CN107001266A - Method for producing Ida Shandong pyridine - Google Patents
Method for producing Ida Shandong pyridine Download PDFInfo
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- CN107001266A CN107001266A CN201580065028.6A CN201580065028A CN107001266A CN 107001266 A CN107001266 A CN 107001266A CN 201580065028 A CN201580065028 A CN 201580065028A CN 107001266 A CN107001266 A CN 107001266A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
There is disclosed herein a kind of method for preparing Ida Shandong pyridine and its pharmaceutically acceptable salt.
Description
Invention field
The present invention relates to N- (2- (the fluoro- lH- indol-3-yls of 6-)-ethyl) -3- (2,2,3,3- tetrafluoros propoxyl group)-benzylamine
The preparation of (INN title Idas Shandong pyridine (idalopirdine)) and its pharmaceutically acceptable salt.
Background technology
N- (2- (the fluoro- lH- indol-3-yls of 6-)-ethyl) -3- (2,2,3,3- tetrafluoros propoxyl group)-benzylamine is a kind of current
Effective and selective 5-HT in clinical development6Receptor antagonist.Its chemical constitution is depicted as chemical combination below
Thing (I).
N- (2- (the fluoro- lH- indol-3-yls of 6-)-second is disclosed in U.S. Patent number 7,157,488 (" ' 488 patent ")
The synthesis of base-(2,2,3,3- tetrafluoros propoxyl group)-benzylamine, it is used to treat the purposes and bag of obstacle (such as cognition dysfunction)
Pharmaceutical composition containing this material.' 488 patents further describe the preparation of corresponding mono-hydrochloric salts.
Although the synthetic method disclosed in the above referred-to references is enough to prepare a small amount of material, there are a variety of peaces in it
Full problem, yield is low or is not suitable for extensive synthesis technique.
A kind of production method for having kilogram material measured used for generation for preclinical, clinical and business is disclosed in state
In border number of patent application WO 2011/076212.
The production method being disclosed in WO 2011/076212 originates in commercially available 6- fluoro indoles and is summarized in option A
In.
Option A
This production method comprises the following steps：
1) make 6- fluoro indoles with from formaldehyde and dimethylamine original position produce imines ion species acidic aqueous solution presence
Lower reaction, to produce compound (II)
2) compound (II) is made to be reacted with KCN in the presence of DMF- water, to produce compound (III)；
3) in NH3In the presence of use Raney nickel (RaNi) hydrogenated compound (III), to produce compound (IV)；
4) and compound (IV) and 3- (2,2,3,3- tetrafluoros propoxyl group)-benzaldehyde (compound (IX)) are made in solvent
In the presence of react, then add reducing agent.
More properly, it is disclosed in (the fluoro- 1H- indol-3-yls of 6-) acetonitrile (compound (III)) in WO 2011/076212
Hydrogenate and comprise the following steps for 2- (the fluoro- 1H- indol-3-yls of 6-) ethamine (compound (IV))：
(a) (the fluoro- 1H- indol-3-yls of 6-) acetonitrile, ammoniacal liquor and RaNi catalyst is mixed in alcoholic solvent；And
(b) H is used2Hydrogenate the mixture.
The synthesis of compound (IX) can be carried out easily as shown in option b.
Option b
The synthesis of compound (IX) comprises the following steps：
1) 2,2,3,3- tetra- fluoro- 1- propyl alcohol are made to be subjected to tosylation, to produce compound (VIII)；
2) and make compound (VIII) displacement reaction in reacted in the presence of base with 3- hydroxy benzaldehydes, with produce
Compound (IX).
WO 2011/076212 further discloses 2- (the fluoro- 1H- indol-3-yls of 6-) ethamine hydrogen L- (+)-tartrate
(the 1 of 2- (the fluoro- 1H- indol-3-yls of 6-) ethamine and L- (+)-tartaric acid:1 salt) and it is a kind of for purifying 2- (the fluoro- 1H- Yin of 6-
Diindyl -3- bases) ethamine method, this method comprises the following steps：
(a) by 2- (the fluoro- 1H- indol-3-yls of 6-) ethylamine in methanol；
(b) L- (+)-tartaric acid solution in addition methanol；And
(c) tartrate precipitation is filtered out.
However, the use of Raney nickel is in the industrial production problematic, because if in storage, use during or conduct
If waste material is dried, it easily catches fire.Therefore, for synthesize N- (2- (the fluoro- lH- indol-3-yls of 6-)-ethyl) -3- (2,2,3,
3- tetrafluoros propoxyl group) alternative, the cost-effective and selective method of-benzylamine is desirable, this method is not having
Avoid using Raney nickel in the case of any notable yield losses.Such a method has been found to and is disclosed in this specially
In profit application.
A kind of synthetic route of parent material 6- fluoro indoles (compound (X)) is by way of classical lime Ge Lubai-Bart mound
(Leimgruber-Batcho) indole synthesis.However, (Fred Gilmore, A.T. (Gillmore, A.T.) etc. as reported previously
People, organic process research and development (Org.Proc.Res.Dev.) 2012,16,1897-1904；Bo Ni, S. (Boini, S.) etc.
People, organic process research and development 2006,10,1205-1211), due to thermal instability, enamine intermediates (such as compound
(XII) separation and processing) is often problematic.The lime Ge Lubai Barts mound indoles that therefore, it has been developed to improvement is closed
Into and disclosed herein.
