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CN109983008A - A kind of Preparation Method And Their Intermediate of pyridinecarboxylic amine derivant - Google Patents

A kind of Preparation Method And Their Intermediate of pyridinecarboxylic amine derivant Download PDF

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Publication number
CN109983008A
CN109983008A CN201880004432.6A CN201880004432A CN109983008A CN 109983008 A CN109983008 A CN 109983008A CN 201880004432 A CN201880004432 A CN 201880004432A CN 109983008 A CN109983008 A CN 109983008A
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formula
compound shown
acid
reaction
compound
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姚飞
邱振均
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a kind of Preparation Method And Their Intermediate of pyridinecarboxylic amine derivant, this method shortens reaction step, improves reaction yield, simple easily manipulation, is conducive to industrial expanding production.

Description

A kind of Preparation Method And Their Intermediate of pyridinecarboxylic amine derivant Technical field
The present invention relates to a kind of Preparation Method And Their Intermediates of pyridinecarboxylic amine derivant.
Background technique
Diuretics is commonly recommended in various countries' Hypertension Guideline as a line antihypertensive drugs, when being suitable for Mild or moderate hypertension, especially senile hypertension or Complicated by Heart Failure.
Clinically, traditional diuretics has the risk for leading to hypokalemia.ROMK is the novel targets of anti-hypertension diuretics exploitation, and ROMK is the K of inward rectification +A member of channel (inwardly rectifying K channels, Kir) family, belongs to Kir1 type, vital to maintaining kidney potassium ion balance to play the role of.In mouse kidney, at least there is the channel ROMK of three kinds of hypotypes: ROMK1, ROMK2 and ROMK3 type.ROMK2 is largely distributed in ascending thick limb of Henle's loop (ascending limb of Henle, TALH)；Mainly (Cortical collecting duct, CCD) is expressed ROMK1 and ROMK3 on concetrated pipe.It is expressed in the ROMK and Na of TALH +/K +/2Cl -Transporter adjusts the secretion and reabsorption of sodium potassium ion together, is expressed in the ROMK and Na of CCD +/K +Transporter adjusts the secretion of potassium ion together.Therefore, block the site ROMK both can be by inhibiting Na +Reabsorption diuretic antihypertensive, and be unlikely to reduce blood potassium excessively to lead to hypopotassaemia, be a good diuretics research direction.
WO2016091042A1 (publication date 2016-06-16) discloses a kind of kidney priopticon secretion potassium channel (ROMK) inhibitor, entitled (R)-5- cyano-N- (1- (2- hydroxyl-2- (the 4- methyl-1-oxo-1 of chemistry, 3- dihydroisobenzofuran -5- base) ethyl) piperidin-4-yl) and -4-methoxypyridine formamide compound, relative to other ROMK inhibitor, the compound increases polar groups, on the basis of keeping ROMK inhibitor activity, reduce ClogP, improve hERG selectivity, increase safety, shown in its structure such as formula (A).
The embodiment 1 of WO2016091042A1 discloses the preparation method of compound A, amounts to the reaction of five steps, and specific reaction is as follows:
There is the problems such as reaction step number is more, batch is small, post-processing approach uses thin layer chromatography, low yield in this method, wherein the yield of second step reaction is 22.4%, the yield that final step prepares product is only 11.3%, is unfavorable for industrial expanding production, it is necessary to improve preparation method.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of methods with compound shown in the completely different preparation formula (I) of the prior art, change starting material and intermediate prepares target product, optimize preparation method by shortening the approach such as the reactants such as reaction step, starting material are simply easily bought, reaction condition is simple controllably, reaction postprocessing method is simple, raising yield is conducive to industry expanding production.
Technical scheme is as follows:
The present invention provides a kind of method for preparing compound shown in formula (I), it is characterized in that, the step of obtaining compound shown in formula (I) under condensing agent effect the method includes compound or its salt shown in compound or its salt shown in formula (III) and formula (II)
The X is selected from acyl group, the halogen, preferably-OH that-OH, alkoxy, alkoxy replace.
In a preferred scheme of the invention, the method is
Under conditions of condensing agent acylation reaction is occurred into for compound shown in compound shown in formula (III-1) and formula (II-1); the condensing agent is selected from CDI, EDC.HCl/HOBT, DIC/HOBT, EDC.HCl/DMAP, HATU, HBTU, DIC/DMAP, preferably DIC/HOBT.
