Search

CN-114805237-B - Preparation method of heterocyclic compound and intermediate thereof

CN114805237BCN 114805237 BCN114805237 BCN 114805237BCN-114805237-B

Abstract

The invention provides a preparation method of an imidazopyridine compound shown in a formula IV and an intermediate shown in a formula I or a formula II. The imidazopyridine compound shown in the formula IV can antagonize a P2X3 receptor and has the effects of inhibiting cough and easing pain.

Inventors

  • ZHANG XUEJUN
  • LI QUN
  • ZANG YANG
  • CAI LIBO
  • CHANG SHAOHUA
  • LI XUEQIANG
  • LI LIE
  • YANG JUN

Assignees

  • 武汉人福创新药物研发中心有限公司
  • 武汉人福创新药物研发中心有限公司
  • 人福医药集团股份公司
  • 人福医药集团股份公司

Dates

Publication Date
20260421
Application Date
20220121
Priority Date
20210122

Claims (20)

  1. 1. A process for the preparation of an imidazopyridine compound of formula IV comprising the steps of: Step 10, reacting an intermediate shown in a formula III with methylamine to obtain a compound shown in a formula IV; Wherein, the The R 2a is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the reaction was carried out in methanol.
  2. 2. The method of manufacturing according to claim 1, further comprising the steps of: step 9, reacting an intermediate shown in a formula II-3 with a compound shown in a formula 7 to obtain an intermediate shown in a formula III; Wherein, the The R 2a is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  3. 3. The method of manufacturing according to claim 2, further comprising the step of: Step 8, reacting the intermediate shown in the formula II-2 with a brominating reagent to obtain an intermediate shown in the formula II-3; Wherein, the The R 2a is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  4. 4. A method of preparing as claimed in claim 3, further comprising the steps of: Step 7, removing intermediate protecting group PG 1 shown in the formula II-1A to obtain a deprotected product, and reacting the deprotected product with a compound shown in the formula 6 under the action of alkali to obtain an intermediate shown in the formula II-2; Wherein, the The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl; the R 2a is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  5. 5. A process for producing a compound II-1A according to claim 4, wherein the intermediate represented by the formula II-1A is produced from the intermediate represented by the formula II-1A, and the process for producing the intermediate represented by the formula II-1A comprises the steps of: Step 5, under the action of a catalyst and an organic base, reacting an intermediate shown in a formula II-1 with carbon monoxide and a compound shown in a formula 4 to obtain an intermediate shown in a formula II-1A; Wherein, the The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl; r 2 is halogen; the R 2a is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  6. 6. A process for producing a compound II-1A according to claim 4, wherein the intermediate represented by the formula II-1A is produced from the intermediate represented by the formula II-1A, and the process for producing the intermediate represented by the formula II-1A comprises the steps of: Step 6, under the action of alkali, reacting an intermediate shown as a formula II-1 with a compound shown as a formula 5 to obtain an intermediate shown as a formula II-1A; Wherein, the The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl; R 2 is carboxyl; the R 2a is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  7. 7. The method of manufacturing according to claim 5 or 6, further comprising the steps of: Step1, preparing an intermediate shown in a formula II-1 by reacting the intermediate shown in the formula I with a compound shown in a formula 1 under the action of an amino metal compound or an alkyl metal compound; Wherein, the The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl; the R 2 is selected from halogen and carboxyl.
  8. 8. The method of manufacturing according to claim 7, further comprising the step of: step 2, preparing an intermediate shown in the formula I by reacting the intermediate shown in the formula I-2 with a compound shown in the formula 2 under the action of organic base and condensing agent; Wherein, PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
  9. 9. The method of preparing as claimed in claim 8, further comprising the steps of: Step 3, preparing an intermediate shown in a formula I-1 by carrying out a reduction reaction on a compound shown in the formula 3; Step 4, preparing an intermediate shown in a formula I-2 by hydrolyzing the intermediate shown in the formula I-1 under the action of inorganic base; Wherein, PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
  10. 10. The method for producing a compound of formula IV according to claim 1, wherein, in step 10, The molar ratio of the intermediate shown in the formula III to the methylamine is 1:4-1:6; Optionally, the reaction temperature of the reaction is 20-25 ℃; Optionally, the reaction time of the reaction is 4-6 hours.