Summary of the invention
A kind of method for prepare compound (IV) is disclosed in one embodiment of the invention
This method comprises the following steps：
(a) NH in a solvent in mixed compound (III), (the fluoro- 1H- indol-3-yls of 6-) acetonitrile, water3And support type
Raney nickel；And
(b) hydrogen hydrogenated mixture is used.
A kind of method for prepare compound (I) is disclosed in another embodiment of the present invention
This method includes the above-mentioned steps of the method for prepare compound (IV).
A kind of method for prepare compound (X) is disclosed in another embodiment of the present invention
Lime Ge Lubai-Bart mound indole synthesis of this method by way of improvement.As shown in scheme C, compound (X) this
The need for new synthesis route avoids separation compound (XII)：
Scheme C
The synthesis of compound (X) comprises the following steps：
(a) compound (XIII) and pyrrolidines and DMF acetal is reacted in a solvent, and then use semicarbazide hydrochloride
The mixture obtained is handled, to obtain solid chemical compound (XI),
(b) compound (XI) is made to be subjected to the reduction step that catalyst and reducing agent are carried out, to produce compound (X).
Detailed description of the invention
The following is the definition of each abbreviation used in such as entire disclosure and claims：
" DEM " is diethoxymethane.
" DMF " is N,N-dimethylformamide.
" MeOH " is methanol.
" THF " is tetrahydrofuran.
" TCE " is 2,2,2- ethapons.
" i-PrOH " is 2- propyl alcohol (isopropanol).
" OTs " is tosilate.
" RaNi "/" Raney nickel " is a kind of work occurred optionally mixed with another metal and with different grain size and form
Change Raney nickel.
" cyanide source " is KCN, NaCN or release CN-Other reagents of anion.
" aq " is aqueous.
" DI " is distillation or ultrapure.
" rt " is room temperature.
" approx. " is about.
" min " is minute.
" h " is hour.
" eq " is equivalent.
" g " is gram.
" mL " is milliliter.
" L " is to rise.
" kg " is kilogram.
" M " is molar concentration.
" w/w " is w/w.
" v/v " is volume/volume.
" HPLC " is high pressure liquid chromatography.
" LC-MS " is liquid chromatography-mass spectrometry.
" Pd/C " is the palladium on charcoal.
" Pt/C " is the platinum on charcoal.
" Rh/C " is the rhodium on charcoal.
" Rh/ aluminum oxide " is the rhodium on aluminum oxide.
" Ni/ silica-aluminas " is the nickel on the mixture of silica and aluminum oxide.
“PRICATTM" it is from village letter Wan Feng technologies company (Johnson Matthey Process
Technologies the nickel catalyst carried trade mark of addition)/be not added with a series of silica of accelerator.
" NMP " is 1-METHYLPYRROLIDONE.
" DMF-DMA " is N,N-dimethylformamide-dimethylacetal.
" EDG " is ethylene glycol.
In entire disclosure and claims, term " Raney nickel " refers to comprising nickel or nickel oxide or its mixture
Catalyst.
A kind of method for prepare compound (IV) is disclosed in one embodiment of the invention
This method comprises the following steps：
(a) NH in a solvent in mixing (the fluoro- 1H- indol-3-yls of 6-) acetonitrile, water3With it is nickel catalyst carried；And
(b) hydrogen hydrogenated mixture is used.
In the first specific embodiment, the solvent is a kind of alcoholic solvent.
In the second specific embodiment, the Raney nickel is supported on silica or aluminum oxide.
In the 3rd specific embodiment of any one of previous embodiment, this is nickel catalyst carried to be selected from the group, the group
Including PRICAT 55/5P and PRICAT 62/15P.
In the 4th specific embodiment of any one of previous embodiment, the alcoholic solvent is methanol, ethanol or 2- propyl alcohol.
In the 5th specific embodiment of any one of previous embodiment, the hydrogenation is in from about 2 to about 10 bars, more
Run under the bar of body from about 2 to about 6 and the most specifically pressure of from about 2 to about 4 bars.
In the 6th specific embodiment of any one of previous embodiment, the hydrogenation has more from about 40 DEG C to about 70 DEG C
Body from about 50 DEG C to about 60 DEG C at a temperature of run.
In the 7th specific embodiment of any one of previous embodiment, the hydrogenation with relative to (the fluoro- 1H- indoles of 6--
3- yls) acetonitrile load from about 8% to about 31% (w/w) it is nickel catalyst carried under conditions of run.
A kind of method for prepare compound (I) is disclosed in another embodiment of the present invention
The step of this method includes any one of above-described embodiment of the method for prepare compound (IV).
In a specific embodiment, compound (IV) is reacted in a solvent with compound (IX), then reduction, with to
Go out compound (I).
In one more specifically embodiment, sodium borohydride is used as to the reducing agent for being used to be reduced to compound I.
A kind of method for prepare compound (X) is disclosed in another embodiment of the present invention
This method comprises the following steps：
(c) compound (XIII) and pyrrolidines and DMF acetal is reacted in a solvent, and then use semicarbazide hydrochloride
The mixture obtained is handled, to obtain solid chemical compound (XI),
(d) compound (XI) is made to be subjected to the reduction step that catalyst and reducing agent are carried out, to produce compound (X).
In a specific embodiment, compound (XIII) is reacted in the DMF or NMP as solvent.