In above scheme, the method also includes
Compound shown in formula (IV) is carried out to removing Boc protection group reaction in acid condition；The acid condition, which is selected from, uses HCl gas/ethyl alcohol, HCl gas/tetrahydrofuran, HCl gas/ethyl acetate, and HCl gas/Isosorbide-5-Nitrae-dioxane is precipitated product from reaction solution at salt with hydrochloric acid, preferably HCl gas/ethyl acetate.
In above scheme, the method also includes
Nucleophilic substitution is occurred into organic solvent for compound shown in compound shown in formula (VI) and formula (V)；The organic solvent is selected from alcohols solvent or nitrile solvents, preferably methanol, ethyl alcohol, isopropanol or acetonitrile；More preferable ethyl alcohol.
The present invention also provides compound shown in a kind of formula (III-1),
The present invention further provides a kind of methods of compound shown in preparation formula (III-1), which is characterized in that the method includes obtaining compound shown in formula (III-1) after the reaction of compound shown in formula (IV),
In above scheme, the method also includes
The present invention also provides compound shown in a kind of formula (IV),
The present invention further provides a kind of methods for preparing compound or its salt shown in formula (IV), it is characterized in that, the method includes compounds shown in formula (VI) to react the step of obtaining compound shown in formula (IV) with compound shown in formula (V)
In above scheme, the method is
In above scheme, the method also includes
In above scheme, the method also includes
The present invention also provides compound shown in a kind of formula (a),
The present invention further provides a kind of methods of compound shown in preparation formula (a), it is characterized in that, the method includes compounds shown in formula (c) to react the step of obtaining compound shown in formula (a) with compound shown in formula (b)
In above scheme, the method also includes
The present invention also provides compound shown in a kind of formula (c),
The present invention further provides a kind of methods of compound shown in preparation formula (c), which is characterized in that the method includes obtaining compound shown in formula (c) after the reaction of compound shown in formula (d),
Compound shown in formula (d) is issued in oxidant effect and answers compound shown in production (c)；The oxidant is selected from osmium tetroxide, the potassium osmate/potassium ferricyanide；More preferable potassium osmate/potassium ferricyanide.
The present invention further provides a kind of methods for preparing compound shown in formula (I), it is characterized in that, the method includes compounds shown in formula (VI) to react to obtain with compound shown in formula (V) and obtains compound shown in compound shown in formula (III-1), formula (III-1) after the reaction of compound shown in compound shown in formula (IV), formula (IV) and react the step of obtaining compound shown in formula (I) with compound shown in formula (II-1)
The invention further relates to a kind of methods of pharmaceutically acceptable salt for preparing compound shown in formula (I), include the steps that in aforementioned schemes, and the step of its pharmaceutically acceptable salt is prepared, is reacted with acid by compound shown in formula (I), the acid is selected from organic acid or inorganic acid, preferably organic acid；The organic acid is selected from tartaric acid, malic acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid, preferably L-TARTARIC ACID or malic acid；The inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
Detailed description of the invention
In order to be easier to understand the present invention, certain technical and scientific terms are defined in detail below.Except separately explicitly defining at apparent in this document it, otherwise all other technical and scientific term used herein all has the normally understood meaning of those skilled in the art of the art.
" halogen or halogen atom " of the present invention refers to fluorine atom, chlorine atom, bromine atom, iodine atom etc..
" alkyl " of the present invention refers to the alkyl containing 1-20 carbon atom of linear chain or branched chain, including such as " C 1-6Alkyl ", " C 1-4Alkyl " etc.; specific example includes but is not limited to: methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2- methyl butyl, neopentyl, 1- ethyl propyl, n-hexyl, isohesyl, 3- methyl amyl, 2- methyl amyl, 1- methyl amyl, 3; 3- dimethylbutyl, 2; 2- dimethylbutyl, 1; 1- dimethylbutyl, 1; 2- dimethylbutyl, 1,3- dimethylbutyl, 2,3- dimethylbutyl, 2- ethyl-butyl, 1,2- dimethyl propyl etc..
Term " alkoxy " refers to-O- (alkyl) and-O- (non-substituted naphthenic base), and wherein alkyl is as defined above.The non-limiting example of alkoxy includes: methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy.Alkoxy can be optionally replacing or non-substituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl or carboxylate.
