WO2023125102A1 - 1H-呋喃并[3,2-b]咪唑并[4,5-d]吡啶化合物的合成方法 - Google Patents

1H-呋喃并[3,2-b]咪唑并[4,5-d]吡啶化合物的合成方法 Download PDF

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WO2023125102A1
WO2023125102A1 PCT/CN2022/139966 CN2022139966W WO2023125102A1 WO 2023125102 A1 WO2023125102 A1 WO 2023125102A1 CN 2022139966 W CN2022139966 W CN 2022139966W WO 2023125102 A1 WO2023125102 A1 WO 2023125102A1
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compound
reaction
add
solvent
water
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French (fr)
Chinese (zh)
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梁从新
李双江
黄君珉
施国强
段亚亚
严普查
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Hangzhou Highlightll Pharmaceutical Co Ltd
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Hangzhou Highlightll Pharmaceutical Co Ltd
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Priority to CN202280087204.6A priority Critical patent/CN118679166A/zh
Priority to CA3244846A priority patent/CA3244846A1/en
Priority to KR1020247025635A priority patent/KR20240129021A/ko
Priority to JP2024539899A priority patent/JP2024546195A/ja
Priority to US18/725,431 priority patent/US20250171458A1/en
Priority to IL313966A priority patent/IL313966A/en
Priority to MX2024008276A priority patent/MX2024008276A/es
Priority to EP22914356.5A priority patent/EP4509509A1/en
Priority to AU2022426316A priority patent/AU2022426316A1/en
Publication of WO2023125102A1 publication Critical patent/WO2023125102A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the technical field of drug synthesis, in particular to a synthesis method of 1H-furo[3,2-b]imidazo[4,5-d]pyridine compounds.
  • 1H-furo[3,2-b]imidazo[4,5-d]pyridine compounds are highly selective JAK1, TYK2 inhibitors, which selectively inhibit one or more protein kinases relative to other related kinases activity and are therefore expected to be useful in the treatment of diseases mediated by selective inhibition of one or more kinases while avoiding adverse side effects associated with inhibition of other kinases, for example, in disorders related to JAK1/TYK2 activity, such as Autoimmune diseases or disorders, or inflammatory diseases or disorders, and cancer or neoplastic diseases or disorders.
  • the object of the present invention is to provide a cost-saving, easy-to-operate, suitable for industrial scale synthesis of 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound method.
  • synthetic route 1 A synthetic method of 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound (hereinafter referred to as "synthetic route 1"), comprising the steps of:
  • step 1
  • step 1 in step 1,
  • the base is an organic base other than N,N-diisopropylethylamine, wherein the organic base is preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); or , the base is an inorganic base, wherein the inorganic base is preferably sodium carbonate (Na 2 CO 3 ), potassium bicarbonate (KHCO 3 ) or sodium bicarbonate (NaHCO 3 ), more preferably sodium bicarbonate (NaHCO 3 ); or the The base is N,N-diisopropylethylamine.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • the base is an inorganic base, wherein the inorganic base is preferably sodium carbonate (Na 2 CO 3 ), potassium bicarbonate (KHCO 3 ) or sodium bicarbonate (NaHCO 3 ), more preferably sodium bicarbonate (NaHCO 3 ); or the The base is N,N-d
  • the solvent is ethanol and/or acetonitrile, preferably, the solvent is ethanol, or a mixed solvent of acetonitrile and ethanol, wherein the volume ratio of acetonitrile to ethanol (mL/mL, or L/L) is 1:0.8 to 1 :1.2, preferably 1:1;
  • the molar ratio of compound 1 to compound 2 is 1:0.8 to 1:1.2, for example, 1:0.8, 1:0.9, 1:1, 1:1.01, 1:1.05, 1:1.1, 1:1.2;
  • the molar ratio of compound 1 to base is 1:2 to 1:2.5, preferably 1:2.1 to 1:2.3, more preferably 1:2.2 to 1:2.25, most preferably 1:2.2 to 1:2.23;
  • the molar ratio of compound 1 to base is 1:1 to 1:1.5, preferably 1:1.1 to 1:1.3;