In one more specifically embodiment, compound (XIII) is converted into compound (XI) using DMF-DMA.
In a specific embodiment, using the palladium in Raney nickel or charcoal as catalyst by compound (XI) being reduced to
Compound (X).
In one more specifically embodiment, compound (XI) is reduced to compound using hydrazine or hydrogen as reducing agent
(X)。
Compound (I) and diversified organic acid and inorganic acid formed pharmaceutically acceptable acid-addition salts and including
The physiologically acceptable salt generally used in pharmaceutical chemistry.Such salt is also the part of the present invention.Such salt includes
Known to the skilled artisan is listed in Bei Ge, S.M. (Berge, S.M.) et al., Journal of Pharmaceutical Sciences (J.Pharm.Sci.)
Pharmaceutically acceptable salt in 1977,66,1-19.Typical inorganic acid for forming such salt includes hydrochloric acid, hydrobromic acid, hydrogen
Acid iodide, nitric acid, sulfuric acid, phosphoric acid, hypophosphoric acid, metaphosphoric acid, pyrophosphoric acid etc..The salt from organic acid can also be used, these have
Machine acid is alkanoic acid, hydroxyl alkane acid and hydroxyalkanoate diacid, the aromatic series replaced such as aliphatic monocarboxylic acid and dicarboxylic acids, phenyl
Acid, aliphatic and aromatic sulphonic acid.Therefore, such pharmaceutically acceptable salt includes chloride, bromide, iodide, nitric acid
Salt, acetate, phenylacetate, trifluoroacetate, acrylates, ascorbate, benzoate, chloro benzoate, dinitro
Benzoate, hydroxy benzoate, methoxy benzoic acid salt, methyl benzoic acid salt, o-acetyl p-methoxybenzoic acid salt, isobutyric acid
Salt, benzenebutanoic acid salt, a- hydroxybutyric acid salts, butine -1,4- dicarboxylates, hexin -1,4- dicarboxylates, caprate, caprylate, meat
Cinnamic acid salt, citrate, formates, fumarate, glycollate, enanthate (heptarioate), hippurate, lactate,
Malate, maleate, hydroxymaleic acid salt, malonate, mandelate, mesylate, nicotinate, isonicotinic acid salt, grass
Hydrochlorate, phthalate, terephthalate, propiolate, propionate, phenylpropionic acid salt, salicylate, sebacate,
Succinate, suberate, benzene sulfonate, brosylate, closilate, ethyl sulfonate, 2- hydroxyethylsulfonics
Salt, metilsulfate, naphthalene-l- sulfonate, naphthalene-2-sulfonic acid salt, naphthalene -1,5- sulfonate, tosilate, xylene monosulfonic acid
Salt, tartrate etc..
Experimental section
General experimental
Unless otherwise specified, all reactions are carried out under nitrogen.Monitored and reacted by LC-MS.Buy all reagents and not
Used through being further purified.Under 500 or 600MHz record NMR spectra (1H NMR), and add relative to residual solvent peak
To calibrate.Abridged following for NMR data：S, it is unimodal；D, it is bimodal；T, triplet；M, multiplet.Coupling constant four is given up five
Enter to closest to 0.5Hz.
LC-MS methods：
Acquity UPLC BEH 1.7 μm of posts of C18；2.1 × 50mm, is operated, wherein the stream of binary gradient at 60 DEG C
Speed is 1.2mL/min, and the binary gradient is made up of the formic acid of water+0.1% (A) and the formic acid of the water of acetonitrile+5%+0.1% (B).
UV is detected at 254nm.
HPLC methods：
Xterra RP18 posts (100mm × 4.6mm, 3.5 μm), mobile phase：10mM ammonium carbonates (pH 8.5)/acetonitrile, 86/
14 to 14/86 (v/v, %), flow velocity：2mL/min, column temperature：About 45 DEG C, detection：UV, at 280nm.
Compound inventory：
(I)：N- (2- (the fluoro- lH- indol-3-yls of 6-)-ethyl-(2,2,3,3- tetrafluoros propoxyl group)-benzylamines
(II)：(the fluoro- 1H- indol-3-yls methyl of 6-)-dimethylamine
(III)：2- (the fluoro- 1H- indol-3-yls of 6-) acetonitrile
(IV)：2- (the fluoro- 1H- indol-3-yls of 6-) ethamine
(V)：2- (the fluoro- 1H- indol-3-yls of 6-) ethamine hydrogen L- (+)-tartrate
(VI)：2- (1H- indol-3-yls) ethamine
(VII)：Double (2- (the fluoro- 1H- indol-3-yls of 6-) ethyl) amine
(VIII)：The fluoropropyl tosilate of 2,2,3,3- tetra-
(IX)：3- (2,2,3,3- tetrafluoros propoxyl group) benzaldehyde
(X)：6- fluoro indoles
(XI)：(E) -2- (the fluoro- 2- nitrostyrolenes bases of 4-) hydrazine -1- formamides
(XII)：(E) -1- (the fluoro- 2- nitrostyrolenes bases of 4-) pyrrolidines
(XIII)：The fluoro- 1- methyl -2- nitrobenzene of 4-
Example 1：The synthesis of compound (XI)
Scheme I
Compound (XIII) (5.0g, 32.2mmol) is dissolved in NMP (10mL).Addition DMF-DMA (4.8g,
40.3mmol) and pyrrolidines (3.0g, 42.0mmol) and reaction is heated up to 50 DEG C and 18h is stirred.Then by resulting solution
Added to the 50 DEG C of stirring temperature of semicarbazide hydrochloride (4.7g, 41.9mmol) and aqueous HCl (36%w/w, 2mL) in water (40mL)
In solution and stir 2h.Reactant mixture is cooled to 20 DEG C and the orange solids of formation are filtered out, is washed with water and 50
In drying 18h under vacuum at DEG C, to produce basis1H NMR are analyzed>The compound (XI) (6.4g, 83%) of 95% purity.
