WO2018001197A1 - 一种尿酸转运体1抑制剂的制备方法 - Google Patents

一种尿酸转运体1抑制剂的制备方法 Download PDF

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WO2018001197A1
WO2018001197A1 PCT/CN2017/089993 CN2017089993W WO2018001197A1 WO 2018001197 A1 WO2018001197 A1 WO 2018001197A1 CN 2017089993 W CN2017089993 W CN 2017089993W WO 2018001197 A1 WO2018001197 A1 WO 2018001197A1
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product
reaction
solvent
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temperature
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PCT/CN2017/089993
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English (en)
French (fr)
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赵桂龙
刘长鹰
刘钰强
陈会慧
李玉荃
张海枝
谢亚非
吴景卫
刘巍
徐为人
邹美香
汤立达
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天津药物研究院有限公司
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Priority to EP17819194.6A priority Critical patent/EP3480188B1/en
Priority to ES17819194T priority patent/ES2878598T3/es
Priority to MYPI2018002985A priority patent/MY190118A/en
Priority to US16/312,164 priority patent/US11091448B2/en
Priority to AU2017290931A priority patent/AU2017290931B2/en
Priority to KR1020197002228A priority patent/KR102326829B1/ko
Publication of WO2018001197A1 publication Critical patent/WO2018001197A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
    • C07C25/18—Polycyclic aromatic halogenated hydrocarbons
    • C07C25/22—Polycyclic aromatic halogenated hydrocarbons with condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
    • C07C331/02—Thiocyanates
    • C07C331/04—Thiocyanates having sulfur atoms of thiocyanate groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention belongs to the field of pharmacy, and in particular, the present invention relates to a uric acid transporter 1 (URAT1) inhibitor 2-((5-bromo-4-((4-bromonaphthalene)-) which has a therapeutic effect on gout and hyperuricemia.
  • URAT1 uric acid transporter 1
  • ZXS-BR Process for the preparation of 1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetic acid
  • Gout is an inflammatory disease caused by the precipitation of uric acid monosodium salt (MSU) in the joints and its surrounding tissues. It is characterized by periodic joint swelling and pain. If it is not treated, it will cause joint deformation and kidney stones, and even kidney failure. , seriously affecting the quality of life and health of patients.
  • MSU uric acid monosodium salt
  • Hyperuricemia is a prerequisite for gout. It is a serum uric acid (SUA) concentration exceeding the solubility limit of uric acid in physiological fluids (pH 7.4, temperature 37 ° C) (6.8 mg / dL, 404 ⁇ mol / L) The state of the disease. At physiological pH, 98% of uric acid is present in the state of ions. Because of the high concentration of extracellular Na + , uric acid is mainly present in the human body in the form of monosodium urate. Due to evolutionary reasons (nitrixase deficiency), uric acid is the end product of steroid metabolism in the human body.
  • SUV serum uric acid
  • hyperuricemia About one-third of the uric acid produced by metabolism is excreted through the gastrointestinal tract, and the remaining two-thirds are excreted through the kidneys. There are two causes of hyperuricemia: one is that too much uric acid is produced, and the other is that the kidneys excrete too little uric acid. About 10% of patients with hyperuricemia produce too much uric acid, and 90% of the kidneys excrete uric acid too. less. Sustained hyperuricemia can cause gout. In Europe and the United States, the incidence of hyperuricemia is about 20-30%, the incidence of gout is about 3%; in China, the incidence of hyperuricemia is about 10%, and the incidence of gout is about 1 %about. Epidemiological surveys in recent years have shown that the incidence of hyperuricemia and gout continues to rise.
  • the first is an anti-inflammatory analgesic drug that can control the symptoms of acute gout attacks, such as colchicine, steroidal anti-inflammatory drugs, and non-steroidal anti-inflammatory drugs; It is a drug that can treat uric acid production in chronic gout and hyperuricemia, mainly xanthine oxidase inhibitor (XOI), such as allopurinol, febuxostat and tomatesine; the third is treatable Chronic gout and hyperuricemia increase uric acid excretion drugs, mainly urate-anion exchanger 1 (URAT1) inhibitors, such as probenecid, sulfinpyrazone, benzbromarone and just listed Lesinurad.
  • XOI xanthine oxidase inhibitor
  • URAT1 urate-anion exchanger 1
  • Some drugs with special structure that are originally used for other indications also have uric acid action, such as losartan for the treatment of hypertension and atorvastatin for the treatment of hyperlipidemia; the fourth type is uricase, which can It is used to treat chronic gout that is ineffective with traditional treatment or to reduce blood uric acid during acute attacks of gout.
  • Bambulamon was also withdrawn from the market in Europe in 2003.
  • the use of the newly approved lesinurad is weak, the dosage is large (200mg), the dosage is very close to the side effect dose (400mg is obvious kidney stones, and renal failure is significantly increased compared with 200mg); uricase
  • the disadvantage is that antibodies are produced in the human body (about 25% of patients will produce antibodies), resulting in low efficiency (about 50%), long-term use of drug efficacy and infusion reactions. Therefore, the development of safe and effective therapeutic drugs has clinical value.
  • Uric acid in the blood is filtered in the glomerulus, and about 90% is reabsorbed back into the bloodstream in the renal tubules, and the URAT1 transporter is responsible for reabsorption.
  • URAT1 is a transporter discovered in 2002 (Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identifica-tion of a renal urate anion exchanger that regulates blood urate levels. Nature 2002, 417 (6887), 447-452) .
  • URAT1 inhibitors can be used to treat gout and hyperuricemia by inhibiting the reabsorption of uric acid by URAT1 in the kidney to increase the discharge of uric acid in the urine to reduce the concentration of blood uric acid.
  • a URAT1 inhibitor 2-((5-bromo-4-((4-bromonaphthalen-1-yl)methyl)-4H-), which is useful in the treatment of gout and hyperuricemia, is disclosed in PCT/CN2016/080468.
  • PCT/CN2016/080468 also discloses a process for the preparation of a ZXS-BR as described above, which is prepared according to the process of Example 1 of PCT/CN2016/080468 (see the third row of the table in which Example 51 is located). The record of the column).
  • This route has the following disadvantages: the starting material A (1,4-dibromonaphthalene) and the reagent sulfur phosgene are expensive; LiAlH 4 and sulfur phosgene are not conducive to industrial mass production because LiAlH 4 has strong activity in the reaction charge and It is dangerous in post-treatment, and the unpleasant smell of sulfur phosgene is very large, which is not conducive to the health of the operator.
  • the formulae A', B', C', D, E, F, G', H', and ZXS-BR each represent a compound represented by the following formula unless otherwise specified.
  • the invention provides a uric acid transporter 1 inhibitor 2-((5-bromo-4-((4-bromonaphthalen-1-yl)methyl)-4H-) as shown by the formula ZXS-BR
  • a method for preparing 1,2,4-triazol-3-yl)thio)acetic acid comprising the steps of:
  • N-bromosuccinimide (NBS) is brominated with the starting material A' (1-methylnaphthalene) to obtain the product B';
  • the solvent of the reaction is acetonitrile (MeCN), the reaction temperature is 30-40 ° C;
  • the free radical initiator is benzoyl peroxide (BPO) or azobisisobutyronitrile (AIBN);
  • the solvent of the reaction is selected from a C 5 -C 17 alkane or a cycloalkane, or a petroleum ether of a 30-150 ° C fraction; more preferably, the C 5 -C 17 alkane or cycloalkane is a n-pentane Alkane, cyclopentane, n-hexane, cyclohexane or n-heptane;
  • the temperature of the reaction is from 36 ° C to 120 ° C; more preferably, the temperature of the reaction is the reflux temperature of the solvent;
  • step 3 The product C' obtained in step 2) is reacted with thiocyanate (MSCN) at a temperature not lower than 100 ° C to obtain a product D;
  • MSCN thiocyanate
  • the thiocyanate is an alkali metal, alkaline earth metal or ammonium thiocyanate; preferably, the thiocyanate is sodium thiocyanate, potassium thiocyanate or ammonium thiocyanate;
  • the solvent of the reaction is selected from an aprotic dipolar solvent; more preferably, the aprotic The dipolar solvent is selected from the group consisting of dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) or hexamethyl phosphate Amide (HMPA);
  • DMF dimethylformamide
  • DMA N,N-dimethylacetamide
  • DMSO dimethyl sulfoxide
  • NMP N-methylpyrrolidone
  • HMPA hexamethyl phosphate Amide
  • the temperature of the reaction is from 100 ° C to the reflux temperature of the solvent; more preferably, the temperature of the reaction is from 120 ° C to 140 ° C;
  • the solvent of the reaction is tetrahydrofuran (THF);
  • step 5) the product E obtained in step 4) is closed in the presence of a base to obtain a product F;
  • the base is an alkali metal carbonate or an alkali metal hydroxide; more preferably Na 2 CO 3 , K 2 CO 3 , NaOH or KOH;
  • the X is selected from the group consisting of Cl, Br or I
  • the R is selected from a C 1 -C 10 alkyl group or a C 3 -C 6 cycloalkyl group; preferably, the R is selected from the group consisting of C 1 -C 4 More preferably, the R is selected from methyl or ethyl;
  • the base is selected from alkali metal hydroxides; more preferably, the base is selected from LiOH, NaOH or KOH;
  • reaction equation of the preparation method is as follows:
  • step 3 The product C' obtained in step 2) and KSCN in a solvent DMF, at a temperature of 140 ° C to obtain a product D;
  • step 4) The product D obtained in step 3) and the formylhydrazine in a solvent THF, at room temperature, to obtain the product E;
  • step 5) The product E obtained in step 4) is reacted with a base to obtain a product F;
  • the base is an alkali metal carbonate or an alkali metal hydroxide; more preferably Na 2 CO 3 , K 2 CO 3 , NaOH or KOH;
  • X is selected from Cl, Br or I, and said R is selected from a C 1 -C 10 alkyl group or a C 3 -C 6 cycloalkyl group;
  • said R is selected from a C 1 -C 4 alkyl group
  • said R is selected from methyl or ethyl
  • the base is an alkali metal hydroxide
  • the base is LiOH, NaOH or KOH.