  • the mass volume ratio (g/mL) of compound 1 to solvent is 1:9 to 1:10;
  • step 1 is optionally carried out under the protection of an inert gas (such as nitrogen);
  • an inert gas such as nitrogen
  • the reaction temperature is 50-80°C, and the reaction time is 16-22h;
  • step 2 in step 2,
  • the reducing agent used in the reduction reaction is a nitro reducing agent other than H 2 /Pd;
  • the reducing agent used in the reduction reaction is Fe/acetic acid, or B 2 (OH) 4 , or SnCl 2 ;
  • the solvent used for the reduction reaction is acetonitrile;
  • the molar ratio of compound 3 to Fe is 1:6 to 1:9, and the molar ratio of compound 3 to acetic acid is 1:12 to 1:14 ;
  • the mass volume ratio (g/mL) of compound 3 to solvent is 1:4 to 1:10, preferably 1:5 to 1:9;
  • the solvent used for the reduction reaction is a mixed solvent of water and methanol, wherein the volume ratio of water and methanol (mL/mL, or L/L) is 1:1 to 9 :1, preferably 3:1 to 5:1, more preferably 4:1; the molar ratio of compound 3 to B 2 (OH) 4 is 1:3 to 1:5; preferably 1:3.5; the mass of compound 3 and solvent
  • the volume ratio (g/mL) is 1:4 to 1:10, preferably 1:5 to 1:9; B 2 (OH) 4 is fed in batches;
  • the solvent used for the reduction reaction is ethyl acetate, wherein the molar ratio of Compound 3 to SnCl 2 is 1:2 to 1:9, preferably 1:3 to 1:6; Compound 3
  • the mass volume ratio (g/mL) with solvent is 1:4 to 1:20, preferably 1:5 to 1:15;
  • step 2 is optionally carried out under the protection of an inert gas (such as nitrogen);
  • an inert gas such as nitrogen
  • the reaction temperature is 15-90°C, and the reaction time is 1-18h;
  • the reducing agent is Fe/acetic acid
  • the reducing agent is B 2 (OH) 4
  • the reaction cool down to 35-45°C, concentrate part of the solvent under reduced pressure, cool down to 0-10°C and stir, filter, and rinse the filter cake with dichloromethane , collect the filtrate and add sodium bicarbonate in batches at 20-30 ° C, and keep stirring, stand still, separate the organic phase, extract the water phase with dichloromethane, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, and Add dropwise ethanol solution of hydrochloric acid at 15-25°C, keep stirring, add dropwise ethyl acetate at 15-25°C, keep stirring, filter, rinse the filter cake with ethyl acetate, and dry to obtain the hydrochloride of compound 4;
  • the reducing agent is SnCl 2
  • the reaction cool down to room temperature, add sodium bicarbonate in an ice bath, stir, filter, rinse the filter cake with ethyl acetate, collect the filtrate, and wash with saturated aqueous sodium bicarbonate Three times, the organic phases were combined, washed three times with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 4.
  • step 3 in step 3,
  • Compound 5 is R-lactic acid
  • Compound 5' is acetic acid or acetic anhydride
  • the ring closure reaction is carried out in a solvent, wherein the solvent is toluene, dioxane, acetic acid, methylcyclohexane or acetic anhydride;
  • the molar ratio of compound 4 to R-lactic acid is 1:4 to 1:30, preferably 1:4 to 1:20, more preferably 1:4 to 1: 10;
  • the mass volume ratio (g/mL) of compound 4 to solvent is 1:1.5 to 1:40, preferably 1:1.5 to 1:30, more preferably 1:1.5 to 1:15;
  • the mass volume ratio (g/mL) of compound 4 and acetic anhydride or acetic acid is 1: 1 to 1:10, preferably 1:2 to 1:5;
  • an acid catalyst in the ring-closing reaction of compound 4 and compound 5 or compound 5', wherein the acid catalyst is preferably methanesulfonic acid;
  • acetic acid or sodium acetate (NaOAc) is optionally added when the reaction reagent/solvent is acetic anhydride;
  • sodium acetate is optionally added when the reaction reagent/solvent is acetic acid;
  • the reaction temperature is 80-120°C, and the reaction time is 5-24h, preferably 16-18h;