Example 2：The synthesis of compound (X)
Scheme II
By the palladium on compound (XI) (7.50g, 31.2mmol) and charcoal, (5%Pd is loaded, and ten thousand rich 338 types, 59.4% are believed in the village
W/w water) mixture of (1.64g, 0.312mmol) in ethanol (75ml) hydrogenates 3h under 50 DEG C and 1.2 Ba Qing.
Reactant mixture is filtered, and filtrate is evaporated to drying.By solid residue and ethanol (50mL) at 50 DEG C
Lower heating, to produce homogeneous solution.Then, it is adjoint to be stirred vigorously lower dropwise addition water (50mL) at 50 DEG C.Gained mixture is existed
It is concentrated into about 1/2 volume at 40 DEG C on the rotary evaporator in a vacuum.Gained suspension is filtered, and by precipitation water
Wash and dried at 40 DEG C in vacuum, to produce the compound (X) (3.58g, 85%) in pale solid, wherein basis
LC-MS analysis UV purity is 100%.
Example 3：The synthesis of compound (II)
The details that compound (II) is synthesized from commercially available 6- fluoro indoles is provided below.It is summarized in the journey in scheme III
Sequence produces " imines ion species " using diethoxymethane and dimethylamine.It has been also provided below and has replaced diethoxy using formaldehyde
The alternative program of methane.
Scheme III
Use the program of diethoxymethane
Filled into reactor A diethoxymethane (DEM) (65mL, 0.52mol), water (50mL) and formic acid (39mL,
1.02mol).Mixture is heated into about 2h under about 80 DEG C (backflow), about 20 DEG C are subsequently cooled to.Into reactor B
Fill 6- fluoro indoles (50g, 0.37mol) and 80% acetic acid (66mL, 1.17mol).Suspension is cooled to 2 DEG C -5 DEG C.Will
40% aqueous dimethylamine (103mL, 2.04mol) is added dropwise in reactor B, and keeping temperature is less than about 15 DEG C.By reaction mixing
Thing stirs about 20min while by temperature adjustment to 2 DEG C -4 DEG C.
Future, autoreactor A mixture (DEM, water, formic acid, formaldehyde and the ethanol that are in about 20 DEG C) was added dropwise to reaction
2 DEG C -8 DEG C are kept the temperature in device B simultaneously.Reactant mixture is stirred for 10min at 2 DEG C -8 DEG C.Will be anti-through the 1h times
Mixture is answered slowly to be heated up to about 40 DEG C.Reactant mixture is stirred for 1h at about 40 DEG C.Reactant mixture is cooled down
To about 20 DEG C.
Aqueous NaOH (800mL, 2.40mol, 3M) is filled into reactor C and solution is cooled to about 10 DEG C.In the future
While keeping the temperature at 10 DEG C of -15 DEG C of (pH in the NaOH solution that autoreactor B reactant mixture is added dropwise in reactor C>
14).By suspension in 5 DEG C of -20 DEG C of (pH>14) 40min is stirred under.Product is collected by filtration and filter cake is washed with water two
Secondary (2 × 250mL).By product under vacuo in drying 16h at about 60 DEG C, to produce compound (II) (67.6g, 95%),
Wherein UV purity is 98% in HPLC analyses.
Use the program of formaldehyde：
Under an inert atmosphere, at about 17 DEG C, by 250L reactors with about 40% aqueous dimethylamine (35.7kg,
317mol) fill.Mixture is cooled to about 4.5 DEG C and glacial acetic acid (43.4kg, 723mol) is added dropwise simultaneously through 140min
Temperature is maintained about 15 DEG C.Stirred at about 3 DEG C after 20min, 37% aqueous formaldehyde is slowly added through about 20min
(25.9kg, 319mol) is while keep the temperature between about 0 DEG C to about 10 DEG C.Addition 6- fluoro indoles (39.2kg,
290mol).The reaction is heat release and final temperature reaches about 40 DEG C, and it then is cooled into about 20 DEG C.Through about
Reaction solution is added slowly in the previously 650L reactors filled with aqueous NaOH (3M) by 40min time.By formation
Suspension stirring about 40min is kept the temperature between 5 DEG C to 20 DEG C simultaneously.Precipitation is filtered out from solution, with water in mistake
Wash, and dried at about 50 DEG C on filter, to provide compound (II) (45.4kg, 81%).
Example 4：The synthesis of compound (III)
Provided in following scheme IV and synthesize compound (III) in detail from compound (II).