  11. 11. The method for preparing a compound represented by formula IV according to claim 10, wherein the molar ratio of the intermediate represented by formula III to methylamine is 1:5; optionally, the reaction time of the reaction is 5 hours.
  12. 12. The process for preparing an intermediate of formula III according to claim 2, wherein in step 9, The molar ratio of the intermediate shown in the formula II-3 to the compound shown in the formula 7 in the reaction is 1:1-1:3; optionally, the reaction is carried out in an organic solvent comprising acetonitrile, dimethyl sulfoxide, ethanol, N-dimethylacetamide, N-dimethylformamide, N-methylpyrrolidone, 1, 4-dioxane, N-propanol or N-butanol; Optionally, the reaction temperature of the reaction is 110-130 ℃; optionally, the reaction time of the reaction is 22-26 hours.
  13. 13. The method for producing an intermediate represented by formula III according to claim 12, wherein the molar ratio of the intermediate represented by formula II-3 to the compound represented by formula 7 in the reaction is 1:2; optionally, the organic solvent is acetonitrile; Optionally, the reaction temperature of the reaction is 120 ℃; Optionally, the reaction time of the reaction is 24 hours.
  14. 14. A process for the preparation of an intermediate of formula II-3 as claimed in claim 3, wherein in step 8, The brominating reagent is N-bromosuccinimide, dibromohydantoin, pyridine tribromide, copper bromide or liquid bromine; Optionally, the molar ratio of the intermediate shown in the formula II-2 to the brominating reagent is 1:1-1:3; Optionally, the reaction is carried out in methylene chloride; Optionally, the reaction temperature of the reaction is 20-25 ℃; Optionally, the reaction time of the reaction is 0.5-2 hours.
  15. 15. The process for preparing an intermediate of formula II-3 according to claim 14, wherein the brominating reagent is liquid bromine; Optionally, the molar ratio of the intermediate shown as the formula II-2 to the brominating reagent is 1:1.2; Optionally, the reaction time of the reaction is 1 hour.
  16. 16. The process for preparing an intermediate of formula II-2 according to claim 4, wherein in step 7, The molar ratio of the intermediate shown in the formula II-1A to the compound shown in the formula 6 is 1:1-1:2; Optionally, the removal of the intermediate protecting group PG 1 shown in the formula II-1A is performed under the action of hydrochloric acid; optionally, the removal of the intermediate protecting group PG 1 as shown in formula II-1A is performed under reaction with hydrogen; Optionally, the reaction temperature of the reaction is 20-25 ℃; Optionally, the base is triethylamine or N, N-diisopropylethylamine; optionally, the deprotecting reaction is carried out in 1, 4-dioxane; optionally, the reaction time of the deprotection is 2-4 hours; Optionally, the reaction of the deprotected product with a compound of formula 6 under the action of a base in dichloromethane; optionally, the reaction time of the deprotection product and the compound shown as the formula 6 under the action of alkali is 10-14 hours.
  17. 17. The method for preparing an intermediate represented by formula II-2 according to claim 16, wherein the molar ratio of the intermediate represented by formula II-1A to the compound represented by formula 6 is 1:1.5; optionally, the base is triethylamine; Optionally, the deprotection reaction time is 3 hours; optionally, the reaction time of the deprotected product with a compound represented by formula 6 under the action of a base is 12 hours.
  18. 18. The process for preparing an intermediate of formula II-1A according to claim 5, wherein in step 5, The catalyst is a transition metal catalyst, and the transition metal catalyst is selected from palladium metal catalyst, ruthenium metal catalyst, iron metal catalyst, cobalt metal catalyst, nickel metal catalyst and rhodium metal catalyst; optionally, the organic base is triethylamine or N, N-diisopropylethylamine; Optionally, the reaction is carried out in pressurized carbon monoxide at a pressure of 40-50 psi; optionally, the reaction temperature of the reaction is 55-65 ℃; optionally, the reaction time of the reaction is 22-26 hours.
  19. 19. The method for preparing an intermediate shown in a formula II-1A according to claim 18, wherein the transition metal catalyst is a palladium metal catalyst, and the palladium metal catalyst is tetrakis (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride, 1-bis (diphenylphosphine) ferrocene palladium chloride, [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, 1, 4-bis (diphenylphosphine butane) palladium dichloride; optionally, the organic base is triethylamine; optionally, the carbon monoxide is at a pressure of 45psi; Optionally, the reaction time of the reaction is 24 hours.
  20. 20. The method for preparing an intermediate of formula II-1A according to claim 19, wherein the palladium metal catalyst is 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride.