  • the present invention provides a synthetic method of a 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound (using "Synthetic Route 1" for the synthesis of compound 6A, 6C, or a hydrate thereof, preferably a hydrate), comprising the steps of:
  • step 1
  • step 1 and step 2 are as described above, and in step 3,
  • the ring closure reaction is carried out in a solvent, wherein the solvent is toluene, dioxane, or methylcyclohexane, preferably toluene or methylcyclohexane, more preferably methylcyclohexane;
  • the molar ratio of compound 4 to R-lactic acid is 1:4 to 1:30, preferably 1:4 to 1:20, more preferably 1:4 to 1:10, most preferably 1:5 to 1:7;
  • the mass volume ratio (g/mL) of compound 4 to solvent is 1:1.5 to 1:40, preferably 1:1.5 to 1:30, more preferably 1:1.5 to 1:15, most preferably 1:1.5 to 1:5 ;
  • the present invention provides a synthetic method of a 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound (using "Synthetic Route 1" for the synthesis of compound 6B or 6D), comprising the steps of:
  • step 1
  • step 1 and step 2 are as described above, in step 3,
  • acetic acid or sodium acetate is optionally added, wherein the molar ratio of compound 4 to acetic acid is 1:0.1 to 1:0.5, preferably 1:0.2 to 1:0.3, for example 1:0.2 , the molar ratio of compound 4 to sodium acetate is 1:0.2 to 1:1, preferably 1:0.4 to 1:0.8, for example 1:0.5;
  • sodium acetate is optionally added, wherein the molar ratio of compound 4 to sodium acetate is 1:1 to 1:3, preferably 1:1.5 to 1:2.5, for example 1:2;
  • the mass volume ratio of compound 4 to acetic anhydride is 1:2 to 1:5, preferably 1:3;
  • the mass volume ratio of compound 4 to acetic acid is 1:3 to 1:8, preferably 1:5;
  • the reaction temperature is 80-120°C, preferably 90-110°C, and the reaction time is 12-24h, preferably 12-18h;
  • the present invention further provides a synthetic method for compound 1, comprising the following steps:
  • Step 1-2
  • step 1-1
  • the aqueous phase is extracted with an organic solvent, adjusted to pH ⁇ 8 with a base, layered, the aqueous phase is extracted with an organic solvent, the organic phases are combined, washed with water, the organic phase is added to anhydrous sodium sulfate to dry, filtered, and the solvent is removed to obtain Compounds 1-3;
  • step 1-1 further, in step 1-1,
  • the mass volume ratio (g/mL) of compound 1-1 to toluene and water is 1:5 to 1:6, and the volume ratio of toluene to water is 8:1 to 9:1;
  • the molar ratio of compound 1-1 to sodium carbonate is 1:1.1 to 1:1.2;
  • the molar ratio of compound 1-1 to triphenylphosphine is 1:1.1 to 1:1.2;
  • step 1-1 is optionally carried out under the protection of an inert gas (eg, nitrogen).
  • an inert gas eg, nitrogen
  • step 1-2 further, in step 1-2,
  • the tert-butoxide metal salt is potassium tert-butoxide or sodium tert-butoxide
  • the alkali used to adjust pH is ammonia water or sodium carbonate
  • the organic solvent used for extraction is methyl tert-butyl ether or ethyl acetate
  • the mass volume ratio of compound 1-2 to dimethyl sulfoxide is 1:3 to 1:5;
  • the molar ratio of compound 1-2 to metal tert-butoxide is 1:1.05 to 1:1.15, preferably 1:1.1;
  • the molar ratio of compound 1-2 to ethyl formate is 1:4 to 1:5;
  • step 1-2 The reaction of step 1-2 is optionally carried out under the protection of an inert gas (eg, nitrogen).
  • an inert gas eg, nitrogen
  • step 1-3 further, in step 1-3,
  • the mass volume ratio (g/mL) of compound 1-3 to dichloromethane is 1:6 to 1:10;
  • the molar ratio of compound 1-3 to boron tribromide is 1:2.0 to 1:3.5, preferably 1:2.5 to 1:3.2;
  • steps 1-3 are optionally carried out under the protection of an inert gas (eg, nitrogen).
  • an inert gas eg, nitrogen
  • step 1-4 further, in step 1-4,
  • the mass volume ratio (g/mL) of compound 1-4 to concentrated sulfuric acid is 1:2 to 1:5;
  • the mass volume ratio (g/mL) of compound 1-4 to dichloromethane is 1:25 to 1:26;
  • the molar ratio of compound 1-4 to benzoyl chloride is 1:1.5 to 1:2.5, preferably 1:2.