  • the invention also provides a compound of formula H':
  • R is selected from C 1 -C 10 alkyl or C 3 -C 6 cycloalkyl; preferably, said R is selected from C 1 -C 4 alkyl; more preferably, said R is selected from Methyl or ethyl;
  • the invention also provides a compound of formula G':
  • R is selected from C 1 -C 10 alkyl or C 3 -C 6 cycloalkyl; preferably, said R is selected from C 1 -C 4 alkyl; more preferably, said R is selected from Methyl or ethyl.
  • the present invention provides compounds represented by the following formulas C', D, E, and F, respectively:
  • the preparation method provided by the present application has the following advantages:
  • reaction yield of A' ⁇ B' ⁇ C' ⁇ D is high, and there is no unfavorable reaction factor such as low yield and unfavorable quality control of intermediates in the original process such as A ⁇ B and B ⁇ C.
  • the preparation method provided by the present application is low in cost, easy to handle, easy to control in quality, and suitable for industrialization as compared with the prior art.
  • the reaction mixture was cooled to room temperature, transferred to a 5 L flask, ethyl acetate (1. 8L). After suction filtration, the filtrate was collected, and the cake was washed with a small amount of ethyl acetate, and the mixture was combined to filtrate.
  • the filtrate was washed with water (1 L ⁇ 5), dried over anhydrous sodium sulfate, and evaporated, evaporated, evaporated, evaporated. Stir, to obtain a clear solution. After the solution was slowly cooled to room temperature with stirring, a yellow syrup was obtained, and the filtrate was collected by suction and evaporated to dryness.
  • the reaction mixture was stirred slowly and carefully poured into ice water (400 mL), stirred, the organic phase was separated, the aqueous phase was extracted with CH 2 Cl 2 (150mL ⁇ 2 ).
  • the combined organic phases were successively (200mL) and washed with 2% diluted hydrochloric acid (300 mL) and 5% brine, dried over anhydrous Na 2 SO 4.
  • the dried organic phase was evaporated to dryness eluting EtOAcqqqqqq 1 H NMR showed that about 8% of the debrominated by-product was contained therein, and further purification was difficult, and it was directly used for the next reaction.
  • reaction mixture was evaporated to dryness on a rotary evaporator, the residue obtained is the crude E, in DMF (80mL) was dissolved, was added solid K 2 CO 3 (3.46g, 25mol ). The reaction mixture was stirred at 50 ° C until the reaction was complete (usually 5 hours).
  • reaction mixture was poured into ice water (400 mL), stirred, and extracted with CH 2 Cl 2 (100mL ⁇ 5 ). The combined organic phases were washed with 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.
  • reaction mixture was poured into ice water (200mL), stirred, and extracted with CH 2 Cl 2 (100mL ⁇ 3 ). The combined organic phases were washed with saturated Na 2 CO 3 solution (100mL ⁇ 3) and 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.
  • the free radical halogenation of the benzylic position of the alkyl group to which the aromatic ring is attached generally employs NBS (N-bromosuccinimide) or NCS (N-chlorosuccinimide).
  • NBS N-bromosuccinimide
  • NCS N-chlorosuccinimide
  • the amine is heated as a halogenating agent, BPO or azobisisobutyronitrile (AIBN) as a radical initiator in a solvent such as CCl 4 .
  • the inventors of the present invention have found that the reaction does not proceed smoothly in a solvent recognized by a person skilled in the art such as CCl 4 , and thus the main reaction conditions for the reaction, that is, a halogenating agent, a radical initiator and a reaction solvent, Intensive and careful optimization of the screening, and finally found that n-hexane is the most suitable solvent for this reaction, BPO is the best free radical initiator, NBS is the best halogenation reagent.
  • a solvent to be screened (40 mL) was added to a dry 250 mL round bottom flask at room temperature, and B' (3.54 g, 16 mmol), a free radical initiator (0.32 mmol) and NBS or NCS (19.2) were added with stirring. Mmmol), the temperature was raised to the specified temperature with stirring, and the reaction was followed by TLC. 0.32 mmol of the free radical initiator was added every 8 hours after the start of the reaction until TLC showed that the reaction ended spontaneously (B' disappeared) or was declared aborted (no reaction occurred after 72 hours).
  • the boiling temperature of a solvent at 760mmHg is the boiling point data of the solvent, but under actual experimental conditions, the actual temperature of a solvent boiling is affected by many factors (such as the altitude of the test site and the solvent). It is common knowledge to one of ordinary skill in the art that the type and concentration of dissolved solutes may fluctuate up and down around their standard melting point.
  • NBS is the best halogenation reagent in this step.
  • the reaction is too slow when using NCS; the initiator is optimal in BPO, and the AIBN effect is general; C 5 -C 17 in all test solvents Alkanes and naphthenes and petroleum ethers of the 30-150 ° C fraction are preferred, and the reaction temperature is about 36 ° C (n-pentane reflux temperature) - 120 ° C (cycloheptane reflux temperature).
  • DMF has a boiling point of 153 ° C under 760 mmHg pressure, but under actual experimental conditions, the actual temperature of DMF boiling is affected by many factors (such as the altitude of the test site and the type and concentration of dissolved solute in DMF). It may be fluctuating up and down around 153 ° C, which is common knowledge to those of ordinary skill in the art.
  • the reflux temperature of several solvents described in the above table is also near its boiling point, the boiling point of MeOH is 65 ° C; the boiling point of EtOH is 78 ° C; the boiling point of acetone is 56.5 ° C; the boiling point of EtOAc is 77 ° C; MeCN The boiling point was 81 ° C; the boiling point of THF was 65 ° C.
  • reaction mixture was cooled to room temperature, poured into ice water (3 L), extracted with dichloromethane (500 mL ⁇ 3), and the combined phases were combined with 5% aqueous Na 2 CO 3 (500 mL ⁇ 5), 10% Na 2 S 2
  • the aqueous solution of O 3 (500 mL) and 5% brine (500 mL) were washed and dried over anhydrous Na 2 SO 4 .
  • the dried organic phase is evaporated to dryness on a rotary evaporator and the residue obtained is purified by column chromatography to afford product B. Colorless oil, 39.80 g, yield 90%.
  • reaction mixture was cooled to room temperature, it was poured into stirring ice water (2000 mL), stirred, and extracted with CH 2 Cl 2 (300 mL ⁇ 3). The combined organic phases were washed with 5% brine (200mL ⁇ 5), dried over anhydrous dried over Na 2 SO 4.
  • reaction mixture was evaporated to dryness on a rotary evaporator, the residue obtained is the crude E, in DMF (80mL) was dissolved, was added a solid K 2 CO 3 (3.46g, 25mol ) and water (10mL) was prepared. The reaction mixture was stirred at 50 ° C until the reaction was complete (usually 5 hours).
  • reaction mixture was poured into ice water (400 mL), stirred, and extracted with CH 2 Cl 2 (100mL ⁇ 5 ). The combined organic phases were washed with 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.
  • reaction mixture was poured into ice water (200mL), stirred, and extracted with CH 2 Cl 2 (100mL ⁇ 3 ). The combined organic phases were washed with saturated Na 2 CO 3 solution (100mL ⁇ 3) and 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.
  • reaction mixture was cooled to room temperature, poured into ice water (5 L), extracted with dichloromethane (500 mL ⁇ 3), and the combined phases were combined with 5% aqueous Na 2 CO 3 (500 mL ⁇ 5), 10% Na 2 S 2
  • the aqueous solution of O 3 (500 mL) and 5% brine (500 mL) were washed and dried over anhydrous Na 2 SO 4 .