Description

Preparation method of heterocyclic compound and intermediate thereof PRIORITY INFORMATION The present application requests the priority and equity of patent application number 202110090536.7 filed on 22 nd 2021 to the national intellectual property agency of China and incorporated herein by reference in its entirety. Technical Field The invention relates to a preparation method of heterocyclic compounds and intermediates thereof, in particular to a preparation method of imidazopyridine compounds and intermediates thereof. Background The P2X receptor is a non-selective ATP-gated ion channel receptor, a purinergic receptor, that binds extracellular ATP, which is primarily derived from damaged or inflamed tissue. The receptor is widely expressed in systems such as nerves, immunity, cardiovascular system, bones, intestines, respiration, endocrine and the like, and is involved in various physiological processes such as heart rhythm and contractility regulation, regulation of vascular tension, regulation of nociception, especially chronic pain, vasoconstriction during ejaculation, bladder constriction during urination, platelet aggregation, macrophage activation, apoptosis, neuron-glia interaction and the like. The P2X receptor comprises seven homologous receptors, namely P2X1, P2X2, P2X3, P2X4, P2X5, P2X6 and P2X7, and three heterologous receptors, namely P2X2/3, P2X4/6 and P2X1/5. P2X3 is a subtype of the P2X receptor family, selectively expressed in the dorsal root ganglion, spinal cord and brain neurons of the nerve endings, i.e. in small and medium diameter primary sensory neurons. Numerous studies have shown that activation of P2X3 and P2X2/3 expressed in primary sensory neurons plays an important role in acute injury, hyperalgesia and hypersensitivity in rodents. Many studies have shown that upregulation of P2X3 receptor expression can lead to hyperalgesia formation, involved in pain signaling. P2X3 knockout mice exhibit reduced pain responses, and P2X3 receptor antagonists have been shown to reduce nociception in pain and inflammatory pain models. P2X3 is distributed in the primary afferent nerves surrounding the airways, and can regulate cough. Studies have shown that ATP released by tissues with damaged or inflamed airways acts on the P2X3 receptor of the primary neurons, triggering depolarization and action potentials that are transmitted to cause cough impulses, causing cough. Preclinical and clinical data strongly demonstrate that the P2X3 receptor plays an important role in cough reflex hypersensitivity, leading to chronic cough. By antagonizing binding to the P2X3 receptor, hypersensitivity reactions to cough reflex can be inhibited, thereby inhibiting excessive cough in chronic cough patients. P2X3 was reported to be involved in controlling the afferent pathways of bladder capacity reflex, with significantly reduced frequency of urination and significantly increased bladder capacity in P2X3 knockout mice. Thus, inhibition of P2X3 receptor antagonist binding to the P2X3 receptor has the effect of treating disorders of urinary storage and urination disorders, such as overactive bladder. Thus, P2X3 antagonists may be potential drugs for the treatment of diseases associated with overactive bladder and the like. In addition, studies have shown that P2X3 antagonists can treat chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension, or asthma, and thus P2X3 antagonists are also promising new drugs for the treatment of these diseases. P2X3 antagonists show great promise in a number of disease areas, and therefore the development of P2X3 antagonists is of clinical importance. Disclosure of Invention The invention provides a preparation method of an imidazopyridine compound and an intermediate thereof. The preparation method has the advantages of mild condition, stable process and simple operation, and is suitable for amplification and industrial production. The invention provides an intermediate shown as a formula I or a formula II: Wherein, the Said R 1 is selected from PG 1 or Said R 2 is selected from halogen, carboxyl or Said R 2a is selected from C 1-C6 alkyl or benzyl; the PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl; The X is selected from H or Br. In a preferred embodiment of the invention, when R 2 is halogen, the halogen is Br or I, preferably Br. In a preferred embodiment of the invention, R 2a is C 1-C6 alkyl, preferably R 2a is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. In a preferred embodiment of the present invention, the intermediate of formula II as described above is selected from any one of the following intermediates: Wherein, the The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl; Said R 2 is selected from halogen, carboxyl or The R 2a has the definition set forth above. The invention also provides a preparation method of the intermediate shown in the formula II-1, which co