Intermediate compound of alplsutentan, alplsutentan and preparation method of alplsutentan

Abstract

The invention discloses an intermediate compound of alpoxivan, alpoxivan and a preparation method of alpoxivan, and relates to the technical field of organic synthesis, the structural general formula of the intermediate compound is # imgabs0 #, X is a leaving group and comprises any one of halogen, OMs, Ots or an ethylene glycol substituent group; r is F or aminosulfonamide. The preparation method comprises the following steps: performing a fluorination reaction on a compound A to obtain a compound I; reacting the compound I with aminosulfonamide to obtain a compound II; substituting the compound II with ethylene glycol to obtain a compound III; and carrying out a reaction on the compound III and 5-bromo-2-chloropyrimidine to obtain the alpoxivan. The preparation method has the characteristics of few reaction steps, simple process operation, controllability, safety and high efficiency, can effectively improve the purity and the total yield of alpoxivan, and is suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to an intermediate compound of aprexitentan, aprexitentan and a preparation method thereof. Background Art

[0002] Aprocitentan is a novel oral dual endothelin receptor antagonist that effectively inhibits the binding of endothelin-1 to endothelin A and endothelin B receptors. Aprocitentan has a low potential for drug interactions and a mechanism of action designed to address the pathophysiology of difficult-to-control hypertension. Aprocitentan is a novel oral dual endothelin receptor antagonist developed by Idorsia that effectively inhibits the binding of ET-1 to ETA and ETB receptors. It is an active metabolite of macitentan and has a longer half-life than macitentan. On March 20, 2024, Idorsia announced that the U.S. FDA has approved TRYVIO TM (Aprocitentan) is used in combination with other antihypertensive drugs to treat adult hypertension in order to lower the blood pressure levels of adult patients whose blood pressure is not effectively controlled. It is the first antihypertensive drug with a new mechanism in 30 years.

[0003] The chemical name of Aprexitentan is: N-[5-(4-bromophenyl)-6-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-4-pyrimidinyl]aminosulfonylamide, with a molecular weight of 546.19 and a molecular formula of C 16 H 14 Br2N6O4S. Its structural formula is as follows:

[0004]

[0005] The last step of one of the possible preparation routes described in WO 02 / 053557 (referred to as "Possibility A" and "Possibility B") can be summarized as shown in Scheme Al which follows.

[0006]

[0007] In Scheme A1, G1 represents a reactive residue, and is preferably a chlorine atom.

[0008] The preparation of macitentan according to "possibility B" of WO 02 / 053557 has been further described in Bolli et al., J. Med. Chem. (2012), 55, pp. 7849-7861. Thus: to a solution containing a large excess of ethylene glycol in dimethoxyethane is added KOtBu and to this is added a compound of formula I1, wherein G1 is C l(See Scheme Al above); heating at 100°C for 70h, after work-up involving extraction and purification by column chromatography, the compound of formula I2 was obtained in 86% yield; and to a suspension of NaH in THF was added the compound of formula I2, the mixture was stirred and diluted with DMF, followed by the addition of 5-bromo-2-chloropyrimidine; after heating at 60°C and work-up involving extraction and crystallization steps, macitentan was obtained in 88% yield.

[0009] However, the above-mentioned method for producing macitentan is not suitable for producing macitentan with sufficient purity unless a number of purification steps are carried out to remove impurities (including ethylene glycol) from the compound of formula I2 before carrying out the step corresponding to "possibility B" of WO 02 / 053557. Therefore, it should be mentioned that ethylene glycol is in fact hazardous and difficult to remove by distillation due to its high boiling point.

[0010] Furthermore, compounds of formula I wherein R is H have been disclosed in WO 2009 / 024906. The final step of a possible preparation route described in WO 2009 / 024906 can be summarized as shown in the following Scheme A2.

[0011]

[0012] In Scheme A2, G2 represents a reactive group such as a halogen atom (preferably a chlorine atom), and PG represents a protecting group such as a benzyl group or a 4-methoxy- or 2,4-dimethoxybenzyl group. According to the route disclosed in WO 2009 / 024906 (see Scheme A2), the compound of formula I0 can be reacted with ethylene glycol in the presence of a base, in the presence or absence of an additional solvent and preferably at elevated temperature. The resulting intermediate can then be reacted with 5-bromo-2-chloropyrimidine or an equivalent of a reactive entity in a solvent such as THF, DMF, dioxane, etc. or a mixture thereof in the presence of a strong base. The protecting group PG can then be removed by standard methods to produce a compound of formula I in which R is H. The manufacturing route disclosed in WO 2009 / 024906, which can also be attempted with PG=Fmoc or PG=Boc, also has the disadvantage of using a large amount of ethylene glycol in one of its later stages.