  • the mass ratio of compound 1-5 to acetic acid in the acetic acid solution of compound 1-5 is 1:9 to 1:11, preferably 1:10;
  • the mass ratio of acetic acid in the mixed solution of compound 1-5 to acetic acid, acetic anhydride and nitric acid is 1:3 to 1:5;
  • the molar ratio of compound 1-5 to acetic anhydride is 1:2 to 1:5, preferably 1:2.6 to 1:4.2;
  • the molar ratio of compound 1-5 to nitric acid is 1:2 to 1:5, preferably 1:2.5 to 1:4.0;
  • steps 1-5 are optionally performed under the protection of an inert gas (eg, nitrogen).
  • an inert gas eg, nitrogen
  • the mass volume ratio of compound 1-6 to toluene is 1:9 to 1:11, preferably 1:10;
  • the molar ratio of compound 1-6 to phosphorus oxychloride is 1:1.8 to 1:2.2, preferably 1:2;
  • steps 1-6 are optionally carried out under the protection of an inert gas (eg, nitrogen).
  • an inert gas eg, nitrogen
  • the present invention when compound 2 is compound 2a, the present invention further provides a method for synthesizing the hydrochloride of compound 2a, comprising the following steps:
  • Step 2-1
  • Step 2-2
  • step 2-1
  • step 2-2
  • step 2-1 further, in step 2-1,
  • the mass volume ratio (g/mL) of compound 2-1 to tetrahydrofuran is 1:10 to 1:12, preferably 1:10 to 1:11;
  • the molar ratio of compound 2-1 to sodium methoxide methanol solution is 1:0.2 to 1:0.3, preferably 1:0.25;
  • step 2-1 The reaction in step 2-1 is optionally performed under the protection of an inert gas (eg, nitrogen).
  • an inert gas eg, nitrogen
  • step 2-2 further, in step 2-2,
  • the mass volume ratio of compound 2-2 to dichloromethane is 1:5 to 1:7, preferably 1:6;
  • the molar ratio of compound 2-2 to hydrogen chloride ethanol solution is 1:2 to 1:5, preferably 1:3;
  • step 2-2 The reaction in step 2-2 is optionally performed under the protection of an inert gas (eg, nitrogen).
  • an inert gas eg, nitrogen
  • the present invention provides another synthetic method of 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound (hereinafter referred to as "Synthetic Route 2", using In synthetic compound 6A and 6B), comprise the steps:
  • the cis-trans isomer mixture 8 is reduced to obtain the cis-trans isomer mixture 9 or its hydrochloride;
  • mixture 10 or the hydrate of mixture 10 wherein R is methyl or ethyl, wherein the methyl or ethyl Optionally substituted by hydroxy, preferably, R is methyl or 1-hydroxyethyl, the hydrate of mixture 10 is preferably the monohydrate of mixture 10;
  • the mixture 10 or the hydrate of the mixture 10 undergoes an isomer conversion reaction under alkaline conditions to obtain the compound 6 or the hydrate of the compound 6, and the hydrate of the compound 6 is preferably a monohydrate of the compound 6.
  • Step 1A, Step 2A and Step 3A follow Step 1, Step 2 and Step 3 of Synthetic Route 1, and in Step 4A, the reaction is carried out under alkaline conditions, and the base is an alkoxide base, preferably an alkali metal C1-6 alkoxide, more preferably, potassium tert-butoxide.
  • the base is an alkoxide base, preferably an alkali metal C1-6 alkoxide, more preferably, potassium tert-butoxide.
  • the present invention provides another synthetic method of compound 6A, comprising step 1A, step 2A, step 3A and step 4A, wherein, step 1A, step 2A and step 3A prepare compound 6A according to the above ( The method described in step 1, step 2 and step 3 of synthetic route 1), wherein:
  • the cis-trans isomer mixture 8 is reduced to obtain the cis-trans isomer mixture 9 or its hydrochloride;
  • the cis-trans isomer mixture 9 or its hydrochloride and R-lactic acid undergo ring closure reaction to obtain the mixture 6Aa or the hydrate of the mixture 6Aa;
  • the mixture 6Aa or the hydrate of the mixture 6Aa undergoes an isomer conversion reaction under alkaline conditions to obtain the hydrate of the compound 6A.