Term term " acyl group that alkoxy replaces " refers to-C (O) (alkoxy).
" alcohols solvent " of the present invention refers to group derived from one or more hydrogen atoms on one or more " hydroxyl " substitutions " alkyl ", " alkyl " as defined hereinabove, specific example includes but is not limited to: methanol, ethyl alcohol, isopropanol, normal propyl alcohol, isoamyl alcohol or trifluoroethanol.
" nitrile solvents " of the present invention refer to group derived from one or more hydrogen atoms on one or more " cyano " substitutions " alkyl ", and " alkyl " as defined hereinabove, specific example includes but is not limited to: acetonitrile or propionitrile.
Advantageous effect of the invention
Compared with prior art, the technical solution that the present invention prepares compound shown in formula (I) has the advantage that
(1) reaction step is reduced, and reaction step disclosed in the prior art is 5 steps, and reaction step of the invention is 3 steps.
(2) compared with the prior art, starting material of the invention and intermediate be not identical, provides a kind of synthetic method of entirely different thinking, and starting material and reactant are simple, easily purchase.
(3) yield improves, and Yield of final product disclosed in the prior art is 11.3%, and Yield of final product of the present invention is 73.7%.
(4) post-processing reacted is simple, and crude product can be directly used for reacting in next step, could put into reaction in next step after not needing each step product purification, be easy to industrial expanding production.
Specific embodiment
With reference to embodiments for further describing the present invention, but these embodiments are not intended to limit the scope of the invention.
Test method without specific conditions in the embodiment of the present invention, usually according to normal condition, or according to condition proposed by raw material or commodity manufacturer.The reagent in specific source is not specified, for the conventional reagent of market purchase.
Embodiment
The structure of compound is by nuclear magnetic resonance (NMR) or/and mass spectrum (MS) come what is determined.NMR is displaced (δ) with 10 -6(ppm) unit provides.The measurement of NMR is to use Bruker AVANCE-500 nuclear magnetic resonance spectrometer, and measurement solvent is DMSO-d 6, inside it is designated as tetramethylsilane (TMS).
The preparation of embodiment 1, (R) -4- methyl -5- (ethylene oxide -2- base) isobenzofuran -1 (3H) -one
The preparation of the first step, formula (h) compound
Sodium borohydride (57.8g) is dissolved in tetrahydrofuran (2000mL), under argon gas protection, it is cooled to 0 DEG C, raw material i (130.0g) is added portionwise, 5-10 DEG C is stirred to react 1 hour, 5-10 DEG C of dropwise addition boron trifluoride ether (237mL), it is stirred at room temperature 4 hours, stop reaction, methanol (800mL) quenching reaction is added dropwise, stirring, 1N hydrochloric acid (1000mL) solution is added dropwise, 0-20 DEG C is stirred 1 hour, vacuum distillation removes organic solvent, solid is precipitated, filtering, water washing (50mL × 2) obtains crude product, ethyl acetate (700mL) dissolution is added, it filters again, ethyl acetate (100mL × 2) washing, filtrate is dry with anhydrous sodium sulfate, it is concentrated to get title product (95g), yield 80.5%.
The preparation of second step, formula (g) compound
Raw material h (120.0g) and trifluoroacetic acid (64mL) are dissolved in acetonitrile (1L), stirring, 0-5 DEG C is cooled under ice bath, solid N- bromo-succinimide (147.0g) is added portionwise, reaction temperature is controlled at 0-8 DEG C, after reaction, under ice bath, wet chemical (potassium carbonate containing 66.0g) quenching reaction of 200mL is added, it is concentrated under reduced pressure, with water (200mL) and ethyl acetate (800mL × 1, 400mL × 2) extraction, merge organic phase, saturated sodium chloride solution (500mL × 1) washing, anhydrous sodium sulfate is dry, it is concentrated under reduced pressure, obtain crude product, 1h is beaten with methylene chloride (380mL), filtering, it is dry, obtain product 150.0g.