[0013] Both of the above solutions use a large amount of ethylene glycol in the final stage. Ethylene glycol has a high boiling point and is difficult to remove by distillation, which increases impurities in the final product and increases the difficulty and cost of industrialization. Summary of the invention

[0014] In view of the problems existing in the background technology, the object of the present invention is to provide an intermediate compound of aprexitentan, aprexitentan and a preparation method thereof, which have the characteristics of few reaction steps, simple process operation, controllable, safe and efficient, and can effectively improve the purity and total yield of aprexitentan, and are suitable for industrial scale-up production.

[0015] The present invention is achieved through the following technical solutions:

[0016] In the first aspect, the present application provides an intermediate compound for preparing aprexitentan, the general structural formula of which is:

[0017]

[0018] Wherein, X is a leaving group, including any one of halogen, OMs, Ots or ethylene glycol substituent groups; and R is F or aminosulfonamide.

[0019] In a specific embodiment, the structural formula is as follows Ⅰ, Ⅱ or Ⅲ:

[0020]

[0021] Wherein, in structural formula I, R is F; X is a leaving group, including any one of halogen, OMs, OTs or ethylene glycol substituent groups;

[0022] In the structural formula II, R is aminosulfonamide; X is a leaving group, including any one of halogen, OMs, OTs or ethylene glycol substituent groups;

[0023] In the structural formula III, R is aminosulfonamide and X is an ethylene glycol substituent group.

[0024] In a second aspect, the present application provides a method for preparing an intermediate compound of aprexitentan, comprising the following steps:

[0025] Step 1: Fluorination reaction of compound A to obtain compound I;

[0026] Step 2: Compound Ⅰ is reacted with aminosulfonamide to obtain compound Ⅱ;

[0027] Step 3: Compound II is substituted with ethylene glycol to obtain compound III;

[0028] Wherein, the structural formula of compound A is: X is a leaving group, which is selected from any one of halogen, OMs and OTs.

[0029] In a specific embodiment, the fluorination reaction of compound A in step 1 is carried out under the action of a fluorination agent; the reaction temperature is 55° C. to 105° C., preferably 75° C. to 85° C. The reaction time is 1 h to 10 h, preferably 5 h.

[0030] In a specific embodiment, the organic solvent used for the fluorination reaction of compound A in step 1 includes any one of tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; the fluorination reagent includes a mixed reagent of any one or more of potassium fluoride, cesium fluoride, and tetrabutylammonium fluoride.

[0031] In a specific embodiment, in step 2, compound I reacts with aminosulfonamide under base catalysis to obtain compound II; the molar ratio of compound I to base is 1:(2-5), preferably 1:3; the molar ratio of compound I to aminosulfonamide is 1:(1-5), preferably 1:3; the mass ratio of compound I in the organic solution is 1:(5-50), preferably 1:30.

[0032] In a specific embodiment, the organic solution of compound I in step 2 includes any one of tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide, and the preferred organic solution is dimethyl sulfoxide; the alkaline reagent includes any one of potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium hydride.

[0033] In a specific embodiment, in step 3, compound II and ethylene glycol are substituted under base catalysis to obtain compound III; the reaction temperature is 55°C to 105°C, and the reaction time is 1h to 20h; the molar ratio of the compound II to the base is 1:(2-5), preferably 1:3; the mass ratio of the compound II in the organic solvent is 1:(5-50), preferably 1:30.

[0034] In a specific embodiment, in step 3, compound II and ethylene glycol are dissolved in an organic solvent, and the organic solvent includes any one of tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide, preferably dimethyl sulfoxide; the alkaline reagent includes any one of potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium hydride, preferably potassium tert-butoxide.