  • the dried organic phase is evaporated to dryness on a rotary evaporator and the residue obtained is purified by column chromatography to afford product B. Colorless oil, 39.80 g, yield 90%.
  • reaction mixture was cooled to room temperature, it was poured into stirring ice water (2000 mL), stirred, and extracted with CH 2 Cl 2 (300 mL ⁇ 3). The combined organic phases were washed with 5% brine (200mL ⁇ 5), dried over anhydrous dried over Na 2 SO 4.
  • reaction mixture was evaporated to dryness on a rotary evaporator, the residue obtained is the crude E, in DMF (80mL) was dissolved, a mixture of solid Na 2 CO 3 (2.65g, 25mol ) and water (10mL) formulated. The reaction mixture was stirred at 50 ° C until the reaction was complete (usually 5 hours).
  • reaction mixture was cooled to room temperature, it was poured into ice water (400 mL), stirred, and adjusted to pH 5-6 with hydrochloric acid, and extracted with CH 2 Cl 2 (150 mL ⁇ 5). The combined organic phases were washed with 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4. The dried organic phase was evaporated to dryness on a rotary evaporator and the residue was purified by column chromatography to afford product F as a white solid.
  • reaction mixture was poured into ice water (400 mL), stirred, and extracted with CH 2 Cl 2 (100mL ⁇ 5 ).
  • the combined organic phases were washed with 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.
  • the reaction mixture was poured into ice water (200mL), stirred, and extracted with CH 2 Cl 2 (100mL ⁇ 3 ).
  • the combined organic phases were washed with saturated Na 2 CO 3 solution (100mL ⁇ 3) and 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.
  • reaction mixture was cooled to room temperature, poured into ice water (5 L), extracted with dichloromethane (500 mL ⁇ 3), and the combined phases were combined with 5% aqueous Na 2 CO 3 (500 mL ⁇ 5), 10% Na 2 S 2
  • the aqueous solution of O 3 (500 mL) and 5% brine (500 mL) were washed and dried over anhydrous Na 2 SO 4 .
  • the dried organic phase is evaporated to dryness on a rotary evaporator and the residue obtained is purified by column chromatography to afford product B. Colorless oil, 39.80 g, yield 90%.
  • reaction mixture was cooled to room temperature, it was poured into stirring ice water (2000 mL), stirred, and extracted with CH 2 Cl 2 (300 mL ⁇ 3). The combined organic phases were washed with 5% brine (200mL ⁇ 5), dried over anhydrous dried over Na 2 SO 4.
  • reaction mixture was poured into ice water (400 mL), stirred, and extracted with CH 2 Cl 2 (100mL ⁇ 5 ).
  • the combined organic phases were washed with 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.
  • the reaction mixture was poured into ice water (200mL), stirred, and extracted with CH 2 Cl 2 (100mL ⁇ 3 ).
  • the combined organic phases were washed with saturated Na 2 CO 3 solution (100mL ⁇ 3) and 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.

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Abstract

提供一种如下式ZXS-BR所示的URAT1抑制剂2-((5-溴-4-((4-溴萘-1-基)甲基)-4H-1,2,4-三唑-3-基)硫代)乙酸的制备方法，其反应方程式如下所示。与现有技术相比，本申请提供的制备方法成本低、易操作、易于质量控制和适合工业化。

Description

一种尿酸转运体1抑制剂的制备方法 技术领域
本发明属于制药领域，具体而言，本发明涉及对痛风和高尿酸血症具有治疗作用的尿酸转运体1(URAT1)抑制剂2-((5-溴-4-((4-溴萘-1-基)甲基)-4H-1,2,4-三唑-3-基)硫代)乙酸(ZXS-BR)的制备方法。
背景技术
痛风是由于尿酸单钠盐(MSU)在关节及其周边组织沉淀引起的一种炎症性疾病，表现为周期性的关节红肿和疼痛，不加治疗的话会引起关节变形和肾结石，甚至肾衰竭，严重影响患者生活质量和生命健康。
高尿酸血症是引发痛风的前提，它是一种血尿酸(SUA)浓度超过尿酸在生理条件下(pH7.4，温度37℃)体液中的溶解度极限(6.8mg/dL，404μmol/L)的疾病状态。在生理pH下，98％的尿酸是以离子的状态存在的，由于细胞外Na+的浓度很高，因此尿酸在人体内主要是以尿酸单钠盐的形式存在。由于进化原因(尿酸酶缺失)，尿酸在人体内是嘌呤类代谢的最终产物，代谢产生的尿酸约有三分之一是通过胃肠道排泄，其余的三分之二通过肾脏排泄。造成高尿酸血症的原因有两种：一是尿酸产生太多，二是肾脏排泄尿酸太少，在高尿酸血症病人中约有10％是尿酸产生太多，90％为肾脏排泄尿酸太少。持续的高尿酸血症可能会引发痛风。在欧美国家，高尿酸血症的发病率约为20-30％，痛风的发病率约为3％左右；在中国，高尿酸血症的发病率约为10％，痛风的发病率约为1％左右。近几年的流行病学调查显示，高尿酸血症和痛风的发病率都在持续上升。
当前，用于治疗痛风的药物主要分四种：第一种是可以控制急性痛风发作症状的消炎镇痛药物，如秋水仙碱、甾体抗炎药物和非甾体抗炎药物；第二种是可以治疗慢性痛风和高尿酸血症的抑制尿酸产生的药物，主要是黄嘌呤氧化酶抑制剂(XOI)，如别嘌呤醇、非布司他和托匹司他；第三种是可以治疗慢性痛风和高尿酸血症的增加尿酸排泄的药物，主要是尿酸转运体1(urate-anion exchanger 1,URAT1))抑制剂，如丙磺舒、苯磺唑酮、苯溴马隆以及刚上市的lesinurad。一些本来用于其他适应症的具有特殊结构的药物，也具有排尿酸作用，如用于治疗高血压的氯沙坦和用于治疗高血脂的阿托伐他汀；第四类是尿酸酶，可以用于治疗使用传统治疗无效的慢性痛风或者在痛风急性发作时降低血尿酸。