The preparation of third step, formula (f) compound
N is added in cuprous cyanide (123.0g), in dinethylformamide (500mL), raw material g (150.0g) is dissolved in N, dinethylformamide (250mL) is added in dropping funel, under argon atmosphere, start the N that raw material g is added dropwise after being heated to 140-150 DEG C, dinethylformamide solution, 145 DEG C are stirred to react 2 hours, after reaction, it is cooled to 90-95 DEG C, it is added dropwise deionized water (62mL), reaction 18 hours, stop reaction, it is down to room temperature, isopropyl acetate/methanol (V/V=4:1 is added in reaction solution, in the mixed solvent 1500mL), stirring 30 minutes, pad silica gel and diatomite filtering, filter cake isopropyl acetate/methanol (V/V=4:1, 100mL × 3) washing, filtrate subtracts Pressure concentration, residue are added slowly in deionized water (3L), are stirred 1 hour, filtering, filter cake are washed with ethyl alcohol (50mL × 3), filtration cakes torrefaction, crude product 133.0g is obtained, crude product is added in ethyl acetate/methanol (V/V=4:1,2.0L), it is heated to flowing back, be filtered after 1 hour, filter cake ethyl acetate/methanol (V/V=4:1,100mL × 2) washing, filtrate decompression concentration, obtains title product (99.0g), yield 87%.
The preparation of 4th step, formula (e) compound
Raw material f (26.0g) is dissolved in methylene chloride (520mL), it is added triethylamine (33mL), ice salt bath is cooled to -5-0 DEG C of dropwise addition Trifluoromethanesulfonic anhydrides (29.2mL), 0-10 DEG C is reacted 2 hours, stop reaction, under condition of ice bath, water (250mL) quenching reaction is added dropwise into reaction solution, layering, water phase is extracted with methylene chloride (100mL × 2), merge organic phase, it is washed with saturated sodium chloride solution (300mL), it is dry with anhydrous sodium sulfate, it is concentrated under reduced pressure, obtain crude product (50.0g), petroleum ether and ethyl acetate (V/V=5:1 is added, in mixed solution 600mL), it is heated to 70 DEG C of dissolutions, separate supernatant liquor, the mixing of layer oily matter petroleum ether and ethyl acetate (V/V=5:1) Solution (300mL × 2) dissolution layering, merges organic phase, is concentrated under reduced pressure, (41.0g) crude product is obtained, is crystallized with petroleum ether and ethyl acetate (V/V=5:1,200mL) mixed solution, obtain title product (31.7g), yield 67.7%.
The preparation of 5th step, formula (d) compound
Raw material e (50.1g) is dissolved in isopropanol (500mL), it is added three potassium fluoborate of ethylene (29.5g) and 1, the bis- Diphenyl phosphino ferrocene palladium chlorides (1.25g) of 1'-, add triethylamine (71mL), under argon atmosphere, back flow reaction 1.5 hours, stop reaction, it is cooled to room temperature, filtering, washs filter cake, merging filtrate with ethyl acetate (20mL × 3), title product (29.0g), yield 98% are obtained through silica gel column chromatography (eluant, eluent is ethyl acetate: petroleum ether=1:5-1:3) purifying after concentration.
The preparation of 6th step, formula (c) compound
In in the potassium ferricyanide (279.0g) addition reaction flask, potassium carbonate (116.0g), hydroquinidine Isosorbide-5-Nitrae-(2,3- benzodiazine) diether ((DHQD) are sequentially added 2PHAL, 1.1g) and two are hydrated potassium osmate (103mg), 2L deionized water is added, stirring 30 minutes, under argon atmosphere, it is added the tert-butyl alcohol (1.5L), stirring 15 minutes, 0-5 DEG C raw material d (49.0g) is added portionwise, it is stirred 4 hours at 0-5 DEG C, it is warming up to and reaction 18 hours is stirred at room temperature, stop reaction, saturated sodium bisulfite solution (800mL) and ethyl acetate (1000mL) is added, it stirs to Quan Rong, layering, aqueous layer with ethyl acetate (300mL × 3) extraction, merge organic phase, it is washed with saturated sodium chloride solution (200mL), vacuum distillation, ethyl acetate (100mL) is added in residue and petroleum ether (100mL) flows back 10 minutes, cooled to room temperature, filtering, filter cake with petroleum ether ( 50mL × 3) washing, obtain title product (54.0g), yield 92%.
The preparation of 7th step, formula (a) compound
Raw material c (54.0g) is added in methylene chloride (600mL), stirring is white opacity, under argon atmosphere, it is added b (46.9g), it is stirred at room temperature 10 minutes, is cooled to 0 DEG C, be added dropwise trim,ethylchlorosilane (54.0g), it is stirred 30 minutes at 0 DEG C, solution becomes clarification, is warming up to room temperature reaction 1 hour, is cooled to 0 DEG C, add b (23.0g), it is warmed to room temperature reaction 30 minutes, stops reaction, reaction solution is concentrated under reduced pressure, crude title product is obtained, is directly used in reacts in next step without further purification.