[0035] In a third aspect, the present application provides a method for preparing aprexitentan, comprising the following steps:

[0036] Step 1: Fluorination reaction of compound A to obtain compound I;

[0037] Step 2: Compound Ⅰ is reacted with aminosulfonamide to obtain compound Ⅱ;

[0038] Step 3: Compound II is substituted with ethylene glycol to obtain compound III;

[0039] Step 4: Compound III is reacted with 5-bromo-2-chloropyrimidine to obtain aprexitentan;

[0040] Wherein, the structural formula of compound A is: X is a leaving group, selected from any one of halogen, OMs, and OTs, preferably halogen, and most preferably chlorine.

[0041] The preparation method of aprexitentan of the present invention has the effect of avoiding the introduction of a large amount of ethylene glycol in the final stage, avoiding ethylene glycol-derived impurities in the final stage, and reducing the introduction of disubstituted impurities in the final step, thereby reducing the difficulty of purification, and reducing risks and costs.

[0042] In a specific embodiment, in step 4, compound III is reacted with 5-bromo-2-chloropyrimidine in the presence of an alkaline reagent to obtain aprexitentan at a reaction temperature of 30°C to 100°C. The molar ratio of the compound III to the base is 1:(2-5), preferably 1:3; the mass ratio of the compound III in the organic solvent is 1:(5-50), preferably 1:30.

[0043] In a specific embodiment, in step 4, compound III and 5-bromo-2-chloropyrimidine are dissolved in an organic solvent, and the organic solvent includes any one of tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; the alkaline reagent includes any one of potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium hydride.

[0044] In a fourth aspect, the present application provides aprexitentan, which is prepared using the above-mentioned intermediate compound or an intermediate compound prepared by its preparation method.

[0045] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0046] (1) The present invention avoids the introduction of a large amount of ethylene glycol in the final stage, greatly reduces the amount of organic solvent used, is beneficial to the protection of the environment and human health, and also reduces the difficulty of removing ethylene glycol.

[0047] (2) No substitution impurities in the final stage of the present invention There is less production of impurities and purification is simpler.

[0048] (3) The route for preparing apremilastan in the present invention has high selectivity, low process cost, high production efficiency and simple process flow. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and should not be regarded as limiting the scope. For those of ordinary skill in the art, other relevant drawings can be obtained based on these drawings without creative work. In the drawings:

[0050] Figure 1 is the HPLC spectrum of aprexitentan prepared in Example 1 of the present invention;

[0051] Figure 2 is an integral graph of the LC-MS spectrum of aprexitentan prepared in Example 1 of the present invention;

[0052] Figure 3 is the m / z graph in the LC-MS spectrum of aprexitentan prepared in Example 1 of the present invention;

[0053] Figure 4 is the NMR spectrum of aprexitentan prepared in Example 1 of the present invention;

[0054] Figure 5 is the HPLC spectrum of Aprexitentan prepared in Comparative Example 1;

[0055] Figure 6 is an integral graph of the LC-MS spectrum of aprexitentan prepared in Comparative Example 1;

[0056] Figure 7 This is the m / z graph of the LC-MS spectrum of Aprexitentan prepared in Comparative Example 1. DETAILED DESCRIPTION

[0057] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with embodiments. The illustrative embodiments of the present invention and their description are only used to explain the present invention and are not intended to limit the present invention.

[0058] In the following description, a large number of specific details are set forth in order to provide a thorough understanding of the present invention. However, it is apparent to one of ordinary skill in the art that these specific details need not be employed to practice the present invention. In other embodiments, in order to avoid confusing the present invention, well-known materials or methods are not specifically described.

[0059] Throughout the specification, references to "one embodiment," "an embodiment," "an example," or "an example" mean that a particular feature, structure, or characteristic described in conjunction with the embodiment or example is included in at least one embodiment of the present invention. Therefore, the phrases "one embodiment," "an embodiment," "an example," or "an example" that appear in various places throughout the specification do not necessarily all refer to the same embodiment or example. In addition, particular features, structures, or characteristics may be combined in one or more embodiments or examples in any appropriate combination and / or sub-combination. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items. In addition, those skilled in the art will be able to combine and combine different embodiments or examples described in this specification and features of different embodiments or examples, without contradicting each other.