  • the base is an alkoxide base, preferably an alkali metal C 1-6 alkoxide, more preferably, potassium tert-butoxide; the hydrate of compound 6A is preferably a monohydrate of compound 6A.
  • step 4A in the synthesis method of compound 6A through steps 1A-4A, in step 4A,
  • reaction is carried out in a solvent, wherein said solvent is preferably tetrahydrofuran;
  • the molar ratio of mixture 6Aa to base is 1:0.05 to 1:0.2, preferably 1:0.1 to 1:0.2;
  • the reaction is carried out at room temperature;
  • the present invention provides another synthetic method of compound 6B, comprising step 1A, step 2A, step 3A and step 4A, wherein, step 1A, step 2A and step 3A prepare compound 6B according to the above ( The method described in step 1, step 2 and step 3 of synthetic route 1), wherein:
  • the cis-trans isomer mixture 8 is reduced to obtain the cis-trans isomer mixture 9 or its hydrochloride;
  • the cis-trans isomer mixture 9 or its hydrochloride and acetic anhydride and/or acetic acid undergo a ring-closing reaction to obtain a mixture 6Ba;
  • the base is an alkoxide base, preferably an alkali metal C 1-6 alkoxide, more preferably, potassium tert-butoxide.
  • step 4A in the synthesis method of compound 6B through steps 1A-4A, in step 4A,
  • reaction is carried out in a solvent, wherein said solvent is preferably tetrahydrofuran;
  • the molar ratio of mixture 6Ba to base is 1:0.05 to 1:0.2, preferably 1:0.1 to 1:0.2;
  • the reaction is carried out at room temperature;
  • the synthesis method of the 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound of the present invention has high yield, less impurities and is easy to control, cost saving and easy to operate, and is suitable for industrial scale.
  • Fig. 1 is the 1 H NMR spectrum of compound 1 prepared in Example 6 of the present invention.
  • Fig. 2 is the LCMS spectrogram of compound 1 prepared in Example 6 of the present invention.
  • Fig. 3 is the 1 H NMR spectrum of compound 2a prepared in Example 8 of the present invention.
  • Fig. 4 is a TsCl-derived HPLC spectrum of compound 2a prepared in Example 8 of the present invention.
  • Fig. 5 is the N ⁇ -(2,4-dinitro-5-fluorophenyl)-L-valinamide derivatized HPLC spectrum of compound 2a prepared in Example 8 of the present invention.
  • Fig. 6 is the 1 H NMR spectrum of compound 6A prepared by method A of Example 13 of the present invention.
  • Fig. 7 is the HPLC spectrum of compound 6A prepared by method A of Example 13 of the present invention.
  • Fig. 8 is the HPLC spectrum of the compound 6A isomer prepared by method A of Example 13 of the present invention.
  • Fig. 9 is the 1 H NMR spectrum of compound 6B prepared by method A in Example 15 of the present invention.
  • Fig. 10 is the HPLC spectrum of compound 6B prepared by method A in Example 15 of the present invention.
  • Fig. 11 is the 1 H NMR spectrum of compound 6B tartrate prepared in Example 16 of the present invention.
  • Fig. 12 is the HPLC spectrogram of compound 6B tartrate prepared in Example 16 of the present invention.
  • Figure 13 is the HPLC spectrogram of Compound 1 prepared in Example 6 of the present invention.
  • Fig. 14 is the 1 H NMR spectrum of compound 6C prepared in Example 14 of the present invention.
  • Figure 15 is the TGA spectrum of compound 6A prepared in Example 13 of the present invention.
  • the chromatographic analysis conditions are:
  • the moisture determination method According to the operating procedures of the moisture determination method, weigh about 0.2-0.5 g of the test sample of compound 1, and the result is accurate to 0.1 mg, add it into the titration cup of the titrator for measurement, record the result, and measure twice in parallel with the same method, and take the result of the two times.
  • the average value is the moisture content of the test product, and the result is kept to one decimal place.
  • Gas chromatograph such as: Shimadzu GC-2014C or similar gas chromatograph
  • Injector temperature 230°C.
  • W1 is the weight of the sample before drying
  • W2 is the weight of the sample after drying
  • the solvent is CDCl 3 , which is tested by an external unit according to USP ⁇ 761>.