The preparation of 8th step, formula (VI) compound
Raw material a (69.6g) is added in methanol (1000mL), it is added potassium carbonate (90.0g), it is stirred at room temperature 2 hours, stop reaction, vacuum distillation, ethyl acetate (500mL) and water (200mL) is added, layering, water phase is extracted with ethyl acetate (100mL × 2), merge organic phase, it is washed with saturated sodium chloride solution (100mL), it is dry with anhydrous sodium sulfate, filtering, vacuum distillation obtains crude product, it is dissolved with ethyl acetate (50mL), it is added petroleum ether (200mL), it is stirred 20 minutes at 50 DEG C, cooled to room temperature, filtering, filter cake is washed with petroleum ether (50mL × 3), drying obtains title product (35.0g), yield 71%.
Embodiment 2, the preparation of 5- cyano -4-methoxypyridine carboxylic acid hydrochloride
The preparation of the first step, formula (p) compound
By raw material n (110.0g), o (150.0g), acetic anhydride (151.5g) is added in reaction flask back flow reaction 4 hours, stop reaction, it is concentrated under reduced pressure, gained residue controls temperature in 0-10 DEG C of dropwise addition ammonium hydroxide and water (V/V=1:1, mixed solution 600mL), when there is the generation of a large amount of solids, it is added ice water (400mL), drop finishes, stirring 30 minutes, being adjusted to pH with concentrated hydrochloric acid is 2-3, stirring 30 minutes, filtering, filter cake is drained, it is beaten 1 hour with dehydrated alcohol (500mL), it filters, filter cake is washed with cold dehydrated alcohol (100mL × 3), dry filter cake, obtain title product (80.0g), yield 59%.
The preparation of second step, formula (q) compound
Sodium hydroxide (43.6g) is incorporated in water (800mL) under ice bath, raw material p (79.8g) is added portionwise in above-mentioned sodium hydrate aqueous solution, remove ice bath, it is heated to back flow reaction 2 hours, terminate reaction, reaction solution ice water is cooled to room temperature, 2M hydrochloric acid solution is added dropwise and adjusts pH to 2-3, stirring 30 minutes, filtering, filter cake ice water (100mL), cold ethyl alcohol (100mL) wash, and obtained solid is dry, obtain title product (71.2g), yield 100%.
The preparation of third step, formula (r) compound
Raw material q (70.3g) is dissolved in phosphorus oxychloride (210mL), 110 DEG C return stirring 2 hours, it is concentrated under reduced pressure and removes phosphorus oxychloride, residue is added into acetonitrile (350mL), under condition of ice bath, it is added dropwise diisopropylethylamine (117.0g), it drips and finishes solution as black suspension, suspension is added dropwise in the ammonium hydroxide under ice bath (350mL), drop Bi Fanying 30 minutes, ethyl acetate (500mL × 3) extraction, merge organic phase, it is washed with saturated sodium chloride solution (500mL), anhydrous sodium sulfate is dry, filtering, filtrate decompression is concentrated to get yellow-brown solid, recrystallization in isopropanol (250mL) is added, obtain title product (44.7g), yield 51%.
The preparation of 4th step, formula (s) compound
Under argon atmospher, raw material r (44.3g) is incorporated in methylene chloride (440mL), under condition of ice bath, 0-5 DEG C of temperature of control, it is added dropwise triethylamine (58.6g), stirring 10 minutes is added dropwise, it is added dropwise trifluoroacetic anhydride (58.5g), it is added dropwise, it is reacted 1 hour under ice bath, stop reaction, reaction solution pH is 7-8, water (400mL) quenching reaction is added, layering, water phase is extracted with methylene chloride (200mL), merge organic phase, it is washed with saturated sodium-chloride (100mL), anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, isopropanol (200mL) hot beating is added in residue, obtain title product (36.3g), yield 91%.