现有的痛风治疗药物有许多不足之处。例如，有些药物的副作用很严重，例如用于控制急性痛风发作的秋水仙碱，常见的不良反应包括腹泻、呕吐、腹痛性痉挛，并且这些也是毒性的第一指征，治疗有效剂量与其引起胃肠道症状的剂量相近，副作用发生率极高(有时是100％)，直到2009年才被FDA批准在美国使用；其他控制急性痛风发作的抗炎镇痛药物只能控制症状，不能减缓或者治疗痛风本身；黄嘌呤氧化酶抑制剂的临床响应率很低，大部分有效率仅在40％-60％左右；另外，别嘌呤醇有严重的过敏反应，有时过敏反应是致命的；传统尿酸排泄药物丙磺舒、苯磺唑酮、苯溴马隆问题也很多，丙磺舒作用较弱，选择性不强(URAT1、OAT1、OAT3、OAT4抑制强度差不多)，苯磺唑酮和苯溴马隆副作用很大(前者抑制血小板和骨髓，后者具有肝毒性)，在美国没有销售，苯溴马隆于2003年在欧洲也撤市，现在仅在少数国家使用；新批准的lesinurad的缺点是药效弱，使用剂量大(200mg)，使用剂量与副作用剂量很近(400mg即有明显的肾结石，且肾衰竭相比200mg增加明显)；尿酸酶缺点是使用时人体内会产生抗体(约有25％的病人会产生抗体)，导致其有效率不高(约50％)、长期使用药效下降以及输液反应。因此，开发安全、有效的治疗药物具有临床价值。
血液中的尿酸在肾小球中被过滤，而后约90％在肾进曲小管中被重吸收回血液，负责重吸收的就是URAT1转运体。URAT1是2002年被发现的一个转运体(Enomoto A,Kimura H,Chairoungdua A,et al.Molecular identifica-tion of a renal urate anion exchanger that regulates blood urate levels.Nature2002,417(6887),447-452)。URAT1抑制剂可以通过抑制肾脏中URAT1对尿酸的重吸收功能来增加尿液中尿酸的排出进而达到降低血尿酸的浓度，从而可以用于对痛风和高尿酸血症的治疗。
PCT/CN2016/080468中公开了一种可用于痛风和高尿酸血症治疗的URAT1抑制剂2-((5-溴-4-((4-溴萘-1-基)甲基)-4H-1,2,4-三唑-3-基)硫代)乙酸(PCT/CN2016/080468的实施例51，结构见下图；在本发明中为了方便，将该化合物命名为ZXS-BR)及其药学上可以接受的盐，该URAT1抑制剂在体外对URAT1介导的HEK293细胞对14C-尿酸摄取的抑制作用很强，其IC50＝0.081μM，为lesinurad(IC50＝7.18μM)的88.6倍，适合制备痛风和高尿酸血症的治疗药物。
Figure PCTCN2017089993-appb-000001
PCT/CN2016/080468同时公开了一种用于制备如上式所述的ZXS-BR的方法，即参照PCT/CN2016/080468中的实施例1的工艺制备(见实施例51所在表格一行的第三列的记载)。该路线具有以下缺点：起始原料A(1,4-二溴萘)和试剂硫光气价格昂贵；LiAlH4和硫光气不利于工业化大规模生产，因为LiAlH4活性强，在反应投料和后处理时比较危险，硫光气不愉快的气味很大，不利于操作人员的健康；化合物A与CuCN反应制备化合物B时，即使在最优化的反应条件下得到的反应液中产物B也同时伴有未反应的原料A和过度氰化的副产物1,4-二氰基萘，反应后处理很复杂，且B的产率很低(张宪生，刘钰强等，RDEA3170的合成工艺研究.现代药物与临床.2015,30(10),1179-1184)；化合物B在使用LiAlH4还原时总是伴随大量脱溴产物，导致最终的B→F的收率很低，脱溴副产物的存在和沿着反应路线的往下传递给C、D和F等中间体的提纯和质量控制带来很大的不确定性，不利于大规模工业化生产。
Figure PCTCN2017089993-appb-000002
发明内容
因此，本发明的一个目的是克服现有技术的缺点和不足，提供一种用于制备URAT1抑制剂ZXS-BR的方法，该方法具有成本低、易操作、易质量控制且适合大规模工业化操作的优点。
在本发明中，除非特别说明，所述式A'、B'、C'、D、E、F、G'、H'、ZXS-BR分别代表如下式所示的化合物。
Figure PCTCN2017089993-appb-000003
一方面，本发明提供了一种如式ZXS-BR所示的尿酸转运体1抑制剂2-((5-溴-4-((4-溴萘-1-基)甲基)-4H-1,2,4-三唑-3-基)硫代)乙酸的制备方法，包括下述步骤：
1)N-溴代丁二酰亚胺(NBS)与原料A'(1-甲基萘)进行溴化反应，得到产物B'；
优选地，所述反应的溶剂为乙腈(MeCN)，反应温度为30-40℃；
2)将步骤1)得到的产物B'与N-溴代丁二酰亚胺在自由基引发剂的存在下反应得到产物C'；
其中，所述自由基引发剂为过氧化苯甲酰(BPO)或偶氮二异丁腈(AIBN)；
优选地，所述反应的溶剂选自C5-C17的烷烃或环烷烃，或30-150℃馏分的石油醚；更优选地，所述C5-C17的烷烃或者环烷烃为正戊烷、环戊烷、正己烷、环己烷或正庚烷；
优选地，所述反应的温度为36℃-120℃；更优选地，所述反应的温度为所述溶剂的回流温度；
3)将步骤2)得到的产物C'与硫氰酸盐(MSCN)在不低于100℃的温度下反应，得到产物D；
其中硫氰酸盐为碱金属、碱土金属或铵的硫氰酸盐；优选地，所述硫氰酸盐为硫氰酸钠、硫氰酸钾或硫氰酸铵；
优选地，所述反应的溶剂选自非质子偶极溶剂；更优选地，所述非质子 偶极溶剂选自二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、二甲基亚砜(DMSO)、N-甲基吡咯烷酮(NMP)或六甲基磷酸三酰胺(HMPA)；
优选地，所述反应的温度为100℃至溶剂的回流温度；更优选地，所述反应的温度为120℃至140℃；
4)将步骤3)得到的产物D与甲酰肼反应，得到产物E；
优选地，所述反应的溶剂为四氢呋喃(THF)；
5)将步骤4)得到的产物E在碱存在下闭环得到产物F；
优选地，所述碱为碱金属的碳酸盐或碱金属氢氧化物；更优选地为Na2CO3、K2CO3、NaOH或KOH；
6)将步骤5)得到的产物F与XCH2CO2R在碱存在下反应，得到产物G'；
其中，所述X选自Cl、Br或I，所述R选自C1-C10的烷基或C3-C6环烷基；优选地，所述R选自C1-C4的烷基；更优选地，所述R选自甲基或乙基；
7)将步骤6)得到的产物G'与NBS反应，得到产物H'；
8)将步骤7)得到的产物H'在碱存在下水解得到ZXS-BR。
优选地，所述碱选自碱金属氢氧化物；更优选地，所述碱选自LiOH、NaOH或KOH；
上述制备方法的反应方程式如下所示：
Figure PCTCN2017089993-appb-000004
在一个优选的实施方案中，所述制备方法的反应方程式如下所示：
Figure PCTCN2017089993-appb-000005
其中，包括下述步骤：
1)在溶剂MeCN中，在30-40℃下，使用N-溴代丁二酰亚胺(NBS)溴化原料A'(1-甲基萘)，得到产物B'；
2)将步骤1)得到的产物B'与NBS和BPO在正己烷中加热至回流反应，得到产物C'；
3)将步骤2)得到的产物C'与KSCN在溶剂DMF中，在140℃的温度下反应，得到产物D；
4)将步骤3)得到的产物D与甲酰肼在溶剂THF中，在室温下反应，得到产物E；
5)将步骤4)得到的产物E与碱反应闭环得到产物F；
优选地，所述碱为碱金属的碳酸盐或碱金属氢氧化物；更优选地为Na2CO3、K2CO3、NaOH或KOH；
6)将步骤5)得到的产物F与XCH2CO2R在碱存在下反应，得到产物G'；
其中，所述X选自Cl、Br或I，所述R选自C1-C10的烷基或C3-C6环烷基；
优选地，所述R选自C1-C4的烷基；
更优选地，所述R选自甲基或乙基；
7)将步骤6)得到的产物G'与NBS反应，得到H'；
8)将步骤7)得到的产物H'用碱水解得到ZXS-BR。
优选地，所述碱为碱金属氢氧化物；
更优选地，所述碱为LiOH、NaOH或KOH。
另一方面，本发明还提供了如下式H'所示的化合物：
Figure PCTCN2017089993-appb-000006
其中，R选自C1-C10的烷基或C3-C6的环烷基；优选地，所述R选自C1-C4的烷基；更优选地，所述R选自甲基或乙基；
另一方面，本发明还提供了如下式G'所示的化合物：
Figure PCTCN2017089993-appb-000007
其中，R选自C1-C10的烷基或C3-C6的环烷基；优选地，所述R选自C1-C4的烷基；更优选地，所述R选自甲基或乙基。
再另一方面，本发明还分别提供了如下式C'、D、E、F所示的化合物：
Figure PCTCN2017089993-appb-000008
与现有技术相比，本申请提供的制备方法具有以下优点：
1)起始原料A'(1-甲基萘)价格便宜，相比原工艺中的A(1,4-二溴萘)可以大幅度节约成本；
2)无价格昂贵的试剂；
3)无类似LiAlH4和硫光气等不利于工业化大规模生产的危险试剂，更易于操作和进行质量控制；
4)A'→B'→C'→D的反应产率高，无类似原工艺中A→B和B→C等导致低产率和不利于中间体质量控制等不利反应因素。
综上，与现有技术相比，本申请提供的制备方法成本低、易操作、易于质量控制和适合工业化。
实施发明的最佳方式
下面结合具体实施方式对本发明进行进一步详细的描述，给出的实施例仅为阐明发明，而不是为了限制本发明的范围。
实施例1  PCT/CN2016/080468的合成路线
Figure PCTCN2017089993-appb-000009
步骤1.化合物B的合成
在1L的干燥圆底烧瓶中加入化合物A(1,4-二溴萘，57.19g，200mmol)、CuCN(10.75g，120mmol)和DMF(600mL)，所得混合物在氮气气氛中130℃下搅拌12小时。
