below:

2. The isopropyl ether solvate of compound III according to claim 1, characterized in that: The isopropyl ether solvate of compound III, in the X-ray powder diffraction pattern detected using Cu-Kα radiation, showed values ​​at 2θ values ​​of 6.8±0.2° and 13.9±0.2°. A characteristic peak is present at 14.7±0.2°.

3. The isopropyl ether solvate of compound III according to claim 2, characterized in that: The isopropyl ether solvate of compound III, in the X-ray powder diffraction pattern detected using Cu-Kα radiation, showed values ​​at 2θ values ​​of 6.8±0.2° and 13.9±0.2°. It has a characteristic peak at 14.7±0.2° and one or more of the following characteristic peaks: 6.1±0.2°, 8.6±0.2°, 9.5±0.2°. 10.2±0.2°,10.4±0.2°,12.5±0.2°,13.1±0.2°,14.5±0.2°,15.2±0.2°,16.5±0.2°,17.2±0.2°, 18.2±0.2°,18.9±0.2°,19.5±0.2°,20.2±0.2°,20.6±0.2°,20.8±0.2°,22.1±0.2°,23.2±0.2°, 23.8±0.2°,24.3±0.2°,25.3±0.2°,30.7±0.2°,33.7±0.2°。 4. The isopropyl ether solvate of compound III according to claim 3, characterized in that: The isopropyl ether solvate of compound III is basically consistent with the XRPD plot shown in Figure 5.

5. The isopropyl ether solvate of compound III according to claim 4, characterized in that: The residual solvent in the gas phase detection of the isopropyl ether solvate of the compound of formula III contains 33,000 to 45,000 ppm of isopropyl ether.

6. The isopropyl ether solvate of compound III according to any one of claims 1 to 5, characterized in that: The isopropyl ether solvate of Formula III compound satisfies one or more of the following conditions: 1) The differential scanning calorimetry (DSC) of the isopropyl ether solvate of the compound of formula III has a characteristic endothermic peak at 111.1 ± 6 °C; 2) The differential scanning calorimetry (DSC) of the isopropyl ether solvate of compound III is basically consistent with the spectrum shown in Figure 6; 3) Thermogravimetric analysis (TGA) of the isopropyl ether solvate of compound III showed a weight loss of 3.0–4.0% before reaching 140 °C; 4) The thermogravimetric analysis (TGA) of the isopropyl ether solvate of compound III is basically consistent with that in Figure 7; 5) The NMR analysis of the polymorph was basically consistent with the spectrum shown in Figure 8.

7. A method for preparing an isopropyl ether solvate of a compound of formula III, characterized in that: The method includes the following steps: Method 1: Step (1) At a suitable temperature, the compound shown in Formula III is mixed with isopropyl ether or a mixed solvent containing isopropyl ether to obtain a suspension. Step (2) involves filtering, separating, and drying the suspension to obtain the isopropyl ether solvate of compound III; Or method two: Step (1) At a suitable temperature, the compound of formula III is dissolved in a nitrile solvent, and then isopropyl ether is added and stirred to obtain a suspension; Step (2) The suspension is filtered and separated, and the resulting filter cake is dried to obtain the isopropyl ether solvate of Formula III.

8. The preparation method according to claim 7, characterized in that: The isopropyl ether mixed solvent is obtained by mixing isopropyl ether with a nitrile solvent; preferably, the nitrile is acetonitrile.

9. The preparation method according to claim 8, characterized in that: The preparation method satisfies one or more of the following conditions: 1) In step (1), the weight-to-volume ratio of compound III to isopropyl ether is 1:(5-15) g / mL; preferably 1: (10-15); more preferably 1:10; 2) In step (1), the weight-to-volume ratio of compound III to acetonitrile in g / mL is 1:(0-2); preferably 1:(0.5-1); A more preferred ratio is 1:0.5; 3) The suitable temperature in step (1) is selected from 10 to 30°C, preferably 15 to 25°C; 4) Step (1) further includes a stirring operation, in which the compound shown in Formula III and isopropyl ether or containing isopropyl ether are stirred to obtain a suspension; 5) The stirring time in step (1) is 8 to 15 hours, preferably 10 to 12 hours; 6) The stirring temperature in step (1) is room temperature, preferably 15-25°C; 7) The drying temperature in step (2) is 40-75℃, preferably 55-65℃, and more preferably 60-65℃; 8) The drying time in step (2) is 8 to 15 hours, preferably 10 to 12 hours.

10. The use of an isopropyl ether solvate of a compound of formula III in the preparation of HIV drugs, characterized in that: This includes methods for preparing isopropyl ether solvates of Formula III compounds according to any one of claims 1 to 5 or isopropyl ether solvates of Formula III compounds according to any one of claims 6 to 9; Preferably, the use of the isopropyl ether solvate of Formula III in the preparation of GS6207 or GS-4182.

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