Preparation method of rafenasin intermediate

Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of a rafenasin intermediate. According to the method, tert-butyl [1, 1 '-biphenyl]-2-yl carbamate and the compound 1-benzyl piperidine-4-alcohol are used as starting materials, the target compound 1-benzyl piperidine-4-yl [1, 1'-biphenyl]-2-yl carbamate is prepared through one-step reaction, the process can effectively avoid use of reagents such as chloroformate with high toxicity, reaction operation is safer, and the method is suitable for industrial production. The method is more suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a refenacin intermediate. Background Art

[0002] Revefenacin, chemically named 1-(2-(4-((4-carbamoylpiperidin-1-yl)methyl)-N-methylbenzamido)ethylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate, is a preparation first discovered and developed by Theravance Biopharmaceuticals of Ireland and jointly developed with Mylan Pharmaceuticals of the United States. It was approved by the US FDA on November 9, 2018 as a new long-acting anticholinergic drug. Its trade name is Revenacin is a long-acting muscarinic receptor antagonist that binds to the M3 muscarinic receptors on bronchial smooth muscle, inhibiting the release of acetylcholine from parasympathetic nerve terminals and causing tracheal contraction. It is mainly used clinically for the maintenance treatment of chronic obstructive pulmonary disease (COPD), including the maintenance treatment of chronic bronchitis and emphysema with dyspnea and the prevention of acute attacks. [2,3] . Its chemical structure is as follows:

[0003]

[0004] There are few literature reports on the synthesis method of revenacin. Its synthesis route is mainly concentrated in the Chinese patents CN1759108A, CN1882556A, CN1930125B, CN102958916B, US20050203133Al and the literature J.Med.Chem., 2015, 58(6), 2609-2622, etc., which are disclosed by the original research company. The classic route is to use 2-biphenyl isocyanate (2) as the starting material, first react with 1-benzylpiperidin-4-ol (3) to obtain 1-benzylpiperidin-4-yl[ 1,1'-biphenyl]-2-ylcarbamate (I), and then the benzyl group is removed to obtain piperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (4), 4 is then reduced and aminated with benzylmethyl(2-oxoethyl)carbamate by sodium triacetoxyborohydride, and then the benzyloxycarbonyl group is removed to generate 1-(2-(methylamino)ethyl)piperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (5), 5 is first reacted with p-formylbenzoic acid, and finally reduced and aminated with piperidine-4-carboxamide (6) by sodium triacetoxyborohydride to obtain the target product 1.

[0005] However, the above process has the following problems: ① The "linear" synthesis strategy is adopted, the reaction steps are relatively long, and most of the intermediates in each step are oily liquids with low melting points, which are difficult to purify, resulting in easy inheritance of impurities, low yield of target products, high production costs, and greater difficulty in industrialization; ② In the subsequent two-step reductive amination, the moisture content of the materials will also cause a serious reduction in yield or even the inability to proceed with the reaction.

[0006] The relevant reaction route is shown below:

[0007]

[0008] From the above, it can be seen that 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (I) can be used as a key intermediate for the preparation of refenacin, so 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (I) can directly affect the production, market supply and quality of the drug. The specific structural formula is as follows:

[0009]

[0010] However, when the above process is used to prepare 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (I), although the yield is about 100%, the material 2-biphenyl isocyanate (2) used has high activity and is expensive, about 17,000 yuan / kg, while the other material 1-benzylpiperidin-4-ol (3) has a commercially available water content of about 0.2-0.5% and a low melting point of about 55-60°C, making it difficult to dry. Therefore, a large amount of the following impurities will be generated during the reaction, further reducing the yield of the single-step reaction. The content of 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (I) in the obtained crude product is low, only about 70%, and further refining and purification is required, which further reduces the yield of this step and increases the production cost. The relevant impurity structures are as follows:

[0011]

[0012] In addition, Chinese invention patent application CN115403509A uses 1-benzylpiperidin-4-ol as the starting material, first acylates with phenyl chloroformate to obtain the intermediate 1-benzylpiperidin-4-yl (4-nitrophenyl) carbonate or 1-benzylpiperidin-4-phenyl carbonate, and then the intermediate is aminolyzed with [1,1'-biphenyl]-2-amine to obtain the target compound - benzylpiperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate (I). Although the product obtained by this process has high purity and yield, the synthesis unit operation is long, and the use of reagents such as chloroformate with high toxicity cannot be avoided. The synthesis route is as follows:

[0013]

[0014] In summary, in view of the many shortcomings in the current preparation of the key intermediate 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (I) of refenacin, it is still a problem to be solved to study and find a preparation process suitable for the industrial production of 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (I) that is simple and safe to operate, has mild reaction conditions, and has high product yield and high purity. Summary of the invention

[0015] In view of the many problems existing in the prior art in preparing 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (I), an intermediate of refenacin, the present invention provides a novel method for preparing 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (I). The method has mild reaction conditions, a safe and simple operation process, and the obtained target product has high purity and yield.

[0016] The present invention is specifically implemented through the following technical solutions:

[0017] A method for preparing a refenacin intermediate 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate: using compound SM-1, i.e. tert-butyl[1,1'-biphenyl]-2-ylcarbamate and compound SM-2, i.e. 1-benzylpiperidin-4-ol, as starting materials, and obtaining the target compound 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate through a one-step reaction, and the chemical reaction formula is as follows:

[0018]

[0019] A method for preparing 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate, a key intermediate of refenacin, specifically comprises the following operations:

[0020] At room temperature, compound SM-1, base and acid anhydride are added to an organic solvent, and the temperature is controlled to T1 for reaction. Then, an acid binding agent and compound SM-2 are added, and the temperature is controlled to reflux for reaction. After the reaction is completed, the reaction solution is poured into purified water, and the organic phase is separated. The organic phase is concentrated to dryness under reduced pressure, and the target product I is obtained after recrystallization from dichloromethane-methanol.

[0021] In a preferred embodiment, the base is one of 2-chloropyridine, 2-fluoropyridine, 2-bromopyridine or a combination thereof, wherein 2-chloropyridine is particularly preferred.

[0022] In a preferred embodiment, the acid anhydride is one of trifluoromethanesulfonic anhydride (Tf2O) and acetic anhydride (Ac2O) or a combination thereof, wherein Tf2O is particularly preferred.

[0023] In a preferred embodiment, the acid binding agent is one of triethylamine, N,N-diisopropylethylamine, sodium carbonate or a combination thereof, wherein triethylamine is particularly preferred.

[0024] In a preferred embodiment, the organic solvent is one of dichloromethane and chloroform or a combination thereof, among which chloroform is particularly preferred.

[0025] In a preferred embodiment, the molar ratio of the compound SM-1 to the compound SM-2, the base, the acid anhydride and the acid binding agent is 1:1.0-1.4:2.5-3.5:1.3-2.0:3.0-5.0, among which 1:1.05:3.0:1.5:4.0 is particularly preferred.

[0026] In a preferred embodiment, the reaction temperature T1 is 10-40°C, preferably 25°C.

[0027] In a preferred embodiment, the volume ratio of dichloromethane to methanol for recrystallization is 2-4:1, ml / ml, preferably 3:1, ml / ml.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] 1. A simple and efficient method for preparing refenacin intermediate 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate is provided. The entire synthetic method has a short route, simple operation steps, mild reaction conditions, and is suitable for large-scale industrial production.

[0030] 2. This process can effectively avoid the use of highly toxic reagents such as chloroformate, making the reaction operation safer and more suitable for industrial scale-up production.

[0031] 3. This process can effectively avoid the generation of related impurities, and the target product obtained by this process has a higher yield and purity. DETAILED DESCRIPTION

[0032] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention all fall within the scope of protection claimed by the present invention.

[0033] The structure of the compound obtained by the present invention is confirmed:

[0034]

[0035] ESI-TOF + -HRMS(m / z):387.2104[M+H] + ; 1H NMR(600MHz, DMSO-d6)δ8.66(s,1H),7.40~7.42(m,2H),7.35~7.37(m,3H),7.33~7.34(m,2H),7.27~7.32(m,6H),7.2 3~7.25(m,1H),7.44~7.48(m,1H),3.42(s,2H),2.56(s,2H),2.10~2.13(m,2H),1.72(d,J=9.78Hz,2H),1.41~1.46(m 2H); 13 C NMR(151MHz,DMSO-d6)δ153.84,139.13,138.37,137.41,134.65,130.13,128.60,128.5 2,128.13,128.05,127.71,127.03,126.88,126.76,125.95,69.95,61.81,50.12,30.63.