  • Mobile phase A (%, V/V) Mobile phase B (%, V/V) 0 80 20 20 50 50 30 30 70 40 30 70 40.01 80 20 50 80 20
  • Reactor 1 was protected under nitrogen, and 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (250kg, 1.0eq) was added, and toluene (1050kg) and drinking water (150kg) were added. Turn on stirring and cool down to 20-25°C. Add sodium carbonate (68.8kg, 0.58eq) in batches, control the temperature in the kettle to ⁇ 30°C, stir for 0.5h, stop stirring, let stand for 20 minutes, separate layers, and keep the upper organic phase. The lower aqueous phase enters reactor 2 and is extracted with toluene (435kg), and the organic phase is combined into reactor 1.
  • the aqueous phase continued to be extracted with toluene (225kg), the lower aqueous phase was discarded, and the organic phase was combined into Reactor 1.
  • the organic phase was washed with saturated brine (204kg), and dried over anhydrous sodium sulfate (150kg). After filtering, the filtrate enters the reactor 3, and the solid is rinsed with toluene (50kg).
  • Reactor 3 was added with triphenylphosphine (350kg, 1.2eq), stirred, the internal temperature rose to 108-115°C, refluxed for 18h, and water was separated with a water separator. After the reaction is finished, the temperature of the materials in the reactor 3 is lowered to 20-30°C.
  • the reaction kettle 1 was cooled to ⁇ 25°C; extracted with ethyl acetate (1320.7kg, 3V) and drinking water (1467.4kg, 3V), the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate, and the organic phase and washed with water (978.3 kg).
  • the organic phase was separated and washed once with water (250.0 kg), the aqueous phases were combined and extracted twice with ethyl acetate (1320.2 kg).
  • Ethyl acetate (1320.7kg, 3V) was added to the aqueous phase and sodium carbonate (54.0kg) was added in batches to adjust the pH to ⁇ 8.
  • the organic phase was separated, the aqueous phase was extracted with ethyl acetate (880.4kg, 2V), the organic phase was washed with saturated aqueous sodium chloride solution (341.3kg), dried with anhydrous sodium sulfate (217.4kg) and suction filtered, and the solid was extracted with ethyl acetate (81.5kg) rinsing, collect filtrate and take off solvent, add n-heptane (337.0kg) beating centrifugal, solid is rinsed with n-heptane (76.0kg), obtains compound 1-3 after drying (output 202.0kg, yield 88.8 %, HPLC purity 97.3%).
  • Reaction kettle 1 was protected by nitrogen, and compound 1-3 (200.0kg, 1.0eq) and dichloromethane (1431.0kg, 6V) were added, and the temperature of the materials in the kettle was controlled at 15-20°C. Add boron tribromide (600.0kg, 2.5eq), and control the temperature of the material in the kettle at 20-30°C. After the addition, keep stirring at 20-30°C for 1h. Slowly add the mixed solution in Reactor 1 dropwise to Reactor 2 containing absolute ethanol (1422.0kg, 10V) at 15-30°C under the protection of nitrogen, and keep stirring the reaction system at 30-35°C for 2h. The solvent was removed under reduced pressure to 1600L, and stripped twice to 1600L with absolute ethanol (570.0kg, 4V).
  • Benzoyl chloride (214.6kg, 2.0eq) was slowly added dropwise to a solution of compound 1-4 (170.0kg, 1.0eq) in dichloromethane (3271.0kg, 25.5V) at 0-10°C. The reaction was stirred at 0-10 °C for 1 h. Slowly add the reaction solution dropwise into the reactor containing sulfuric acid (1518.0kg, 4.85V) at 15-25°C, and keep stirring for 1h. The reaction was quenched with water (850.0 kg, 5V) at 0-10 °C.
  • Nitric acid (52.5kg) was added dropwise to Reactor 1 containing acetic acid (141.0kg) and acetic anhydride (89.25kg) at 15-30°C, and stirred at 20-30°C for 0.5h.
  • acetic acid 141.0kg
  • acetic anhydride 89.25kg
  • acetic acid 450.0kg, 10W
  • compound 1-5 45.0kg, 1.0eq
  • the solid was stirred in dichloromethane (1224.0kg, 13V) for 15 minutes, and 5% aqueous sodium bicarbonate solution (357.0kg) and diatomaceous earth (35.7kg) were added, and stirred for 0.5 hours.