将反应混合物冷却到室温，转移到5L的烧瓶中，加入乙酸乙酯(1.8L)，室温下搅拌2-3小时，得到灰褐色浆状物。抽滤，收集滤液，滤饼用少量乙酸乙酯洗涤，洗涤液合并到滤液中。滤液用水(1L×5)洗涤，无水硫酸钠干燥，在旋转蒸发仪上蒸去溶剂，得到的黄色固体中加入乙酸乙酯-石油醚(400mL,体积比1:3)，升温至70℃，搅拌，得到澄清溶液。该溶液在搅拌下慢慢冷却到室温后，得到黄色浆状物，抽滤收集滤液，在旋转蒸发仪上蒸干，得到的残余物经硅胶柱层析纯化，用乙酸乙酯-石油醚(1:50→1:30)洗脱，得到B的纯品，白色固体，12.53g，收率27％。mp 103-104℃；1H NMR(DMSO-d6,400MHz),δ8.26-8.31(m,1H,Ar-H),8.13-8.18(m,1H,Ar-H),8.07(s,2H,Ar-H),7.85-7.92(m,3H,Ar-H)。
步骤2.化合物C的合成
将化合物B(11.60g,50mmol)溶于干燥的THF(200mL)中，搅拌，在冰水浴冷却下慢慢分批加入LiAlH4(2.77g,73mmol)，加完后，将反应混合物在冰水浴中继续搅拌2小时。
将反应混合物小心慢慢倾倒入搅拌的冰水(400mL)中，搅拌，用CH2Cl2(200mL×3)萃取。合并萃取有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物C，无色油状物，1H NMR显示其中含有约30％的脱溴副产物(即萘-1-甲胺)，难以进一步提纯，将该混合物直接用于下一步反应。
步骤3.化合物D的合成
上述步骤2制备的粗品化合物C(按照50mmol计)和二异丙基乙基胺(DIPEA，19.39g，150mmol)溶于干燥的CH2Cl2(200mL)中，所得溶液在冰水浴冷却下搅拌，而后慢慢滴加CSCl2(6.90g,60mmol)，滴加完毕后，所得溶液在室温下继续搅拌1小时，此时TLC检查发现反应完成。
反应混合物小心慢慢倾倒入搅拌的冰水(400mL)中，搅拌，分出有机相，水相用CH2Cl2(150mL×2)萃取。合并有机相，依次用2％稀盐酸(300mL)和5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物D，白色固体，8.21g,产率59％。1H NMR显示其中含有约8％的脱溴副产物，进一步提纯比较困难，直接用于下一步反应。少量上述粗品D经过连续3次柱层析和2次重结晶得到纯品D的样品用于结构表征，白色固体，熔点94.5-97.5℃；1H NMR(DMSO-d6,400MHz),δ8.21-8.24(m,1H),8.11-8.14(m,1H),7.92(d,1H,J＝7.6Hz),7.73-7.78(m,2H),7.52(d,1H,J＝8.0Hz),5.41(s,2H)。
步骤4.化合物F的合成
上述粗品化合物D(6.95g,按25mmol计)以THF(100mL)溶解，室温下搅拌，加入甲酰肼(1.80g,30mmol)，然后继续搅拌过夜，此时TLC检测反应完成。
反应混合物在旋蒸仪上蒸干，得到的残余物即为E的粗品，以DMF(80mL)溶解，加入固体K2CO3(3.46g,25mol)。反应混合物在50℃下搅拌，直到反应完成(通常5小时)。
反应混合物冷却到室温后，倾倒到冰水(400mL)中，搅拌，以盐酸调节pH＝5-6，用CH2Cl2(150mL×5)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物F，白色固体，1H NMR显示其中含有约5％的脱溴副产物，将该粗品F使用乙酸乙酯结晶两次，可以得到纯品F，6.96g,产率87％(D→F)。熔点243-244℃；1H NMR(DMSO-d6,400MHz),δ 13.88(brs,1H),8.37(s,1H),8.22(d,2H,J＝7.6Hz),7.90(d,1H,J＝7.2Hz),7.72(m,2H),7.18(d,1H,J＝7.2Hz),5.61(s,2H)。
步骤5.化合物G的合成
化合物F(6.40g,20mmol)溶于DMF(100mL)中，室温下搅拌，加入固体K2CO3(8.29g,60mmol)和溴乙酸甲酯(3.67g,24mmol)。所得反应混合物在室温下继续搅拌，直到TLC检测发现反应完成(通常5小时以内)。
反应混合物倾倒到冰水(400mL)中，搅拌，用CH2Cl2(100mL×5)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物G，白色固体，7.37g,产率94％。熔点112.5-114℃；1H NMR(DMSO-d6,400MHz),δ8.67(s,1H),8.22-8.25(m,1H),8.15-8.17(m,1H),7.88(d,1H,J＝7.6Hz),7.72-7.79(m,2H),6.92(d,1H,J＝7.6Hz),5.72(s,2H),4.07(s,2H),3.62(s,3H)。
步骤6.化合物H的合成
化合物G(3.92g,10mmol)溶于乙腈(50mL)中，室温下搅拌，加入NBS(2.14g,12mmol)，继续在室温下搅拌，直到TLC检测反应完成(通常12小时以内)。
反应混合物倾倒到冰水(200mL)中，搅拌，用CH2Cl2(100mL×3)萃取。合并有机相，依次用饱和Na2CO3溶液(100mL×3)和5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物H，白色固体，熔点141-143℃，3.49g,产率74％。1H NMR(DMSO-d6,400MHz),δ8.21-8.26(m,2H),7.84(d,1H,J＝8.0Hz),7.76-7.82(m,2H),6.49(d,1H,J＝7.6Hz),5.74(s,2H),4.08(s,2H),3.61(s,3H)。
步骤7.ZXS-BR的合成
化合物H(3.30g,7mmol)加入甲醇(50mL)中，室温下搅拌，加入由LiOH·H2O(0.84g,20mmol)和水(3mL)配成的溶液，而后室温下搅拌，直到TLC检测发现反应完成(通常2小时)。
反应混合物倾倒到冰水(200mL)中，搅拌，用盐酸调节pH＝2-3，用CH2Cl2(100mL×4)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过 柱层析纯化，得到产物ZXS-BR，白色固体，2.82g,产率88％。熔点169.5-171.5℃；1H NMR(DMSO-d6,400MHz),δ12.97(brs,1H),8.22-8.26(m,2H),7.83(d,1H,J＝8.0Hz),7.76-7.81(m,2H),6.51(d,1H,J＝8.0Hz),5.73(s,2H),4.01(s,2H).
实施例2步骤B'→C'的反应条件的筛选研究
Figure PCTCN2017089993-appb-000010
本领域内一般技术人员公认的是，芳环所连的烷基的苄位的自由基卤化，一般使用NBS(N-溴代丁二酰亚胺)或者NCS(N-氯代丁二酰亚胺)作为卤化剂、BPO或者偶氮二异丁腈(AIBN)等作为自由基引发剂、在CCl4等溶剂中加热进行。但是本发明的发明人发现，该反应在CCl4等本领域一般技术人员公认的溶剂中反应进行并不顺利，于是对该反应的主要反应条件，即卤化试剂、自由基引发剂和反应溶剂，进行了深入和仔细优化筛选，最终发现正己烷是本反应最合适的溶剂，BPO是最佳自由基引发剂，NBS是最佳卤化试剂。
反应操作：室温下向一只干燥的250mL的圆底烧瓶中加入待筛选溶剂(40mL)，搅拌下加入B'(3.54g,16mmol)、自由基引发剂(0.32mmol)和NBS或者NCS(19.2mmol)，搅拌升温至指定温度，并用TLC跟踪该反应的情况。反应开始后每8小时添加0.32mmol自由基引发剂一次，直到TLC显示反应自行结束(B'消失)或者被宣布中止(72小时后仍无反应发生)。如果TLC发现没有反应发生，或者没有C'/C”生成，则反应不需要处理；如果，有C'/C”生成，则按照如下步骤处理：反应结束后，将体系降至室温，反应混合物在旋转蒸发仪上浓缩至体积的1/3，倾倒到水(200mL)中，搅拌，用CH2Cl2(50mL×3)萃取，合并萃取相，依次用饱和NaHCO3溶液(50mL×3)和5％食盐水(50mL)洗涤，无水Na2SO4干燥，抽滤除去干燥剂后，滤液在旋转蒸发仪上蒸干，残余物柱层析纯化，分离得到C'/C”纯品，并计算其产率，反应条件和结果如表1所示。
表1反应条件和结果
Figure PCTCN2017089993-appb-000011
Figure PCTCN2017089993-appb-000012
*注：某种溶剂在760mmHg压力下沸腾的温度为该溶剂的沸点数据，但是在实际实验条件下，某种溶剂沸腾时实际温度受到多种因素影响(如试验场所的海拔影响和该溶剂中所溶解的溶质的种类和浓度)，可能会在其标准熔点附近上下波动，这是本领域一般技术人员的常识。上表所述的几种溶剂的实际回流温度，也是在其沸点附近，CCl4的沸点为76.8℃；CHCl3的沸点为61℃；CH2Cl2的沸点为39.8℃；丙酮的沸点为56.5℃；MeCN的沸点为81℃；THF的沸点为65℃；正己烷沸点为69℃；环己烷沸点为80℃；正戊烷沸点为36℃；环戊烷沸点为49℃；正庚烷沸点为98.5℃；环庚烷沸点为118.5℃(在本实验中约120℃时达到合理的中等回流速度)；30-60℃馏分的石油醚大约在35℃时中等程度回流；60-90℃馏分的石油醚大约在65℃时中等程度回流；90-120℃馏分的石油醚大约在95℃时中等程度回流；120-150℃馏分的石油醚大约在125℃时中等程度回流。