[0036] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0037] Example 1

[0038] At room temperature, compound SM-1 (26.93 g, 0.10 mol), 2-chloropyridine (34.06 g, 0.30 mol) and trifluoromethanesulfonic anhydride (42.32 g, 0.15 mol) were added to chloroform (250 ml), and the temperature was controlled at 25°C for reaction for 1 h. After the reaction of compound SM-1 was completed, triethylamine (40.48 g, 0.40 mol) and compound SM-2 (20.08 g, 0.105 mol) were added, and the temperature was controlled to reflux for reaction. After the reaction was completed, the reaction solution was poured into purified water (1000 ml), the organic phase was separated, and the aqueous phase was extracted with chloroform (150 ml×2). The organic phases were combined and washed with saturated brine (250 ml). The organic phase was concentrated to dryness under reduced pressure and recrystallized from dichloromethane-methanol (V:V=3:1, 100 ml) to obtain the target product I with a yield of 98.6% and a purity of 99.95%.

[0039] Example 2

[0040] At room temperature, compound SM-1 (26.93 g, 0.10 mol), 2-chloropyridine (28.39 g, 0.25 mol) and acetic anhydride (15.31 g, 0.15 mol) were added to dichloromethane (250 ml), and the temperature was controlled at 10°C for reaction for 1 hour. After the reaction of compound SM-1 was completed, triethylamine (40.48 g, 0.40 mol) and compound SM-2 (20.08 g, 0.105 mol) were added, and the temperature was controlled to reflux for reaction. After the reaction was completed, the reaction solution was poured into purified water (1000 ml), the organic phase was separated, and the aqueous phase was extracted with chloroform (150 ml×2). The organic phases were combined and washed with saturated brine (250 ml). The organic phase was concentrated to dryness under reduced pressure and recrystallized from dichloromethane-methanol (V:V=3:1, 100 ml) to obtain the target product I with a yield of 94.5% and a purity of 99.72%.

[0041] Example 3

[0042] At room temperature, compound SM-1 (26.93 g, 0.10 mol), 2-chloropyridine (39.47 g, 0.35 mol) and trifluoromethanesulfonic anhydride (42.32 g, 0.15 mol) were added to chloroform (250 ml), and the temperature was controlled at 40°C for reaction for 1 hour. After the reaction of compound SM-1 was completed, triethylamine (40.48 g, 0.40 mol) and compound SM-2 (20.08 g, 0.105 mol) were added, and the temperature was controlled to reflux for reaction. After the reaction was completed, the reaction solution was poured into purified water (1000 ml), the organic phase was separated, and the aqueous phase was extracted with chloroform (150 ml×2). The organic phases were combined and washed with saturated brine (250 ml). The organic phase was concentrated to dryness under reduced pressure and recrystallized from dichloromethane-methanol (V:V=3:1, 100 ml) to obtain the target product I with a yield of 95.1% and a purity of 99.62%.

[0043] Example 4

[0044] At room temperature, compound SM-1 (26.93 g, 0.10 mol), 2-fluoropyridine (29.13 g, 0.30 mol) and trifluoromethanesulfonic anhydride (27.30 g, 0.13 mol) were added to chloroform (250 ml), and the temperature was controlled at 25°C for reaction for 1 hour. After the reaction of compound SM-1 was completed, triethylamine (40.48 g, 0.40 mol) and compound SM-2 (20.08 g, 0.105 mol) were added, and the temperature was controlled to reflux for reaction. After the reaction was completed, the reaction solution was poured into purified water (1000 ml), the organic phase was separated, and the aqueous phase was extracted with chloroform (150 ml×2). The organic phases were combined and washed with saturated brine (250 ml). The organic phase was concentrated to dryness under reduced pressure and recrystallized from dichloromethane-methanol (V:V=3:1, 100 ml) to obtain the target product I with a yield of 94.4% and a purity of 99.69%.