[0060] The "range" disclosed in the present application is defined in the form of a lower limit and an upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of the particular range. The range defined in this way can be inclusive or exclusive of the end values, and can be arbitrarily combined, that is, any lower limit can be combined with any upper limit to form a range. For example, if a range of 60 to 120 and 80 to 110 is listed for a particular parameter, it is understood that a range of 60 to 110 and 80 to 120 is also expected. In addition, if the minimum range values ​​1 and 2 are listed, and if the maximum range values ​​3, 4 and 5 are listed, the following ranges can all be expected: 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4 and 2 to 5. In the present application, unless otherwise specified, the numerical range "a to b" represents an abbreviation of any real number combination between a and b, where a and b are both real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" are listed in this document, and "0-5" is just an abbreviation of these numerical combinations. In addition, when a parameter is expressed as an integer ≥ 2, it is equivalent to disclosing that the parameter is, for example, an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0061] If there is no special explanation, all steps of the present application can be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), which means that the method may include steps (a) and (b) performed sequentially, or may include steps (b) and (a) performed sequentially. For example, the method may further include step (c), which means that step (c) may be added to the method in any order. For example, the method may include steps (a), (b) and (c), or may include steps (a), (c) and (b), or may include steps (c), (a) and (b), etc.

[0062] Example 1

[0063] This embodiment provides a method for preparing aprexitentan, which is carried out according to the following steps:

[0064] S1. Preparation of [5-(4-bromophenyl)-6-fluoropyrimidin-4-yl]azanesulfonamide

[0065] Weigh 10.05g of 5-(4-bromophenyl)-pyrimidine-4,6-dichloro (1.0eq) and 12.54g of sodium fluoride (2.5eq) into a 250ml single-mouth bottle, add 100ml of dimethyl sulfoxide, heat and stir at 50℃ for reaction, react for 2h, add 10.26g of anhydrous potassium carbonate (2.0eq) and 14.27g of aminosulfonamide (4.0eq), heat to 70℃, heat and stir for reaction, react for 5h, cool to 30℃, add 500ml of 2N hydrochloric acid aqueous solution for quenching, extract with ethyl acetate, and concentrate the organic phase to dryness. The concentrate weighs 10.56g, with a yield of 92%. LC-MS: m / z=349.1 (M+H).

[0066] The reaction formula is:

[0067] S2. Preparation of [5-(4-bromophenyl)-6-[(2-hydroxyethyl)oxy]pyrimidin-4-yl]azanesulfonamide

[0068] Weigh 6.76g potassium tert-butoxide (2eq, 60.5mmol) and add it to a mixed solution of 2.15g ethylene glycol (1.2eq, 36.29mmol) and 30ml DMSO, stir at 70℃ for 10min, take 10.5g (1.0eq, 30.25mmol) of [5-(4-bromophenyl)-6-fluoropyrimidin-4-yl] azanesulfonamide and dissolve it in 50ml DMSO solution, then slowly drop it into the reaction solution, stir at 70℃ for 3 hours, pour the reaction solution into 300ml 2N hydrochloric acid aqueous solution, extract with 150ml ethyl acetate and concentrate to obtain 10.23g product; yield: 87%. LC-MS: m / z=391.1 (M+H).

[0069] The reaction formula is:

[0070] S3. Preparation of Aprexitentan

[0071] Weigh 2.38g of sodium hydrogen and slowly add it to 20ml of THF. Weigh 10g of [5-(4-bromophenyl)-6-[(2-hydroxyethyl)oxy]pyrimidin-4-yl]azanesulfonamide and dissolve it in 20ml of THF. Slowly drop it into the THF solution of sodium hydrogen, stir at 20°C for 30 minutes, add 9.91g of 5-bromo-2-chloropyrimidine dissolved in tetrahydrofuran solution, stir at an external temperature of 40°C for 4h after the addition, pour the reaction solution into 200ml of 2N hydrochloric acid aqueous solution, extract with 60ml of ethyl acetate and concentrate, crystallize the concentrate with DCM, and filter to obtain 12.94g of product; yield: 92%. HPLC spectrum is shown in Figure 1 ; LC-MS: t = 17.59min, [M + H] ' = 544.70, see the spectrum Figure 2 and 3 ; l H-NMR (300MHz,CDCl3)δ8.46-8.47(d,3H),7.50-7.53(m,2H),7.12-7.16(m,2H),5.76(s,2H),5.30(s,1H),4.70-4.73(dd,2H),4.59-4.62(dd,2H), spectrum see Figure 4 .