结论：由上表1可见，在该步中，NBS是最佳的卤化试剂，使用NCS时反应太慢；引发剂以BPO最优，AIBN效果一般；所有测试溶剂中以C5-C17的烷烃和环烷烃以及30-150℃馏分的石油醚最佳，反应温度大约在36℃(正戊烷回流温度)-120℃(环庚烷回流温度)均可。
实施例3步骤C'→D的反应温度的筛选研究
Figure PCTCN2017089993-appb-000013
本领域内一般技术人员公认，芳香族卤化苄与硫氰酸盐的反应比较容易，由于反应一般能在较低温度下进行，通常没有动机在较高温度下操作(节省能源动力消耗)，因此我们在室温下尝试C'与KSCN在DMF中反应时，发 现反应非常迅速(0.5小时内即可完成)，产物非常单一，但是分离并做结构鉴定后发现产物不是期望的D(异硫氰酸酯)，而是其异构体D'(硫氰酸酯)，后者为KSCN中的硫氰酸根离子的S端与C'反应的产物。为此，我们对该反应的硫氰酸盐种类和温度进行了详细和深入的研究，最终发现本反应需要在特定的较高温度范围内进行才能确保硫氰酸根离子的N端对C'反应的选择性。
反应操作：干燥的250mL的圆底烧瓶中加入化合物C'(3.00g,10mmol)，以干燥的溶剂(30mL)溶解，而后搅拌下升温至指定温度，在1分钟内分三批加入硫氰酸盐MSCN(12mmol)。加完后，反应混合物在该指定温度下继续搅拌1小时，此时反应完成。反应混合物冷却到室温后，倾倒入搅拌的冰水(200mL)中，搅拌，以CH2Cl2(50mL×3)萃取。合并有机相，用5％食盐水(50mL×5)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，分离得到产物D和D'，分别计算产率，试验条件和结果见表2。
表2试验条件和结果
Figure PCTCN2017089993-appb-000014
Figure PCTCN2017089993-appb-000015
*注：DMF在760mmHg压力下沸点为153℃，但是在实际实验条件下，DMF沸腾时实际温度受到多种因素影响(如试验场所的海拔影响和DMF中所溶解的溶质的种类和浓度)，可能会在153℃附近上下波动，这是本领域一般技术人员的常识。同样，上表所述的几种溶剂的回流温度，也是在其沸点附近，MeOH的沸点为65℃；EtOH的沸点为78℃；丙酮的沸点为56.5℃；EtOAc的沸点为77℃；MeCN的沸点为81℃；THF的沸点为65℃。
结论：从上表2中可以看出，与本领域内一般技术人员公认的不一样，化合物C'与硫氰酸盐的反应很快，室温下即可迅速完成；但是产物的分布具有明显的温度依赖性，在较高温度下产物倾向于本发明需要的D，而在较低温度下，产物主要是异构体D'，D/D'倾向性的逆转温度大约在100度左右。同时，该反应在非质子偶极溶剂(aprotic dipolar solvent)中进行的很好，如DMF、DMA、DMSO、NMP和HMPA等，在其他溶剂中进行的不好。
实施例4本发明的合成路线
Figure PCTCN2017089993-appb-000016
步骤1.化合物B'的合成
在1L的干燥圆底烧瓶中加入化合物A'(1-甲基萘,28.44g,200mmol)、NBS(42.72g,240mmol)和MeCN(700mL)，所得混合物在30℃-40℃下搅拌12小时。
反应混合物冷却到室温，倾倒到冰水(3L)中，二氯甲烷(500mL×3)萃取，合并萃取相，依次用5％Na2CO3水溶液(500mL×5)、10％Na2S2O3水溶液(500mL)和5％食盐水(500mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物B'。无色油状物，39.80g，收率90％。1H NMR(DMSO-d6,400MHz),δ8.14-8.16(m,1H),8.07-8.09(m,1H),7.76(d,1H,J＝7.6Hz),7.66-7.70(m,2H),7.30(d,1H,J＝7.6Hz),2.63(s,3H)。
步骤2.化合物C'的合成
室温下向干燥的1L的圆底烧瓶中加入正己烷(400mL)，搅拌下加入B'(35.37g,160mmol)、过氧化苯甲酰(BPO,0.775g,3.2mmol)和NBS(34.17g,192mmol)，搅拌升温至回流，直到TLC显示反应完成(反应开始后每8小时添加0.775g BPO一次；反应通常在36小时以内完成)。
反应结束后，将体系降至室温，搅拌2小时后抽滤，滤饼加入800mL水中室温搅拌1小时，抽滤，滤液弃去，滤饼再次加入800mL水中室温搅拌1小时，抽滤，滤液弃去。所得滤饼用800mL正己烷打浆搅拌2小时，抽滤，滤饼干燥即得C'纯品，白色固体，34.56g，收率72％。熔点104.0-105.5℃。1H NMR(DMSO-d6,400MHz),δ8.20-8.26(m,2H),7.86(d,1H,J＝8.0Hz),7.72-7.78(m,2H),7.62(d,1H,J＝7.6Hz),5.21(s,2H)。
步骤3.化合物D的合成
一只干燥的1L的圆底烧瓶中加入化合物C'(30.00g,100mmol)，以干燥的DMF(300mL)溶解，而后搅拌下升温至140℃，在1分钟内分三批加入KSCN(11.66g,120mmol)。加完后，反应混合物在140℃下继续搅拌1小时。
反应混合物冷却到室温后，倾倒入搅拌的冰水(2000mL)中，搅拌，以CH2Cl2(300mL×3)萃取。合并有机相，用5％食盐水(200mL×5)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物D，白色固体，25.59g,产率92％。熔点94.5-97.5℃；1H NMR(DMSO-d6,400MHz),δ8.21-8.24(m,1H),8.11-8.14(m,1H),7.92(d,1H,J＝7.6Hz),7.73-7.78(m,2H),7.52(d,1H,J＝8.0Hz),5.41(s,2H)。
步骤4.化合物F的合成
上述粗品化合物D(6.95g,按25mmol计)以THF(100mL)溶解，室温下搅拌，加入甲酰肼(1.80g,30mmol)，然后继续搅拌过夜，此时TLC检测反应完成。
反应混合物在旋蒸仪上蒸干，得到的残余物即为E的粗品，以DMF(80mL)溶解，加入由固体K2CO3(3.46g,25mol)和水(10mL)配制的溶液。反应混合物在50℃下搅拌，直到反应完成(通常5小时)。
反应混合物冷却到室温后，倾倒到冰水(400mL)中，搅拌，以盐酸调节pH＝5-6，用CH2Cl2(150mL×5)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物F，白色固体，1H NMR显示其中含有约5％的脱溴副产物，将该粗品F使用乙酸乙酯结晶两次，可以得到纯品F，6.96g,产率87％(D→F)。熔点243-244℃；1H NMR(DMSO-d6,400MHz),δ13.88(brs,1H),8.37(s,1H),8.22(d,2H,J＝7.6Hz),7.90(d,1H,J＝7.2Hz),7.72(m,2H),7.18(d,1H,J＝7.2Hz),5.61(s,2H)。
步骤5.化合物G的合成
化合物F(6.40g,20mmol)溶于DMF(100mL)中，室温下搅拌，加入固体K2CO3(8.29g,60mmol)和溴乙酸甲酯(3.67g,24mmol)。所得反应混合物在室温下继续搅拌，直到TLC检测发现反应完成(通常5小时以内)。
反应混合物倾倒到冰水(400mL)中，搅拌，用CH2Cl2(100mL×5)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机 相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物G，白色固体，7.37g,产率94％。熔点112.5-114℃；1H NMR(DMSO-d6,400MHz),δ8.67(s,1H),8.22-8.25(m,1H),8.15-8.17(m,1H),7.88(d,1H,J＝7.6Hz),7.72-7.79(m,2H),6.92(d,1H,J＝7.6Hz),5.72(s,2H),4.07(s,2H),3.62(s,3H)。
步骤6.化合物H的合成
化合物G(3.92g,10mmol)溶于乙腈(50mL)中，室温下搅拌，加入NBS(2.14g,12mmol)，继续在室温下搅拌，直到TLC检测反应完成(通常12小时以内)。
反应混合物倾倒到冰水(200mL)中，搅拌，用CH2Cl2(100mL×3)萃取。合并有机相，依次用饱和Na2CO3溶液(100mL×3)和5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物H，白色固体，熔点141-143℃，3.49g,产率74％。1H NMR(DMSO-d6,400MHz),δ8.21-8.26(m,2H),7.84(d,1H,J＝8.0Hz),7.76-7.82(m,2H),6.49(d,1H,J＝7.6Hz),5.74(s,2H),4.08(s,2H),3.61(s,3H)。
步骤7.ZXS-BR的合成
化合物H(3.30g,7mmol)加入甲醇(50mL)中，室温下搅拌，加入由LiOH·H2O(0.84g,20mmol)和水(3mL)配成的溶液，而后室温下搅拌，直到TLC检测发现反应完成(通常2小时)。