[0045] Example 5

[0046] At room temperature, compound SM-1 (26.93 g, 0.10 mol), 2-bromopyridine (41.40 g, 0.30 mol) and trifluoromethanesulfonic anhydride (42.0 g, 0.20 mol) were added to chloroform (250 ml), and the temperature was controlled at 25°C for reaction for 1 h. After the reaction of compound SM-1 was completed, triethylamine (40.48 g, 0.40 mol) and compound SM-2 (20.08 g, 0.105 mol) were added, and the temperature was controlled to reflux for reaction. After the reaction was completed, the reaction solution was poured into purified water (1000 ml), the organic phase was separated, and the aqueous phase was extracted with chloroform (150 ml×2). The organic phases were combined and washed with saturated brine (250 ml). The organic phase was concentrated to dryness under reduced pressure and recrystallized from dichloromethane-methanol (V:V=3:1, 100 ml) to obtain the target product I with a yield of 95.1% and a purity of 99.60%.

[0047] Example 6

[0048] At room temperature, compound SM-1 (26.93 g, 0.10 mol), 2-chloropyridine (34.06 g, 0.30 mol) and trifluoromethanesulfonic anhydride (42.32 g, 0.15 mol) were added to chloroform (250 ml), and the temperature was controlled at 35°C for reaction for 1 h. After the reaction of compound SM-1 was completed, triethylamine (30.36 g, 0.30 mol) and compound SM-2 (20.08 g, 0.105 mol) were added, and the temperature was controlled to reflux for reaction. After the reaction was completed, the reaction solution was poured into purified water (1000 ml), the organic phase was separated, and the aqueous phase was extracted with chloroform (150 ml×2). The organic phases were combined and washed with saturated brine (250 ml). The organic phase was concentrated to dryness under reduced pressure and recrystallized from dichloromethane-methanol (V:V=2:1, 100 ml) to obtain the target product I with a yield of 93.2% and a purity of 99.75%.

[0049] Example 7

[0050] At room temperature, compound SM-1 (26.93 g, 0.10 mol), 2-chloropyridine (34.06 g, 0.30 mol) and trifluoromethanesulfonic anhydride (42.32 g, 0.15 mol) were added to dichloromethane (250 ml), and the temperature was controlled at 10°C for reaction for 1 h. After the reaction of compound SM-1 was completed, triethylamine (50.60 g, 0.50 mol) and compound SM-2 (20.08 g, 0.105 mol) were added, and the temperature was controlled to reflux for reaction. After the reaction was completed, the reaction solution was poured into purified water (1000 ml), the organic phase was separated, and the aqueous phase was extracted with chloroform (150 ml×2), the organic phases were combined, and the organic phases were washed with saturated brine (250 ml). The organic phase was concentrated to dryness under reduced pressure and recrystallized from dichloromethane-methanol (V:V=4:1, 100 ml) to obtain the target product I with a yield of 95.6% and a purity of 99.65%.

[0051] Example 8

[0052] At room temperature, compound SM-1 (26.93 g, 0.10 mol), 2-chloropyridine (34.06 g, 0.30 mol), and trifluoromethanesulfonic anhydride (42.32 g, 0.15 mol) were added to chloroform (250 ml), and the temperature was controlled at 25 °C for 1 h. After the reaction of compound SM-1 was completed, N,N-diisopropylethylamine (51.70 g, 0.40 mol) and compound SM-2 (19.1 3g, 0.10mol), control the temperature and reflux to react. After the reaction is completed, pour the reaction solution into purified water (1000ml), separate the organic phase, extract the aqueous phase with chloroform (150ml×2), combine the organic phases, wash with saturated brine (250ml), concentrate the organic phase to dryness under reduced pressure, and then recrystallize from dichloromethane-methanol (V:V=3:1, 100ml) to obtain the target product I, with a yield of 95.3% and a purity of 99.74%.