[0072] The reaction formula is:

[0073] Example 2

[0074] This example provides a method for preparing aprexitentan. The difference from Example 1 is that the method for preparing [5-(4-bromophenyl)-6-fluoropyrimidin-4-yl]azanesulfonamide in this example is different from that in Example 1, and is specifically carried out in the following steps:

[0075] S1. Preparation of [5-(4-bromophenyl)-6-fluoropyrimidin-4-yl]azanesulfonamide

[0076] Weigh 1.05g of [5-(4-bromophenyl)-6-(sulfonic acid methyl) pyrimidin-4-yl] methanesulfonic acid (1.0eq) and 0.86g of sodium fluoride (2.5eq) in a 250ml single-mouth bottle, add 10ml of dimethyl sulfoxide, heat and stir at 60℃ for reaction, react for 4h, add 0.68g of anhydrous potassium carbonate (2.0eq) and 1.04g of aminosulfonamide (4.0eq), heat to 70℃, heat and stir for reaction, react for 5h, cool to 30℃, add 50ml of 2N hydrochloric acid aqueous solution for quenching, extract with ethyl acetate, and concentrate the organic phase to dryness. The concentrate weighs 0.90g, with a yield of 83.0%. LC-MS: m / z=349.1 (M+H).

[0077] The reaction formula is:

[0078] S2. Preparation of [5-(4-bromophenyl)-6-[(2-hydroxyethyl)oxy]pyrimidin-4-yl]azanesulfonamide

[0079] Weigh 6.76g potassium tert-butoxide (2eq, 60.5mmol) and add it to a mixed solution of 2.15g ethylene glycol (1.2eq, 36.29mmol) and 30ml DMSO, stir at 70℃ for 10min, take 10.5g (1.0eq, 30.25mmol) of [5-(4-bromophenyl)-6-fluoropyrimidin-4-yl] azanesulfonamide and dissolve it in 50ml DMSO solution, then slowly drop it into the reaction solution, stir at 70℃ for 3 hours, pour the reaction solution into 300ml 2N hydrochloric acid aqueous solution, extract with 150ml ethyl acetate and concentrate to obtain 10.23g product; yield: 87%. LC-MS: m / z=391.1 (M+H).

[0080] The reaction formula is:

[0081] S3. Preparation of Aprexitentan

[0082] Weigh 2.38g of sodium hydrogen and slowly add it to 20ml of THF, weigh 10g of [5-(4-bromophenyl)-6-[(2-hydroxyethyl)oxy]pyrimidin-4-yl]azanesulfonamide and dissolve it in 20ml of THF, slowly dropwise add it to the THF solution of sodium hydrogen, stir at 20°C for 30 minutes, add a tetrahydrofuran solution in which 9.91g of 5-bromo-2-chloropyrimidine is dissolved, stir at an external temperature of 40°C for 4h after the addition, pour the reaction solution into 200ml of 2N hydrochloric acid aqueous solution, extract with 60ml of ethyl acetate and concentrate, crystallize the concentrate with DCM, and filter to obtain 12.94g of product; yield: 92%. Its spectrum detection result is basically the same as that of Example 1.

[0083] The reaction formula is:

[0084] Comparative Example 1

[0085] This comparative example provides a method for preparing aprexitentan, which is a prior art method and is carried out according to the following steps:

[0086] S1. Preparation of benzyl-sulfonamide [5-(4-bromophenyl)-6-chloro-pyrimidin-4-yl]-amide

[0087] Weigh 37.1 g of 5-(4-bromophenyl)-pyrimidine-4,6-dichloro (1.0 eq, 122.1 mmol) and 68.3 g of benzylsulfonamide potassium salt (2.5 eq, 305 mmol) in 275 ml of DMSO and stir at 25°C for 24 h. Then add 1800 ml of 10% citric acid aqueous solution dropwise, stir and filter. The filtered solid is rinsed with water and dried at 40°C for 48 h to obtain 52.1 g of the target compound (yield: 93.9%). LCMS: m / z = 452.95 (M+H).