Scheme IV
Progressively program：
By (the fluoro- 1H- indol-3-yls methyl of 6-)-dimethylamine (II) (65g, 0.338mol), KCN (31g, 0.476mol),
DMF (195mL) and water (104mL) filling are into reactor.Reactant mixture is heated to about into 100 DEG C -105 DEG C (strong inverse flows) to hold
Renewed treaty 5-8h.Reactant mixture is cooled to 20 DEG C -25 DEG C.Water (780mL) and toluene (435mL) are filled into reactor simultaneously
And be stirred vigorously mixture>2h.Organic layer and water layer are separated.Organic layer is used into 5%NaHCO respectively3(6 × 260mL), water
Property HCl (260mL, 2M), 5%NaHCO3(260mL) and 5%NaCl (260mL) are washed.Organic layer is filtered and concentrated to dry
It is dry.Solution and is concentrated to dryness (260mL) by addition MeOH, with produce in brown oil compound (III) (53.0g,
90%), wherein it is 95% to analyze UV purity according to HPLC.
Example 5：The screening of palladium catalyst：
At room temperature, additive is added in EtOH (2.0mL) solution to compound (III) (200mg, 1.15mmol)
With Pd/C catalyst.By mixture at the specified temperature in hydrogenating the stipulated time under 4 bars.It is mixed by the reaction of LC-MS Direct Analysis
Compound.By the results are shown in Table 1.
The screening of the heterogeneous palladium catalyst of table 1.1
1. according to the reaction condition of universal method.
2. it is derived from the catalyst of village letter Wan Feng technologies company.
3. the UV area percentages in LC-MS.
4. relative to compound (III) with the loading of the catalyst of mol% catalyst gauges.
Example 6：The screening of homogeneous catalyst：
To the solid mixture addition solvent (1.0mL) of metal complex and any part.Stir the mixture for 30min,
And it is mixed in solvent (1.0mL) to add it to additive (10mol%) and compound (III) (200mg, 1.15mmol)
In compound.
Mixture is hydrogenated into the stipulated time under 4 bars and set point of temperature.Pass through LC-MS Direct Analysis reactant mixtures.
The screening of the homogeneous catalyst of table 2.1
1. according to the reaction condition of universal method.
2. the UV area percentages in LC-MS.
3. pair (2- methylallyls) (1,5- cyclo-octadiene) ruthenium (II), cas 12289-94-0.
4.DPPF：1,1 '-bis- (diphenylphosphino) ferrocene, No. cas：12150-46-8.
5. three (triphenylphosphine) ruthenous chlorides (II), cas 15529-49-4.
6. hydrogenate three (triphenylphosphine) rhodium carbonyls (I), cas 17185-29-4.
Dichloro 7. (mesitylene) ruthenium (II) dimer, cas 52462-31-4.
Dichloro 8. (p-cymene) ruthenium (II) dimer, cas 52462-29-0.
9. relative to compound (III) with the loading of the catalyst of mol% catalyst gauges.
Example 7：The screening of rhodium, platinum and Raney nickel
At room temperature, additive and catalysis are added in the solution of solvent to compound (III) (200mg, 1.15mmol)
Agent.By mixture at the specified temperature in hydrogenating the stipulated time under 4 bars.Pass through LC-MS Direct Analysis reactant mixtures.
The screening of the rhodium of table 3. and platinum catalyst1
1. according to the reaction condition of universal method.
2. it is derived from village letter Wan Feng technologies company (sign：) or Sigma-Aldrich company (Sigma- JM
Aldrich A/S) (sign：S-A catalyst).
3. the UV area percentages in LC-MS.
4. relative to compound (III) with the loading of the catalyst of mol% catalyst gauges.
The screening of the Raney nickel of table 4.1
1. according to the reaction condition of universal method.
2. the catalyst of village letter Wan Feng technologies company is derived from, except being derived from Sigma-Aldrich company
Outside the first catalyst.
3. the UV area percentages in LC-MS.
4. relative to compound (III) with the loading of the catalyst of weight % catalyst gauges.
Example 8：2- (the fluoro- 1H- indol-3-yls of 6-) ethamine hydrogen L- (+)-tartrate (V) synthesis
At room temperature, to compound (III), (10.0g, 57.4mmol, UV purity is 96%) in ammoniacal liquor in LC-MS
PRICAT type 55/5P catalyst is added in solution in (59.2g, 65.0mL, 834mmol, 24%w/w) and IPA (35.0mL)
(3.0g).Mixture is transferred in steel autoclave and at 50 DEG C in hydrogenating 23h under 4 Ba Qing.Mixture is cooled down and made
Filtered with other IPA (35mL) by glass microfiber filters (graceful (Whatman) GF/A of water).By steaming in a vacuum
Hair concentrates the filtrate to about 1/3 volume.IPA (70mL) is added, and mixture is again concentrated to about 1/3 volume.Will
IPA is added and evaporation order is repeated twice.Mixture is evaporated in vacuo to drying last time.
Residue is dissolved in IPA (200mL) and water (10mL) is added.Solution is heated to backflow.Then, in backflow
Under, solution of L- (+)-tartaric acid (8.62g, 57.4mmol) in water (30mL) is added slowly to stir by the time through 10min
Mix in solution.Resulting solution is slowly cooled to room temperature under agitation.By the suspension filtering of formation and precipitation is used
Cold IPA (50mL) is washed and is dried in a vacuum, to produce the compound (V) (14.5g, 77% yield) of white powder, its
In LC-MS analysis in UV purity>99.9%.