反应混合物倾倒到冰水(200mL)中，搅拌，用盐酸调节pH＝2-3，用CH2Cl2(100mL×4)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物ZXS-BR，白色固体，2.82g,产率88％。熔点169.5-171.5℃；1H NMR(DMSO-d6,400MHz),δ12.97(brs,1H),8.22-8.26(m,2H),7.83(d,1H,J＝8.0Hz),7.76-7.81(m,2H),6.51(d,1H,J＝8.0Hz),5.73(s,2H),4.01(s,2H)。
实施例5本发明的合成路线
Figure PCTCN2017089993-appb-000017
步骤1.化合物B'的合成
一只1L的干燥圆底烧瓶中加入化合物A'(1-甲基萘,28.44g,200mmol)、NBS(42.72g,240mmol)和MeCN(700mL)，所得混合物在30℃-40℃下搅拌12小时。
反应混合物冷却到室温，倾倒到冰水(5L)中，二氯甲烷(500mL×3)萃取，合并萃取相，依次用5％Na2CO3水溶液(500mL×5)、10％Na2S2O3水溶液(500mL)和5％食盐水(500mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物B'。无色油状物，39.80g，收率90％。1H NMR(DMSO-d6,400MHz),δ8.14-8.16(m,1H),8.07-8.09(m,1H),7.76(d,1H,J＝7.6Hz),7.66-7.70(m,2H),7.30(d,1H,J＝7.6Hz),2.63(s,3H)。
步骤2.化合物C'的合成
室温下向一只干燥的1L的圆底烧瓶中加入正己烷(400mL)，搅拌下加入B'(35.37g,160mmol)、过氧化苯甲酰(BPO,0.775g,3.2mmol)和NBS(34.17g,192mmol)，搅拌升温至回流，直到TLC显示反应完成(反应开始后每8小时添加0.775g BPO一次；反应通常在36小时以内完成)。
反应结束后，将体系降至室温，搅拌2小时后抽滤，滤饼加入800mL水中室温搅拌1小时，抽滤，滤液弃去，滤饼再次加入800mL水中室温搅拌1小时，抽滤，滤液弃去。所得滤饼用800mL正己烷打浆搅拌2小时，抽滤，滤饼干燥即得C'纯品，白色固体，34.56g，收率72％。熔点104.0-105.5℃。1H NMR(DMSO-d6,400MHz),δ8.20-8.26(m,2H),7.86(d,1H,J＝8.0Hz),7.72-7.78(m,2H),7.62(d,1H,J＝7.6Hz),5.21(s,2H)。
步骤3.化合物D的合成
一只干燥的1L的圆底烧瓶中加入化合物C'(30.00g,100mmol)，以干燥的DMF(300mL)溶解，而后搅拌下升温至140℃，在1分钟内分三批加入KSCN(11.66g,120mmol)。加完后，反应混合物在140℃下继续搅拌1小时。
反应混合物冷却到室温后，倾倒入搅拌的冰水(2000mL)中，搅拌，以CH2Cl2(300mL×3)萃取。合并有机相，用5％食盐水(200mL×5)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物D，白色固体，25.59g,产率92％。熔点94.5-97.5℃；1H NMR(DMSO-d6,400MHz),δ8.21-8.24(m,1H),8.11-8.14(m,1H),7.92(d,1H,J＝7.6Hz),7.73-7.78(m,2H),7.52(d,1H,J＝8.0Hz),5.41(s,2H)。
步骤4.化合物F的合成
上述粗品化合物D(6.95g,按25mmol计)以THF(100mL)溶解，室温下搅拌，加入甲酰肼(1.80g,30mmol)，然后继续搅拌过夜，此时TLC检测反应完成。
反应混合物在旋蒸仪上蒸干，得到的残余物即为E的粗品，以DMF(80mL)溶解，加入由固体Na2CO3(2.65g,25mol)和水(10mL)配制的混合物。反应混合物在50℃下搅拌，直到反应完成(通常5小时)。
反应混合物冷却到室温后，倾倒到冰水(400mL)中，搅拌，以盐酸调节pH＝5-6，用CH2Cl2(150mL×5)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物F，白色固体，1H NMR显示其中含有约5％的脱溴副产物，将该粗品F使用乙酸乙酯结晶两次，可以得到纯品F，6.80g,产率85％(D→F)。熔点243-244℃；1H NMR(DMSO-d6,400MHz),δ13.88(brs,1H),8.37(s,1H),8.22(d,2H,J＝7.6Hz),7.90(d,1H,J＝7.2Hz),7.72(m,2H),7.18(d,1H,J＝7.2Hz),5.61(s,2H)。
步骤5.化合物G'-1的合成
化合物F(6.40g,20mmol)溶于DMF(100mL)中，室温下搅拌，加入固体K2CO3(8.29g,60mmol)和氯乙酸乙酯(2.94g,24mmol)。所得反应混合物在室温下继续搅拌，直到TLC检测发现反应完成(通常10小时以内)。
反应混合物倾倒到冰水(400mL)中，搅拌，用CH2Cl2(100mL×5)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机 相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物G'-1，白色固体，7.72g,产率95％。ESI-MS,m/z＝406,408([M+H]+)。
步骤6.化合物H'-1的合成
化合物G'-1(4.06g,10mmol)溶于乙腈(50mL)中，室温下搅拌，加入NBS(2.14g,12mmol)，继续在室温下搅拌，直到TLC检测反应完成(通常12小时以内)。
反应混合物倾倒到冰水(200mL)中，搅拌，用CH2Cl2(100mL×3)萃取。合并有机相，依次用饱和Na2CO3溶液(100mL×3)和5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物H'-1，白色固体，3.69g,产率76％。ESI-MS,m/z＝486([M+H]+)。
步骤7.ZXS-BR的合成
化合物H'-1(3.40g,7mmol)加入甲醇(40mL)中，室温下搅拌，加入由NaOH(0.8g,20mmol)和水(1mL)配成的溶液，而后室温下搅拌，直到TLC检测发现反应完成(通常2小时)。
反应混合物倾倒到冰水(200mL)中，搅拌，用盐酸调节pH＝2-3，用CH2Cl2(100mL×4)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物ZXS-BR，白色固体，2.82g,产率88％。熔点169.5-171.5℃；1H NMR(DMSO-d6,400MHz),δ12.97(brs,1H),8.22-8.26(m,2H),7.83(d,1H,J＝8.0Hz),7.76-7.81(m,2H),6.51(d,1H,J＝8.0Hz),5.73(s,2H),4.01(s,2H)。
实施例6本发明的合成路线
Figure PCTCN2017089993-appb-000018
步骤1.化合物B'的合成
一只1L的干燥圆底烧瓶中加入化合物A'(1-甲基萘,28.44g,200mmol)、NBS(42.72g,240mmol)和MeCN(700mL)，所得混合物在30℃-40℃下搅拌12小时。
反应混合物冷却到室温，倾倒到冰水(5L)中，二氯甲烷(500mL×3)萃取，合并萃取相，依次用5％Na2CO3水溶液(500mL×5)、10％Na2S2O3水溶液(500mL)和5％食盐水(500mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物B'。无色油状物，39.80g，收率90％。1H NMR(DMSO-d6,400MHz),δ8.14-8.16(m,1H),8.07-8.09(m,1H),7.76(d,1H,J＝7.6Hz),7.66-7.70(m,2H),7.30(d,1H,J＝7.6Hz),2.63(s,3H)。
步骤2.化合物C'的合成
室温下向一只干燥的1L的圆底烧瓶中加入正己烷(400mL)，搅拌下加入B'(35.37g,160mmol)、过氧化苯甲酰(BPO,0.775g,3.2mmol)和NBS(34.17g,192mmol)，搅拌升温至回流，直到TLC显示反应完成(反应开始后每8小时添加0.775g BPO一次；反应通常在36小时以内完成)。
反应结束后，将体系降至室温，搅拌2小时后抽滤，滤饼加入800mL水中室温搅拌1小时，抽滤，滤液弃去，滤饼再次加入800mL水中室温搅拌1小时，抽滤，滤液弃去。所得滤饼用800mL正己烷打浆搅拌2小时，抽滤，滤饼干燥即得C'纯品，白色固体，34.56g，收率72％。熔点104.0-105.5℃。1H NMR(DMSO-d6,400MHz),δ8.20-8.26(m,2H),7.86(d,1H,J＝8.0Hz),7.72-7.78(m,2H),7.62(d,1H,J＝7.6Hz),5.21(s,2H)。
步骤3.化合物D的合成
一只干燥的1L的圆底烧瓶中加入化合物C'(30.00g,100mmol)，以干燥的DMF(300mL)溶解，而后搅拌下升温至140℃，在1分钟内分三批加入KSCN(11.66g,120mmol)。加完后，反应混合物在140℃下继续搅拌1小时。
反应混合物冷却到室温后，倾倒入搅拌的冰水(2000mL)中，搅拌，以CH2Cl2(300mL×3)萃取。合并有机相，用5％食盐水(200mL×5)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物D，白色固体，25.59g,产率92％。熔点94.5-97.5℃；1H NMR(DMSO-d6,400MHz),δ8.21-8.24(m,1H),8.11-8.14(m,1H),7.92(d,1H,J＝7.6Hz),7.73-7.78(m,2H),7.52(d,1H,J＝8.0Hz),5.41(s,2H)。