[0088] The reaction formula is:

[0089] S2. Preparation of benzyl-sulfonamide [5-(4-bromo)-6-2-hydroxyethoxy]-pyrimidin-4-yl]-amide

[0090] 148.0g potassium tert-butoxide (12.33eq, 1.4mol) was weighed and added in batches to a solution of 52.0g (1.0eq, 114.6mmol) of benzyl-sulfonamide [5-(4-bromophenyl)-6-chloro-pyrimidin-4-yl]-amide in 445g (66.25eq, 7.59mol) of ethylene glycol, and diluted with 600ml DME. After stirring the mixture at 95°C for 24h, the mixture was cooled to room temperature, 400ml of water and 2000ml of 10% citric acid aqueous solution were added dropwise to the reaction solution, and the reaction solution was extracted with 2×2400ml of ethyl acetate and concentrated to obtain 52.0g of product; yield: 94.7%. LCMS: m / z=479.08 (M+H).

[0091] The reaction formula is:

[0092] S3, preparation of benzyl-sulfonamide [5-(4-bromo)-6-2-(5-bromo-2-yloxy)-ethoxy]-pyrimidin-4-yl]-amide

[0093] NaH (14.2 g, 324.8 mmol, 55% mineral oil dispersion) was slowly dripped into a solution of benzyl-aminesulfonic acid [5-(4-bromo)-6-2-hydroxyethoxy]-pyrimidin-4-yl]-amide (51.9 g, 108 mmol) in THF (960 mL). After the mixture was stirred for 10 minutes, 2-chloro-5-bromo-pyrimidine (31.44 g, 162.3 mmol) was added. The mixture was diluted with DMF (120 mL) and then stirred at room temperature for 20 minutes. After heating the mixture to 60°C and stirring for 3 hours, it was cooled to room temperature again. 2000 ml of 10% citric acid aqueous solution was dripped to quench the reaction, and the mixture was extracted with EA (2×2400 mL). The organic phase was washed with water. The combined phases were dried over MgSO4, filtered and concentrated to dryness. The crude product was crystallized from MeOH. Filter, rinse the filter cake with another portion of MeOH and dry under reduced pressure to obtain the desired product as a white powder (52.0 g, yield: 75.5%). LC-MS: m / z = 634.98 (M+H).

[0094] The reaction formula is:

[0095]

[0096] S4. Preparation of Aprexitentan

[0097] Boron tribromide (204 mL, 1M DCM) solution was slowly added to a solution of benzyl-sulfonamine acid [5-(4-bromo)-6-2-(5-bromo-2-yloxy)-ethoxy]-pyrimidin-4-yl]-amide (52.0 g, 81.6 mmol) in chloroform (2000 mL). The mixture became cloudy and an oily residue separated. The mixture was stirred at room temperature. Another portion of BBr3 solution (40 ml) was added after 6 h, 24 h and 33 h. After the last addition of BBr3, the beige suspension was stirred vigorously for 2 h and then MeOH was carefully added dropwise to quench the reaction. The solution was washed with cold water (0 °C, 2×1200 mL). The aqueous phase was re-extracted with DCM. The combined organic extracts were washed with water, dried over Mg2SO4, filtered and concentrated. The concentrate was purified by column chromatography eluting with a 1:1 mixture of n-heptane:EA and then crystallized from DCM. The purified crystals were dried under vacuum at 45°C for 48 hours to obtain the desired product as a white crystalline powder (12.96 g, yield: 29.04%). Figure 5 ; LC-MS: [M+H]'=544.70, see the spectrum Figure 6 and 7 .

[0098] The reaction formula is:

[0099] The contents of related substances or impurities in the aprexitentan prepared by the methods of Example 1 and Comparative Example 1 were measured, wherein the measurement method and specific parameters are shown in Table 1 below.

[0100] Table 1

[0101]

[0102]

[0103] After testing, it was found that there was an impurity in Comparative Example 1 that was difficult to remove in the API. By LC-MS (such as Figure 2 ) shows that the impurity RT = 6.97min, its m / z = 221.1, so it is inferred that its structure may be M = 219.03, m / z = M+H, consistent with the structure.

[0104] The comparison of the test results of Example 1 and Comparative Example 1 is shown in Table 2 below.

[0105] Table 2

[0106]

[0107] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to replace some or all of the technical features therein by equivalents. These modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present invention, and they should all be included in the scope of the claims and specification of the present invention.