The analyze data of compound (V)：1H NMR(600MHz,CDCl3)δH2.96 (t, J=7.5Hz, 2H), 3.05 (t,
J=7.5Hz, 2H), 6.87 (dt, J=2.0,10Hz, 1H), 7.14 (dd, J=2.0,10Hz, 1H), 7.54 (dd, J=5.5,
10.0Hz,1H),11.1(br s,1H)；13C NMR(150MHz,DMSO-d6)δC(23.6,39.7,72.4 tartrate),
97.9 (d, J=25.5Hz), 107.4 (d, J=24.5Hz), 110.4,119.6 (d, J=10.0Hz), 124.0,124.5,
136.6 (d, J=12.5Hz), 159.4 (d, J=232.5Hz), 175.2 (tartrates)；LC-MS(APPI):M/e is directed to
C10H12FN2[M+H]+Calculated value is 179.10, and discovery value is 179.2 (free alkalis).
Example 9：The extensive synthesis of 2- (the fluoro- 1H- indol-3-yls of 6-) ethamine hydrogen L-TARTARIC ACID salt (V)
Hydrogenation
By PRICAT type 55/5P catalyst (14.0kg) filling into reactor, compound (III) is then filled with
The solution of (46.3kg, 266mol) in isopropanol (76.4kg).Then, filling isopropanol (106L) and ammoniacal liquor (302L,
25%).Mixture is transferred in steel autoclave under nitrogen, reactor is cleaned using extra isopropanol (92L).By high pressure
Kettle is evacuated, then with pressurized with hydrogen to 3 bars.Content is heated to 55 DEG C and 48h is hydrogenated under 3 Ba Qing.Content is cooled down
Purged to 25 DEG C, and by autoclave with nitrogen, and content is filtered on pressure suction filter.By filter isopropanol
Wash (2 × 145L).This produces the solution of compound (IV).
Precipitation
To the greatest extent may be used by being evaporated in vacuo the amount of the solution of the compound (IV) hydrogenated twice from above scale being concentrated into
The minimum volume of energy, is diluted with IPA (486L) and is concentrated again by vacuum distillation.By its with two batches isopropanol (285L, so
After be 306L) be repeated twice.Then, addition isopropanol (930L) and ethyl acetate (450kg), and heat the mixture to 60
℃.Time through about 30min is by L- (+)-tartaric acid (39.9kg, 26.6mol) in water (85L) and isopropanol (280L)
Solution is added slowly in the solution.The suspension of formation is stirred into 3h at 60 DEG C, and the time through 3h is cooled to 25 DEG C.
Suspension is filtered on pressure suction filter, and by filter cake isopropanol (170L), ethyl acetate (78kg) and water (17L)
Mixture is washed twice.Filter cake is crushed and dried 5 days on pallet in vacuum drying oven at 60 DEG C, is in canescence to produce
The compound (V) (163kg, 94%) of solid.
Example 10：2- (the fluoro- 1H- indol-3-yls of 6-) ethamine hydrogen L- (+)-tartrate (V) precipitation
Compound (IV) (5.4g, 30.3mmol) is dissolved in isopropanol (60mL) and 60 DEG C are heated to.Prepare L-
Solution of (+)-tartaric acid (4.55g, 30.3mmol) in water (12mL), and through 5min be added dropwise about 1/3rd this is molten
Liquid, and allow before crystal seed is added solution being stirred for 10min.It was observed that precipitation.Other 1/3rd this solution is added dropwise,
And after 10min, the remainder of the aqueous solution is added dropwise.Allow suspension stirring 30min at 60 DEG C, then allow cooling
To 50 DEG C, and 1h is stirred at such a temperature.Then allow suspension being cooled to room temperature (about 22 DEG C) and stay overnight (about
16h).Suspension is filtered, and residue is dried under vacuum, to provide compound (V) (7.7g, 77% in solid
Yield).
Example 11：From the middle precipitation 2- of thick 2- (the fluoro- 1H- indol-3-yls of 6-) ethyl -1- amine (III), (6- is fluoro- after hydrogenation
1H- indol-3-yls) ethamine hydrogen L- (+)-tartrate (I)
Crude compound (IV) (329g, 1.8mol) is dissolved in isopropanol (660mL) and solution is heated up to 50 DEG C.
Transfer them in 10L flasks, and add more isopropanols (2.3L).Then, will be raw using thermostatically controlled heating mantle
Into solution be heated to and maintain 60 DEG C.Dividually, L- (+)-tartaric acid (246g, 1.6mol) is prepared in water (650mL)
Solution, cumulative volume 800mL.A part (266mL) for this aqueous solution is added in amine aqueous solution with 25mL/min speed.Add
After the solution for increasing about 80mL, it was observed that precipitation.Other 130mL solution is added with 2mL/min speed.Then, with
6mL/min speed adds the remainder of the solution.Then heating mantle is turned off, and allows to stay overnight suspension and be cooled to
23 DEG C (about 17h).Then suspension is cooled to 20 DEG C using water-bath, and filtered.Filter cake is crushed and at 50 DEG C in true
The lower drying of sky, to provide the compound (V) (443g, 73%) in solid.
Example 12：The synthesis of compound (IX)
Plan V
To the fluoro- 1- propyl alcohol of addition in paratoluensulfonyl chloride (140g, 0.734mol) 2,2,3,3- tetra- (100g,
0.757mol), water (440mL) is then added.Stirring mixture is slowly added aqueous NaOH (100mL, 27.7%w/w) simultaneously.