[0053] Example 9

[0054] At room temperature, compound SM-1 (26.93 g, 0.10 mol), 2-chloropyridine (34.06 g, 0.30 mol) and trifluoromethanesulfonic anhydride (42.32 g, 0.15 mol) were added to chloroform (250 ml), and the temperature was controlled at 25°C for reaction for 1 h. After the reaction of compound SM-1 was completed, sodium carbonate (42.40 g, 0.40 mol) and compound SM-2 (26.78 g, 0.14 mol) were added, and the temperature was controlled to reflux for reaction. After the reaction was completed, the reaction solution was poured into purified water (1000 ml), the organic phase was separated, and the aqueous phase was extracted with chloroform (150 ml×2). The organic phases were combined and washed with saturated brine (250 ml). The organic phase was concentrated to dryness under reduced pressure and recrystallized from dichloromethane-methanol (V:V=3:1, 100 ml) to obtain the target product I with a yield of 96.1% and a purity of 99.62%.

[0055] Example 10

[0056] At room temperature, compound SM-1 (26.93 g, 0.10 mol), 2-chloropyridine (24.98 g, 0.22 mol) and trifluoromethanesulfonic anhydride (21.0 g, 0.10 mol) were added to chloroform (250 ml), and the temperature was controlled to 8°C for reaction for 1 h. After the reaction of compound SM-1 was completed, triethylamine (28.33 g, 0.28 mol) and compound SM-2 (19.13 g, 0.10 mol) were added, and the temperature was controlled to reflux for reaction. After the reaction was completed, the reaction solution was poured into purified water (1000 ml), the organic phase was separated, and the aqueous phase was extracted with chloroform (150 ml×2). The organic phases were combined and washed with saturated brine (250 ml). The organic phase was concentrated to dryness under reduced pressure and recrystallized from dichloromethane-methanol (V:V=3:1, 100 ml) to obtain the target product I with a yield of 87.3% and a purity of 98.95%.

[0057] Embodiment 11

[0058] At room temperature, compound SM-1 (26.93 g, 0.10 mol), 2-chloropyridine (42.01 g, 0.37 mol) and trifluoromethanesulfonic anhydride (46.21 g, 0.22 mol) were added to chloroform (250 ml), and the temperature was controlled at 42°C for reaction for 1 h. After the reaction of compound SM-1 was completed, triethylamine (52.62 g, 0.52 mol) and compound SM-2 (30.60 g, 0.16 mol) were added, and the temperature was controlled to reflux for reaction. After the reaction was completed, the reaction solution was poured into purified water (1000 ml), the organic phase was separated, and the aqueous phase was extracted with chloroform (150 ml×2). The organic phases were combined and washed with saturated brine (250 ml). The organic phase was concentrated to dryness under reduced pressure and recrystallized from dichloromethane-methanol (V:V=3:1, 100 ml) to obtain the target product I with a yield of 90.2% and a purity of 96.87%.

Claims

1. A method for preparing a revenacin intermediate, characterized in that: The preparation method comprises the following steps: At room temperature, compound SM-1, base and acid anhydride are added to an organic solvent, and the temperature is controlled to T1 for reaction. Then, an acid binding agent and compound SM-2 are added, and the temperature is controlled to reflux for reaction. After the reaction is completed, the reaction solution is poured into purified water, and the organic phase is separated. The organic phase is concentrated to dryness under reduced pressure, and the target product I is obtained after recrystallization from dichloromethane-methanol; The reaction route is as follows:

2. The preparation method according to claim 1, characterized in that: The base is selected from one of 2-chloropyridine, 2-fluoropyridine and 2-bromopyridine.

3. The preparation method according to claim 1, characterized in that: The acid anhydride is selected from one of trifluoromethanesulfonic anhydride (Tf2O) and acetic anhydride (Ac2O).

4. The preparation method according to claim 1, characterized in that: The organic solvent is selected from dichloromethane, chloroform or a combination thereof; the reaction temperature T1 is 10-40°C.

5. The preparation method according to claim 1, characterized in that: The acid binding agent is selected from one of triethylamine, N,N-diisopropylethylamine and sodium carbonate.

6. The preparation method according to claim 1, characterized in that: The molar ratio of the compound SM-1 to the compound SM-2, the base, the acid anhydride and the acid binding agent is 1:1.0-1.4:2.5-3.5:1.3-2.0:3.0-5.

0.

7. The preparation method according to claim 1, characterized in that: The volume ratio of dichloromethane to methanol for the recrystallization is 2-4:1, ml / ml.

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