步骤4.化合物F的合成
上述粗品化合物D(6.95g,按25mmol计)以THF(100mL)溶解，室温下搅拌，加入甲酰肼(1.80g,30mmol)，然后继续搅拌过夜，此时TLC检测反应完成。
反应混合物在旋蒸仪上蒸干，得到的残余物即为E的粗品，以DMF(80mL)溶解，加入由固体NaOH(1.00g,25mol)和水(5mL)配制的混合物。反应混合物在50℃下搅拌，直到反应完成(通常5小时)。
反应混合物冷却到室温后，倾倒到冰水(400mL)中，搅拌，以盐酸调节pH＝5-6，用CH2Cl2(150mL×5)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物F，白色固体，1H NMR显示其中含有约5％的脱溴副产物，将该粗品F使用乙酸乙酯结晶两次，可以得到纯品F，6.64g,产率83％(D→F)。熔点243-244℃；1H NMR(DMSO-d6,400MHz),δ13.88(brs,1H),8.37(s,1H),8.22(d,2H,J＝7.6Hz),7.90(d,1H,J＝7.2Hz),7.72(m,2H),7.18(d,1H,J＝7.2Hz),5.61(s,2H)。
步骤5.化合物G'-1的合成
化合物F(6.40g,20mmol)溶于DMF(100mL)中，室温下搅拌，加入固体K2CO3(8.29g,60mmol)和氯乙酸乙酯(2.94g,24mmol)。所得反应混合物在室温下继续搅拌，直到TLC检测发现反应完成(通常10小时以内)。
反应混合物倾倒到冰水(400mL)中，搅拌，用CH2Cl2(100mL×5)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机 相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物G'-1，白色固体，7.72g,产率95％。ESI-MS,m/z＝406,408([M+H]+)。
步骤6.化合物H'-1的合成
化合物G'-1(4.06g,10mmol)溶于乙腈(50mL)中，室温下搅拌，加入NBS(2.14g,12mmol)，继续在室温下搅拌，直到TLC检测反应完成(通常12小时以内)。
反应混合物倾倒到冰水(200mL)中，搅拌，用CH2Cl2(100mL×3)萃取。合并有机相，依次用饱和Na2CO3溶液(100mL×3)和5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物H'-1，白色固体，3.69g,产率76％。ESI-MS,m/z＝486([M+H]+)。
步骤7.ZXS-BR的合成
化合物H'-1(3.40g,7mmol)加入甲醇(40mL)中，室温下搅拌，加入由KOH(1.12g,20mmol)和水(1mL)配成的溶液，而后室温下搅拌，直到TLC检测发现反应完成(通常2小时)。
反应混合物倾倒到冰水(200mL)中，搅拌，用盐酸调节pH＝2-3，用CH2Cl2(100mL×4)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na2SO4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物ZXS-BR，白色固体，2.82g,产率88％。熔点169.5-171.5℃；1H NMR(DMSO-d6,400MHz),δ12.97(brs,1H),8.22-8.26(m,2H),7.83(d,1H,J＝8.0Hz),7.76-7.81(m,2H),6.51(d,1H,J＝8.0Hz),5.73(s,2H),4.01(s,2H)。

Claims (10)

  1. 一种如式ZXS-BR所示的尿酸转运体1抑制剂2-((5-溴-4-((4-溴萘-1-基)甲基)-4H-1,2,4-三唑-3-基)硫代)乙酸的制备方法，包括下述步骤：
    1)N-溴代丁二酰亚胺与原料A'进行溴化反应得到产物B'；
    优选地，所述反应的溶剂为乙腈，反应温度为30-40℃；
    2)将步骤1)得到的产物B'与N-溴代丁二酰亚胺在自由基引发剂的存在下反应得到产物C'；
    3)将步骤2)得到的产物C'与硫氰酸盐在不低于100℃的温度下反应，得到产物D；
    4)将步骤3)得到的产物D与甲酰肼反应，得到产物E；
    优选地，所述反应的溶剂为四氢呋喃；
    5)将步骤4)得到的产物E在碱存在下闭环得到产物F；
    优选地，所述碱为碱金属的碳酸盐或碱金属氢氧化物；更优选地为Na2CO3、K2CO3、NaOH或KOH；
    6)将步骤5)得到的产物F与XCH2CO2R在碱存在下反应，得到产物G'；
    其中，所述X选自Cl、Br或I，所述R选自C1-C10的烷基或C3-C6环烷基；优选地，所述R选自C1-C4的烷基；更优选地，所述R选自甲基或乙基；
    7)将步骤6)得到的产物G'与N-溴代丁二酰亚胺反应，得到产物H'；
    8)将步骤7)得到的产物H'在碱存在下水解得到ZXS-BR；
    优选地，所述碱选自碱金属氢氧化物；更优选地，所述碱选自LiOH、NaOH或KOH；
    其中，所述式A'、B'、C'、D、E、F、G'、H'、ZXS-BR分别代表如下式所示的化合物：
    Figure PCTCN2017089993-appb-100001
    Figure PCTCN2017089993-appb-100002
  2. 如权利要求1所述的方法，其中在步骤2)中，所述自由基引发剂为过氧化苯甲酰或偶氮二异丁腈。
  3. 如权利要求1所述的方法，其中在步骤2)中，所述反应的溶剂选自C5-C17的烷烃或环烷烃，或30-150℃馏分的石油醚；优选地，所述C5-C17的烷烃或者环烷烃为正戊烷、环戊烷、正己烷、环己烷或正庚烷。
  4. 如权利要求1所述的方法，其中在步骤2)中，所述反应的温度为36℃-120℃；优选地，所述反应的温度为所述溶剂的回流温度。
  5. 如权利要求1所述的方法，其中在步骤3)中，硫氰酸盐为碱金属、碱土金属或铵的硫氰酸盐；优选地，所述硫氰酸盐为硫氰酸钠、硫氰酸钾或硫氰酸铵。
  6. 如权利要求1所述的方法，其中在步骤3)中，所述反应的溶剂选自非质子偶极溶剂；更优选地，所述非质子偶极溶剂选自二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、N-甲基吡咯烷酮或六甲基磷酸三酰胺。
  7. 如权利要求1所述的方法，其中在步骤3)中，所述反应的温度为100℃至溶剂的回流温度；更优选地，所述反应的温度为120℃至140℃。
  8. 如权利要求1-7中任一项所述的方法，其中，所述方法包括下述步骤：
    1)在溶剂乙腈中，在30-40℃下，N-溴代丁二酰亚胺进行原料A'进行溴化反应得到产物B'；
    2)将步骤1)得到的产物B'与N-溴代丁二酰亚胺和过氧化苯甲酰在正己烷中加热至回流反应，得到产物C'；
    3)将步骤2)得到的产物C'与硫氰酸钾在溶剂二甲基甲酰胺中，在 140℃的温度下反应，得到产物D；
    4)将步骤3)得到的产物D与甲酰肼在溶剂四氢呋喃中，在室温下反应，得到产物E；
    5)将步骤4)得到的产物E与碱反应闭环得到产物F；
    优选地，所述碱为碱金属的碳酸盐或碱金属氢氧化物；更优选地为Na2CO3、K2CO3、NaOH或KOH；
    6)将步骤5)得到的产物F与XCH2CO2R在碱存在下反应，得到产物G'；
    其中，所述X选自Cl、Br或I，所述R选自C1-C10的烷基或C3-C6环烷基；
    优选地，所述R选自C1-C4的烷基；
    更优选地，所述R选自甲基或乙基；
    7)将步骤6)得到的产物G'与N-溴代丁二酰亚胺反应，得到产物H'；
    8)将步骤7)得到的产物H'用碱水解得到ZXS-BR；
    优选地，所述碱为碱金属氢氧化物；
    更优选地，所述碱为LiOH、NaOH或KOH。
  9. 一种分别如下式H'或G'所述的化合物：
    Figure PCTCN2017089993-appb-100003
    其中，R选自C1-C10的烷基或C3-C6的环烷基；
    优选地，所述R选自C1-C4的烷基；
    更优选地，所述R选自甲基或乙基。
  10. 一种分别如下式C'、D、E或F所示的化合物：
    Figure PCTCN2017089993-appb-100004
PCT/CN2017/089993 2016-06-29 2017-06-26 一种尿酸转运体1抑制剂的制备方法 WO2018001197A1 (zh)

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US16/312,164 US11091448B2 (en) 2016-06-29 2017-06-26 Method for preparing urate transporter 1 inhibitor
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KR1020197002228A KR102326829B1 (ko) 2016-06-29 2017-06-26 요산염 음이온 트랜스포터 1 억제제의 제조 방법

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