Heat the mixture to 50 DEG C and maintain 5h at such a temperature.Mixture is cooled to room temperature, and adds toluene (700mL).
15min is stirred the mixture for, and is separated each.By organic phase ammoniacal liquor (250mL, 5%w/w), salt solution (200mL, 5%
W/w) wash twice and finally filter and be evaporated to drying, with produce in colorless oil compound (IX) (183g,
87%).
By from crude compound (VIII) (45.8g, 0.160mol) above and potassium carbonate (32.2g, 0.233mol) and
3- hydroxy benzaldehydes (25.0g, 0.205mol) are mixed in 1-METHYLPYRROLIDONE (137mL).Mixture is stirred at 90 DEG C
1h is mixed, then 3h is stirred at 100 DEG C.Mixture is cooled to 50 DEG C, and adds water (220mL).Gained mixture is added
Add to toluene (400mL), salt solution (75mL, 15%w/w), water (200mL) and aqueous NaOH (60mL, 27.7%w/w) mixing
In thing.It is separated by mixture simple agitation and by each.Organic phase is sequentially washed two with aqueous NaOH (230mL, 2M)
It is secondary, with aqueous HCl (150mL, 2M), aqueous NaHCO3(150mL, 5%w/w) is washed, and finally uses salt solution (50mL, 5%w/
W) wash.Organic phase is filtered and is evaporated in vacuo to drying.Gained grease is stripped two with isopropanol (100mL)
It is secondary, to produce the compound (IX) (34.4g, 91%) in grease.
Example 13：It is used as the synthesis of the compound (I) of HCl- salt
Plan V I
Program：
By compound (V) (49.3g, 0.150mol) toluene (270mL), THF (100mL), aqueous NaOH (200mL,
2M) and in aqueous NaCl (65mL, 15%w/w) mixture it is stirred.It is separated each.By the aqueous NaCl of organic phase
(200mL, 5%w/w) is washed.Organic phase is concentrated to dryness under reduced pressure and residue is dissolved in isopropanol (400mL)
In.
By compound (IX) (39.0g, 0.165mol) and isopropanol (200mL) filling into reactant mixture.Will reaction
Mixture heats 2.5h at 60 DEG C, is subsequently cooled to about 55 DEG C.NaBH is filled into thermal reaction mixture4(7.4g,
0.196mol) the suspension in isopropanol (100 and 50mL).Reactant mixture is heated into 2.5h at 55 DEG C, then cooled down
To about 15 DEG C -20 DEG C.Aqueous HCl (80mL, 2M) is added dropwise in time through about 30min.Time through 15min adds aqueous HCl
(140mL, 2M).Mixture is stirred vigorously 15min.Mixture is concentrated into half volume, aqueous NaOH is then added
(83mL, 6M) is to pH >=14.Add toluene (400mL).By it is each phase separation and by organic phase respectively with aqueous NaOH (200mL,
2M), aqueous NH4Cl (200mL, 3%w/w) and water (200mL) washing.Organic phase is filtered and concentrated to drying.By residue
It is dissolved in toluene (550mL) and acetonitrile (50mL).Aqueous HCl (33mL, 6M) is added dropwise.Gained suspension is stirred 2-4 hours,
Then filter.Filter cake is used into toluene respectively:Acetonitrile mixture (9:1,2 × 75mL) and aqueous HCl (2 × 75mL, 0.1M) washings.
By the thick HCl salt of compound (I) at about 45 DEG C under vacuum dry about 16h.
By the final purifying that the salt of separation is dissolved in the HCl salt that compound (I) is carried out in acetone (300mL) first.
Solution is filtered and concentrated to about 90-120mL volume.The aqueous HCl (1900mL, 0.1M) of filtering is added dropwise through 30min.By institute
Obtain suspension and 16h is stirred at 20 DEG C -25 DEG C, then filter.By filter cake respectively with the HCl (200mL, 0.1M) and filtering filtered
Water (150mL) washing.By the purifying HCl salt (52.2g, 80%) of compound (I) at 40 DEG C under vacuum dry about 16h simultaneously
And white solid is separated into, wherein the UV purity in HPLC analyses>99.5%.
Claims (14)
1. one kind is used for the method for prepare compound (IV)
It comprises the following steps：
(a) NH in a solvent in mixing (the fluoro- 1H- indol-3-yls of 6-) acetonitrile, water3With it is nickel catalyst carried；And
(b) H is used2Hydrogenate the mixture.
2. the method as described in claim 1, the wherein solvent are a kind of alcoholic solvents.
3. method as claimed in claim 1 or 2, wherein the Raney nickel is by silica or alumina load.
4. the method as any one of claim 1-3, wherein this it is nickel catalyst carried be selected from the group, the group includes
PRICAT 55/5P and PRICAT 62/15P.
5. the method as any one of claim 1-4, the wherein alcoholic solvent are methanol, ethanol or 2- propyl alcohol.
6. the method as any one of claim 1-5, the wherein hydrogenation are run under the pressure of from about 2 to about 10 bars.
7. the method as any one of claim 1-6, the wherein hydrogenation are transported at a temperature of from about 40 DEG C to about 70 DEG C
OK.
8. the method as any one of claim 1-7, the wherein hydrogenation are with relative to (the fluoro- 1H- indol-3-yls of 6-)
Acetonitrile load from about 8% to about 31% (w/w) it is nickel catalyst carried under conditions of run.
