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CN-119462502-B - Tenapanol Process for the preparation of intermediates

CN119462502BCN 119462502 BCN119462502 BCN 119462502BCN-119462502-B

Abstract

The invention provides a preparation method of a Tenaparo intermediate. The method comprises the following steps: The compound shown in the formula I is subjected to oxidative dehydrogenation to obtain a compound shown in the formula II, and the compound shown in the formula II is subjected to catalytic reduction to obtain the target compound (S) -4- (3-bromophenyl) -6, 8-dichloro-2-methyl-1, 2,3, 4-tetrahydroisoquinoline shown in the formula III. The method provided by the invention overcomes the defects of poor atomic economy, complex operation, difficult industrialization, high technical cost and the like of the existing resolution process, so that the preparation of the Tenaprano intermediate is simpler and more convenient to operate, the raw materials are simple and easy to obtain, the cost is controllable, the industrialization is easier, and the product yield and chiral purity are high.

Inventors

  • WANG CHUANDONG
  • WANG YUEMING
  • LI JUN
  • QIN YONGZHONG
  • ZHANG HAN

Assignees

  • 杭州善礼生物医药科技有限公司

Dates

Publication Date
20260508
Application Date
20241009

Claims (8)

  1. 1. A preparation method of a Tenapanol intermediate is characterized by comprising the following steps: ; in the compound shown in the formula I, II or III, X is Br, F, cl, I or NH 2 , ① The method comprises the steps of carrying out oxidative dehydrogenation on a compound shown in a formula I under the action of a dehydrogenation reagent and a solvent to obtain a compound shown in a formula II, wherein the dehydrogenation reagent is one or a combination of any more of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, tetrachlorobenzoquinone and manganese dioxide; ② The compound shown in the formula II is subjected to catalytic reduction under the action of a reduction catalyst, a ligand, alkali, a reaction solvent and a reducing agent to obtain a target compound shown in the formula III, wherein the reduction catalyst is one or more of acetate or fluoroborate of chiral rhodium (Rh), ruthenium (Ru) or iridium (Ir), the ligand is one or more of (S, S) - (R, R) -PhTRAP, (S) -BINAP, (S, S) -Et-DuPHOS, (R, R) -DIOP, the alkali is one or more of cesium carbonate, potassium acetate, diisopropylethylamine, DBU and triethylamine, and the reducing agent is hydrogen.
  2. 2. The method of claim 1, wherein the amount of the compound of formula I to the dehydrogenation reagent is 1.0:2.5-6.0 in step ①.
  3. 3. The method of claim 1, wherein in the step ①, the solvent is one or more of dichloromethane, tetrahydrofuran, chloroform, 1, 2-dichloroethane, methyltetrahydrofuran, 1, 4-dioxane, toluene, and/or the mass-to-volume ratio of the compound represented by formula I to the solvent is 1.0:5.0-20.
  4. 4. The method of claim 1, wherein in the step ①, the reaction temperature is 20 to 110 ℃ and the reaction time is 2 to 24 hours.
  5. 5. The method of claim 1, wherein the ratio of the amount of the reducing catalyst to the amount of the ligand species in step ② is 1.0:1.0 to 4.0, and/or the ratio of the amount of the compound II to the amount of the catalyst species is 1.0:0.1% to 3.0%.
  6. 6. The method according to claim 1, wherein in the step ②, the amount of the base added is 0.02 to 2.00eq based on the amount of the substance of the compound II.
  7. 7. The method of claim 1, wherein in step ②, the mass to volume ratio of the compound II to the reaction solvent is 1.0:5-10.
  8. 8. The method according to claim 1, wherein in the step ②, the reaction temperature is 20 ℃ to 120 ℃ and the reaction time is 1 to 48 hours, and/or the pressure required for the catalytic reduction reaction is 0.1MPa to 8.0MPa.