The preparation of 5th step, formula (t) compound
By raw material s (25.6g), cesium carbonate (49.2g) is dissolved in N, in dinethylformamide (260mL), ice bath is cooled to 0 DEG C, methanol (9.5g) is added dropwise under ice bath, 0 DEG C is reacted 6 hours, 20-25 DEG C is risen to stir 12 hours, stop reaction, water (650mL) quenching reaction is added in reaction solution, it is extracted with ethyl acetate (200mL × 3), merge organic phase, it is washed with saturated sodium-chloride (200mL), it is dry with anhydrous sodium sulfate, it is concentrated under reduced pressure, residue n-hexane and ethyl acetate (V/V=1.5:1, mixed solution recrystallization 80mL), obtain title product (16.8g), yield 67%.
The preparation of 6th step, formula (II-1) compound
By t (22.0g), palladium acetate (1.46g), 1, bis- (diphenylphosphine) propane (2.68g) of 3-, triethylamine (36mL) is added in mixed solution, 10bar is pressurized to carbon monoxide, 70 DEG C are warming up to react 18 hours, stop reaction, concentration removes organic solvent, water phase adds saturated sodium chloride solution, methylene chloride extracts (300mL × 3), merge organic phase, active carbon decoloring, filtering, organic phase adjusts pH=1 with concentrated hydrochloric acid, there is solid precipitation, after 50mL isopropanol is added, concentration removes methylene chloride, filtration drying obtains product (23.6g), yield 84.3%.
The preparation of embodiment 3, (R)-5- cyano-N- (1- (2- hydroxyl-2- (4- methyl-1-oxo-1,3- dihydroisobenzofuran-5- base) ethyl) piperidin-4-yl)-4-methoxypyridine formamide (formula (I))
The synthesis of the first step, intermediate (IV)
4.0L dehydrated alcohol is put into reaction flask, (R) -4- methyl -5- (ethylene oxide -2- base)-benzisoxa furans -1 (3H) -one (274.8g) is added under stirring condition, 4-Boc- amino piperidine (341.2g), it is heated to 65-70 DEG C, it is stirred to react 18-20h, stops heating.Naturally cool to 50-55 DEG C, 8.0L n-hexane is added under stirring condition, stirring is down to 20-25 DEG C to temperature naturally, and a large amount of solids are precipitated, are cooled to 0-5 DEG C under the conditions of ice-water bath, stirring, it filters, filter cake is washed twice (250ml × 2) with n-hexane, dry, it obtains solid (354.3g), yield 62.8%.
The synthesis of second step, intermediate (III-1)
5.2L ethyl acetate is put into vial, is cooled to 0-5 DEG C under stirring condition.Stop stirring, be passed through hydrogen chloride gas (0.48kg), control reacting liquid temperature is lower than 5 DEG C during leading to hydrogen chloride.It is slowly stirred down, upper step product (349.3g) is added in reaction solution.It finishes, is stirred to react 3-4 hours, reaction temperature rises to 20-25 DEG C naturally, stops stirring.It filters, filter cake is washed (1.0L × 3) three times with ethyl acetate, and filter cake obtains solid (322.8g), yield 99.3% in 40-45 DEG C of vacuum drying 6-8h；Hydrochloric acid ratio in product dihydrochloride is measured as 20.5% with silver nitrate titration method.
The synthesis of third step, formula (I) compound
4.0L N is put into reaction flask, dinethylformamide, step product (317.8g) is sequentially added under stirring, 5- cyano -4-methoxypyridine carboxylic acid hydrochloride II-1 (205.9g), triethylamine (528.2g), 1- hydroxy benzo triazole (152.7g), N, N- diisopropylcarbodiimide (142.6g).It finishes, argon gas is replaced three times, is heated to 40-45 DEG C and is stirred to react 16-18h.Stop heating, reaction solution is poured into ice water (30L), stirs 1h.It filters, filter cake three times, uses dehydrated alcohol (3.0L) in 20-25 DEG C of mashing 1h with purifying water washing after draining.It filters, dry 10-12h obtains crude product (290.4g), yield 73.7%, purity: 97.76%；
By N under stirring, dinethylformamide (2.0L) is added in (290.4g) crude product, reaction solution is heated to 70-75 DEG C, it is added 20.3g active carbon (7%w/w), insulated and stirred 1h, it filters while hot, with the N of heat, (70-75 DEG C of dinethylformamide, 200mL) wash filter residue, merging filtrate, filtrate is heated to 70-75 DEG C, it is added with stirring (65-70 DEG C of heat, 5L) in the supreme step reaction solution of dehydrated alcohol, stirring and crystallizing, it is down to 20-25 DEG C naturally to temperature, reaction flask is transferred in ice-water bath and continues to stir 1h, it filters, filter cake is washed with dehydrated alcohol, dry solid 219.5g, gross production rate 55.7%, purity: 99.69%.