  • the solid was separated and rinsed with dichloromethane (195.3kg, 2V), the filtrate was collected and the dichloromethane layer was separated and extracted with dichloromethane (474.3kg, 5V), the dichloromethane layers were combined and washed with saturated brine (485.5kg), without Sodium sulfate water (107.0kg, 1.5W) was dried for 1 hour, filtered, the solid was rinsed with dichloromethane (188.7kg, 2V), the filtrate was collected and activated carbon (7.0kg, 0.1W) was added, stirred at 20-30°C for 1 hour The solid was then filtered and rinsed with dichloromethane (93.8 kg, 1V).
  • Compound 3a was prepared by the same preparation method as Method B except that the added base was different from Method B, wherein the added base was sodium carbonate (2.2eq), and the HPLC detection content was 72%.
  • Compound 3a was prepared by the same preparation method as Method B except that the added base was different from Method B, wherein the added base was potassium bicarbonate (2.2 eq), and the HPLC detection content was 83%.
  • the organic phase was washed successively with 20% sodium citrate aqueous solution (water 60kg, sodium citrate 15kg, 0.47eq) and 15% sodium chloride aqueous solution (water 61.3kg, sodium chloride 10.8kg) and added anhydrous sodium sulfate (41.5 kg) and silica gel (5.23kg) were stirred for 30min. Filter and rinse with ethyl acetate (67kg). Distill under reduced pressure, add 30kg of isopropanol to the system, evaporate to dryness under reduced pressure, add 30kg of isopropanol and evaporate to dryness under reduced pressure, add 101.15kg of isopropanol, stir and heat up to 80°C to dissolve the clear.
  • the TGA spectrum shows that there is 5.353 % step weight loss, corresponding to lose the weight of a molecule of water), output 14.76kg, moisture 5.2%, isopropanol residual 0.0405%, the HPLC purity of compound 6A is 99.94%; The HPLC content of compound 6A isomer is 0.21%, Yield: 66.2%. See Figure 6 for the 1 H NMR spectrum, Figure 7 for the HPLC spectrum of Compound 6A, and Figure 8 for the HPLC spectrum of the isomer of Compound 6A.
  • compound 6A was prepared by the same preparation method as method A, wherein the compound 4a was 1 g, and the reaction solvent was 1,4-dioxane (6mL), R-lactic acid (20eq) , and add methanesulfonic acid (2g), detect HPLC content 91.1%, HPLC content 98.2% after sodium hydroxide hydrolysis.
  • compound 6A was prepared by the same preparation method as method A, wherein the compound 4a was 1g, the reaction solvent was 1,4-dioxane (10mL), R-lactic acid (30.2eq ), heated at 95-105° C. for 16 hours, detected HPLC content of 70%, after sodium hydroxide hydrolysis, HPLC content of 99.6%, chiral purity of 99.0%.
  • compound 6A was prepared by the same preparation method as method A, wherein the compound 4a was 10 g, the reaction solvent was toluene (75 mL), heated at 108-113 ° C for 10 hours, and the HPLC content was detected to be 97 %, chiral purity 96%.
  • compound 6B was prepared by the same preparation method as method A, wherein the hydrochloride (0.5g) of compound 4a, the reaction reagent/solvent was acetic acid (2.5mL), and the temperature was controlled at 100-110 °C, 23 hours to detect the HPLC content was 26%.
  • compound 6B was prepared by the same preparation method as method A, wherein the hydrochloride salt (0.5g) of compound 4a, the reaction reagent/solvent was acetic acid (2.5mL), and sodium acetate (0.24 g, 2eq), the HPLC content detected in 23 hours was 93%.
  • compound 6B was prepared by the same preparation method as method A, wherein acetic acid (0.2 eq) was added to the system, and the HPLC content was 99% after 18 hours.
  • Compound 6B was prepared by the same preparation method as Method A except for the following differences with Method A, wherein sodium acetate (0.5 eq) was added to the system, and the HPLC content was 99% after 18 hours.
  • Embodiment 17 Preparation of cis-trans isomer mixture 8
  • Embodiment 18 Preparation of cis-trans isomer mixture 9

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