Description

Tenapanol Process for the preparation of intermediates Technical Field The invention belongs to the technical field of organic synthesis route design, raw material medicines and intermediate preparation thereof, and particularly relates to a preparation method of a new medicine tenapano (Tenapanor) intermediate for treating constipation of irritable bowel syndrome. Background Tenapanol (tenapanor) is a new drug for treating constipation-predominant irritable bowel syndrome (IBS-C), developed by the United states Ardelyx biopharmaceutical company and approved by the FDA for marketing in 2019, month 9. Irritable Bowel Syndrome (IBS) is a common functional gastrointestinal disorder syndrome, with abdominal pain or discomfort, constipation or diarrhea, and other bowel habits and morphological changes, and symptoms are mostly recurrent or chronic persistent. In addition, near half IBS patients also present with upper gastrointestinal symptoms such as burning sensation of stomach, nausea, emesis, etc., and extra-intestinal symptoms such as back pain, headache, palpitation, frequent urination, urgent urination, sexual dysfunction, heart and kidney diseases, etc. There are also different levels of psychological and mental abnormalities, such as anxiety, depression, tension, etc. Defecation habits and morphological changes such as constipation and diarrhea of IBS are mainly classified into diarrhea type (IBS-D), constipation type (IBS-C), mixed type (IBS-M) and atypical type (IBS-U) according to Bristol typing. Constipation-predominant irritable bowel syndrome (IBS-C) is a common gastrointestinal disorder characterized by recurrent abdominal pain and prolonged gastrointestinal transit. The pathogenesis of IBS-C is not completely elucidated, and the current drugs for treating IBS-C mainly relieve symptoms, so that a new target is urgently needed. The tanpano (tenapanor) is an IBS sodium-hydrogen ion exchanger-3 (NHE 3) inhibitor, and can reduce the absorption of sodium by small intestine and colon and promote the secretion of water into intestinal tract by inhibiting sodium/hydrogen exchanger 3 (NHE 3) molecule, thereby promoting the peristalsis of intestinal tract, softening feces, relieving abdominal pain and treating constipation type irritable bowel syndrome. In addition, the national multi-star medical stock control company is expanding its indications and carrying out clinical trial research on hyperphosphatemia for treating patients suffering from heart and kidney diseases. Tenapanol (tenapanor, code RDX5791, AZD 1722) chemical name 3- ((S) -6, 8-dichloro-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -N- (26- (3- ((S) -6, 8-dichloro-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenyl) sulphonamido) -10, 17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexa-carbonyl) benzenesulfonamide, molecular formula C 50 H66 Cl4 N8 O10S2, molecular weight 1145.049, structural formula: One of the key intermediates, (S) -3- (6, 8-dichloro-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzenesulfonyl chloride has the structural formula: The synthesis of this intermediate was disclosed at the earliest in patent WO2010078449 filed by company ardelyx in the united states: 4- (3-bromophenyl) -6, 8-dichloro-2-methyl-1, 2,3, 4-tetrahydroisoquinoline is subjected to chiral resolution, so that the yield is low, the atomic economy is poor, and the residual byproduct of resolution cannot be utilized. Based on the analysis, the invention aims to design and synthesize an intermediate which can be used for preparing the Tenapranol, and the synthetic route overcomes the defects of high cost, poor atomic economy and the like of the prior art, so that the Tenapranol intermediate is better, simpler, more convenient, controllable in cost and easier to industrialize. Disclosure of Invention In order to overcome the defects of high cost, difficult industrialization and the like in the synthesis process of a Tenapranol intermediate (S) -4- (3-bromophenyl) -6, 8-dichloro-2-methyl-1, 2,3, 4-tetrahydroisoquinoline in the prior art, the preparation method provided by the invention has the following reaction formula: In the compound shown in the formula I, II or III, X is Br, F, cl, I or NH 2. ① Carrying out oxidative dehydrogenation on a compound shown in a formula I to obtain a compound shown in a formula II; ② The compound shown in the formula II is subjected to catalytic reduction to obtain a target compound (S) -4- (3-bromophenyl) -6, 8-dichloro-2-methyl-1, 2,3, 4-tetrahydroisoquinoline shown in the formula III. In step ①, the dehydrogenation reagent is one or more of palladium acetate, 2-iodoxybenzoic acid, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, tetrachlorobenzoquinone, and manganese dioxide. In one specific embodiment, in step ①, the ratio of the amount of the compound represented by formula I to the amount of the dehydrogenation reagent is 1.0:2.5-6.0. In step ①, the solvent is one or more of dichloromethane, tetrahydrofuran, chlorofo