Claims

1. An intermediate compound for preparing aprexitentan, characterized in that: The general structural formula is: Wherein, X is a leaving group, including any one of halogen, OMs, OTs or ethylene glycol substituent groups; and R is F or aminosulfonamide.

2. An intermediate compound for preparing aprexitentan according to claim 1, characterized in that: Structural formula such as Ⅰ, Ⅱ or Ⅲ: Wherein, in structural formula I, R is F; X is a leaving group, including any one of halogen, OMs, OTs or ethylene glycol substituent groups; In the structural formula II, R is aminosulfonamide; X is a leaving group, including any one of halogen, OMs, OTs or ethylene glycol substituent groups; In the structural formula III, R is aminosulfonamide; X is an ethylene glycol substituent group.

3. A method for preparing an intermediate compound of aprexitentan, characterized in that: The following steps are involved: Step 1: Fluorination reaction of compound A to obtain compound I; Step 2: Compound Ⅰ is reacted with aminosulfonamide to obtain compound Ⅱ; Step 3: Compound II is substituted with ethylene glycol to obtain compound III; Wherein, the structural formula of compound A is: X is a leaving group, which is selected from any one of halogen, OMs and OTs.

4. The method for preparing an intermediate compound of aprexitentan according to claim 3, characterized in that: The fluorination reaction of compound A in step 1 is carried out under the action of a fluorination agent; the reaction temperature is 55°C to 105°C.

5. The method for preparing an intermediate compound of aprexitentan according to claim 4, characterized in that: In step 1, the organic solvent used for the fluorination reaction of compound A includes any one of tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; the fluorination reagent includes any one or more of potassium fluoride, cesium fluoride, and tetrabutylammonium fluoride.

6. The method for preparing an intermediate compound of aprexitentan according to claim 3, characterized in that: In step 2, compound I reacts with aminosulfonamide under base catalysis to obtain compound II; the molar ratio of compound I to base is 1:(2-5); the molar ratio of compound I to aminosulfonamide is 1:(1-5); the mass ratio of compound I in the organic solution is 1:(5-50).

7. The method for preparing an intermediate compound of aprexitentan according to claim 6, characterized in that: The organic solution of compound I in step 2 includes any one of tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; the alkaline reagent includes any one of potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium hydride.

8. The method for preparing an intermediate compound of aprexitentan according to claim 3, characterized in that: In step 3, compound II and ethylene glycol are substituted under base catalysis to obtain compound III; the reaction temperature is 55°C to 105°C; the molar ratio of compound II to base is 1:(2-5); the mass ratio of compound II in organic solvent is 1:(5-50).

9. The method for preparing an intermediate compound of aprexitentan according to claim 8, characterized in that: In step 3, compound II and ethylene glycol are dissolved in an organic solvent, wherein the organic solvent includes any one of tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; and the alkaline reagent includes any one of potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium hydride.

10. A method for preparing aprexitentan, characterized in that: The following steps are involved: Step 1: Fluorination reaction of compound A to obtain compound I; Step 2: Compound Ⅰ is reacted with aminosulfonamide to obtain compound Ⅱ; Step 3: Compound II is substituted with ethylene glycol to obtain compound III; Step 4: Compound III is reacted with 5-bromo-2-chloropyrimidine to obtain aprexitentan; Wherein, the structural formula of compound A is: X is a leaving group, which is selected from any one of halogen, OMs and OTs.

11. The method for preparing aprexitentan according to claim 10, characterized in that: Step 4: Compound III is reacted with 5-bromo-2-chloropyrimidine in the presence of an alkaline reagent to obtain aprexitentan; the reaction temperature is 30° C. to 100° C.; the molar ratio of the compound III to the base is 1:(2-5); the mass ratio of the compound III in the organic solvent is 1:(5-50).

12. The method for preparing aprexitentan according to claim 11, characterized in that: In step 4, compound III and 5-bromo-2-chloropyrimidine are dissolved in an organic solvent, wherein the organic solvent includes any one of tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; and the alkaline reagent includes any one of potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium hydride.

13. A kind of aprexitentan, characterized in that: Prepared from the intermediate compound according to any one of claims 1 or 2, or prepared from the intermediate compound prepared by the preparation method of any one of claims 2 to 9, or prepared by the preparation method of any one of claims 10 to 12.

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