9. one kind is used for the method for prepare compound (X)
It comprises the following steps：
A. the acetal of the fluoro- 1- methyl -2- nitrobenzene of 4- and pyrrolidines and DMF is made to react in a solvent, and
Obtained mixture is then handled with semicarbazide hydrochloride, to obtain solid (E) -2- (the fluoro- 2- nitrostyrolenes bases of 4-) hydrazine -1-
Formamide,
B. (E) -2- (the fluoro- 2- nitrostyrolenes bases of 4-) hydrazine -1- formamides are made to be subjected to the reduction that catalyst and reducing agent are carried out
Step, to produce compound (X).
10. method according to claim 9, the wherein solvent are DMF or 1-METHYLPYRROLIDONE.
11. the acetal of the method according to any one of claim 9 or 10, wherein DMF is N, N- bis-
NMF dimethylacetal.
12. method according to claim 9, the wherein catalyst are the palladiums on Raney nickel or charcoal.
13. method according to claim 9, the wherein reducing agent are hydrazine or hydrogen.
14. one kind is used for the method for prepare compound (I)
It includes the one or more steps as any one of claim 1-13.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| DKPA201400721 | 2014-12-12 | ||
| DKPA201400721 | 2014-12-12 | ||
| PCT/EP2015/079209 WO2016091997A1 (en) | 2014-12-12 | 2015-12-10 | A process for the manufacture of idalopirdine |
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| CN201580065028.6A Pending CN107001266A (en) | 2014-12-12 | 2015-12-10 | Method for producing Ida Shandong pyridine |
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|---|---|
| EP (1) | EP3230265A1 (en) |
| JP (1) | JP2017537128A (en) |
| KR (1) | KR20170093821A (en) |
| CN (1) | CN107001266A (en) |
| AU (1) | AU2015359347A1 (en) |
| BR (1) | BR112017012021A2 (en) |
| CA (1) | CA2968770A1 (en) |
| CL (1) | CL2017001466A1 (en) |
| CO (1) | CO2017005357A2 (en) |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3042685A (en) * | 1962-07-03 | Process of making g-fluoro tryptamine | ||
| CN101677547A (en) * | 2007-03-23 | 2010-03-24 | 史密丝克莱恩比彻姆公司 | Indole carboxamides as the IKK2 inhibitor |
| CN102656146A (en) * | 2009-12-23 | 2012-09-05 | H.隆德贝克有限公司 | Processes for the manufacture of a pharmaceutically active agent |
-
2015
- 2015-12-09 MA MA041148A patent/MA41148A/en unknown
- 2015-12-10 MX MX2017007510A patent/MX2017007510A/en unknown
- 2015-12-10 KR KR1020177015206A patent/KR20170093821A/en unknown
- 2015-12-10 JP JP2017531139A patent/JP2017537128A/en active Pending
- 2015-12-10 EP EP15821029.4A patent/EP3230265A1/en not_active Withdrawn
- 2015-12-10 BR BR112017012021A patent/BR112017012021A2/en not_active Application Discontinuation
- 2015-12-10 CA CA2968770A patent/CA2968770A1/en not_active Abandoned
- 2015-12-10 RU RU2017120216A patent/RU2017120216A/en not_active Application Discontinuation
- 2015-12-10 CN CN201580065028.6A patent/CN107001266A/en active Pending
- 2015-12-10 AU AU2015359347A patent/AU2015359347A1/en not_active Abandoned
-
2017
- 2017-05-23 IL IL252471A patent/IL252471A0/en unknown
- 2017-05-26 CO CONC2017/0005357A patent/CO2017005357A2/en unknown
- 2017-06-08 CL CL2017001466A patent/CL2017001466A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3042685A (en) * | 1962-07-03 | Process of making g-fluoro tryptamine | ||
| CN101677547A (en) * | 2007-03-23 | 2010-03-24 | 史密丝克莱恩比彻姆公司 | Indole carboxamides as the IKK2 inhibitor |
| US8071584B2 (en) * | 2007-03-23 | 2011-12-06 | Glaxosmithkline Llc | Indole carboxamides as IKK2 inhibitors |
| CN102656146A (en) * | 2009-12-23 | 2012-09-05 | H.隆德贝克有限公司 | Processes for the manufacture of a pharmaceutically active agent |
Non-Patent Citations (2)
| Title |
|---|
| ADAM T. GILLMORE，等: "Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor", 《ORG. PROCESS RES. DEV.》 * |
| SATHISH BOINI，等: "Development of a Manufacturing Process for 1-(1-Pyridin-2-yl methyl-piperidin-4-yl)-1H-indole: A Key Intermediate for Protein Kinase C Inhibitor LY317615", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
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| Publication number | Publication date |
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| KR20170093821A (en) | 2017-08-16 |
| CL2017001466A1 (en) | 2018-01-05 |
| JP2017537128A (en) | 2017-12-14 |
| CA2968770A1 (en) | 2016-06-16 |
| RU2017120216A (en) | 2019-01-15 |
| CO2017005357A2 (en) | 2017-09-20 |
| MX2017007510A (en) | 2017-08-22 |
| IL252471A0 (en) | 2017-07-31 |
| EP3230265A1 (en) | 2017-10-18 |
| AU2015359347A1 (en) | 2017-06-08 |
| BR112017012021A2 (en) | 2018-03-13 |
| MA41148A (en) | 2017-10-17 |
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