1H-NMR(400MHz,DMSO-d 6)δ8.88(s,1H),8.75(d,1H),7.77(s,1H),7.71-7.69(m,2H),5.43-5.40(m,2H),5.35(s,1H),5.08(s,1H),4.09(s,3H),3.78(s,1H),2.95(s,3H),2.38(s,1H),2.27(s,3H),2.25(s,2H),1.72(s,4H).

Claims (19)

  1. A method of preparing compound shown in formula (I), it is characterized in that, the step of obtaining compound shown in formula (I) under condensing agent effect the method includes compound or its salt shown in compound or its salt shown in formula (III) and formula (II)
    The X is selected from acyl group, the halogen, preferably-OH that-OH, alkoxy, alkoxy replace.
  2. The method as described in claim 1, which is characterized in that the method is
  3. The method as described in claim 1, which is characterized in that the method also includes
  4. Method according to claim 2, which is characterized in that the method also includes
  5. Compound shown in a kind of formula (III-1),
  6. A kind of method of compound shown in preparation formula (III-1), which is characterized in that the method includes obtaining compound shown in formula (III-1) after the reaction of compound shown in formula (IV),
  7. Method as claimed in claim 6, which is characterized in that the method also includes
  8. Compound shown in a kind of formula (IV),
  9. A method of preparing compound or its salt shown in formula (IV), it is characterized in that, the method includes compounds shown in formula (VI) to react the step of obtaining compound shown in formula (IV) with compound shown in formula (V)
  10. A method of preparing compound shown in formula (VI), which is characterized in that the method includes obtaining compound shown in formula (VI) after the reaction of compound shown in formula (a),
  11. Method as claimed in claim 10, which is characterized in that the method also includes
  12. Method as claimed in claim 11, which is characterized in that the method also includes
  13. Compound shown in a kind of formula (a),
  14. A kind of method of compound shown in preparation formula (a), which is characterized in that the method includes compounds shown in formula (c) to react the step of obtaining compound shown in formula (a) with compound shown in formula (b),
  15. Method as claimed in claim 14, which is characterized in that the method also includes
  16. Compound shown in a kind of formula (c),
  17. A kind of method of compound shown in preparation formula (c), which is characterized in that the method includes obtaining compound shown in formula (c) after the reaction of compound shown in formula (d),
  18. A method of preparing compound shown in formula (I), it is characterized in that, the method includes compounds shown in formula (VI) to react to obtain with compound shown in formula (V) and obtains compound shown in compound shown in formula (III-1), formula (III-1) after the reaction of compound shown in compound shown in formula (IV), formula (IV) and react the step of obtaining compound shown in formula (I) with compound shown in formula (II-1)
  19. A method of preparing the pharmaceutically acceptable salt of compound shown in formula (I), including step described in step described in any one of Claims 1-4 or claim 18, and the step of its pharmaceutically acceptable salt is prepared, is reacted with acid by compound shown in formula (I), the acid is selected from organic acid or inorganic acid, preferably organic acid；The organic acid is selected from tartaric acid, malic acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid, preferably L (+)-tartaric acid or malic acid；The inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
CN201880004432.6A 2017-07-10 2018-07-09 A kind of Preparation Method And Their Intermediate of pyridinecarboxylic amine derivant Pending CN109983008A (en)

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WO2006099884A1 (en) * 2005-03-24 2006-09-28 Actelion Percurex Ag Beta-aminoalcohol antibiotics
WO2014085210A1 (en) * 2012-11-29 2014-06-05 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
WO2016091042A1 (en) * 2014-12-08 2016-06-16 江苏恒瑞医药股份有限公司 Pyridinecarboxamide derivatives, preparation method therefor and pharmaceutical uses thereof

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WO2006099884A1 (en) * 2005-03-24 2006-09-28 Actelion Percurex Ag Beta-aminoalcohol antibiotics
WO2014085210A1 (en) * 2012-11-29 2014-06-05 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
WO2016091042A1 (en) * 2014-12-08 2016-06-16 江苏恒瑞医药股份有限公司 Pyridinecarboxamide derivatives, preparation method therefor and pharmaceutical uses thereof

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