CN109956914A - A kind of Preparation Method And Their Intermediate of indole amine 2,3-dioxygenase inhibitor - Google Patents
A kind of Preparation Method And Their Intermediate of indole amine 2,3-dioxygenase inhibitor Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
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Abstract
The present invention relates to a kind of Preparation Method And Their Intermediates of indole amine 2,3-dioxygenase inhibitor.The invention discloses a kind of preparation method capable of being industrialized, this method solve synthetic route in the prior art is long, low yield is not suitable for industrialized problem.The invention further relates to some intermediates for generating indoleamine 2,3-dioxygenase inhibitor, especially logical formula (I) intermediate.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of preparation method of indoleamine 2,3-dioxygenase inhibitor
And its intermediate.
Background technique
Indole amine 2,3-dioxygenase 1 (indoleamine 2,3-dioxygenase 1, IDO 1) is a kind of containing ferrous iron
The protein fermentoid of ferroheme can be catalyzed L-Trp and decompose along kynurenine pathway (Kynurenine pathway, KP)
Metabolism.
IDO1 can pass through the immune tolerance of three aspect inducing T cells as a kind of new immunologic test point:
(1) microenvironment for lacking tryptophan, the T cell arrest proliferation for relying on tryptophan are caused by tryptophan of degrading.
(2) some metabolites of KP can inhibit the function of T cell.
(3) amplification of regulatory T cells is induced, and the up-regulation of regulatory T cells is the important obstruction of immunotherapy of tumors.
Existing research shows to over-express IDO1 in many tumor tissues, to reduce T cell in tumor microenvironment
Infiltration makes tumour cell escape the attack of immune system.And IDO inhibitor can inhibit the activity of IDO enzyme, so that enhancing is immune
The anti-tumor capacity of system.IDO inhibitor usually with immunization therapy (such as: PD-1/PD-L1 antibody), radiotherapy or chemotherapy combined
Apply the growth to inhibit tumour.
2009, Incyte company passed through high flux screening (high throughput screening, HTS) first and obtains
A series of N- hydroxyamidines analog derivatives were obtained, the metabolic process of IDO catalysis tryptophan can be competitively inhibited.Wherein, phenyl ring
On meta position replace and 3,4 disubstituted compound activities are higher.Oxygen atom on hydroxyamidines can be blood red with IDO1
Plain ferrous combination, and the amino-substituent on oxadiazoles ring can form hydrogen bond with the propionic acid group of heme ring.
2017, Jiangsu Hao Sen company disclosed a kind of indoleamine 2 in patent PCT/CN2017/079585, and 3- is bis- to be added
Oxygenase inhibitor, wherein representative compound chemical name are as follows: (Z)-N- (the bromo- 4- fluoro-phenyl of 3-) -4- ((2- (N- (cyclopropyl
Sulfonyl)-methylsulfinyl imines) ethyl) amino)-N'- hydroxyl -1,2,5- oxadiazoles -3- carbonamidine, structure is as follows:
The compound has very high inhibitory activity to IDO, can effectively inhibit IDO active, it can also be used to inhibit patient
Immunosupress.
Compared with prior art, present invention has the advantage that
1, it avoids using hazardous agents；
2, the operation using post separation is avoided；
3, synthetic route greatly shortens, and substantially increases total recovery；
4, chiral induction or chiral oxidization are taken, highly selective has obtained target chiral centers；
5, technique is optimized, can satisfy industrial amplification demand.
Summary of the invention
The purpose of the present invention is to provide the preparation methods of a kind of indole amine 2,3-dioxygenase inhibitor and its intermediate.
It is long to there is synthetic route in existing literature report route, needs using hazardous agents, and chiral non-selectivity in synthesizing, finally
The disadvantages of chiral preparatory column separation can only be taken through, cause supplies consumption big, efficiency is too low, can not comply with green chemistry
Trend, while being unable to satisfy industrialization production requirements.Route disclosed by the invention takes chiral induction or chiral oxidization, high
Selectivity has obtained target chiral centers, avoids the subsequent operation using chiral post separation, greatly reduces supplies consumption,
Production efficiency is improved, while technique is optimized, shortens synthetic route, avoids the use of hazardous agents, it can be with
Meet industrial amplification demand.
A kind of logical formula (I) and its isomers general formula (I-1) compound represented, its stereoisomer are further related in the present invention
Or its pharmaceutically-acceptable salts:
Wherein:
R is selected from hydrogen atom, D-atom, alkyl, deuteroalkyl, halogenated alkyl or alkoxy；And
N is 0,1,2 or 3.
A kind of intermediate for preparing logical formula (I) compound represented according to claim 1 is further related in the present invention,
It is logical formula (II) and its isomers general formula (II-1) and general formula (II-2) compound represented, its stereoisomer or its pharmacy
Upper acceptable salt:
Wherein:
R is selected from C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl or C1-6Alkoxy；And
N is 0,1,2 or 3.
A kind of method for preparing logical formula (I) compound represented is further related in the present invention, it is characterised in that include following step
Suddenly,
Wherein:
R and n is as described in logical formula (I).
A kind of intermediate for preparing logical formula (II) compound represented and its isomers is further related in the present invention, is general formula
(III) and its isomers general formula (III-1) and general formula (III-2) compound represented, its stereoisomer or its pharmaceutically may be used
Receive salt:
Wherein:
R is selected from C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl or C1-6Alkoxy；
R1Selected from C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, halogen, ammonia
Base ,-(CH2)xNR2R3、-(CH2)xC(O)NR2R3、-(CH2)xNR2C(O)R3With-(CH2)xNR2S(O)mR3；
R2And R3It is identical or different, and it is each independently selected from hydrogen atom, D-atom, C1-6Alkyl, C1-6Deuteroalkyl, C1-6
Halogenated alkyl, hydroxyl, amino, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 5-8 member aryl and 5-8 unit's heteroaryl, wherein the C1-6
Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 5-8 member aryl and 5-8 unit's heteroaryl are optional
Further it is selected from D-atom, C1-6Alkyl, halogen, hydroxyl, amino, nitro, cyano, C1-6Alkoxy, C1-6Hydroxyalkyl, C3-8Ring
Replaced one or more substituent groups in alkyl, 5-8 circle heterocyclic ring base, 5-8 member aryl and 5-8 unit's heteroaryl；
N is 0,1,2 or 3；
X is 0,1,2 or 3；And
M is 0,1 or 2.
A kind of method for preparing general formula (II-1) compound represented is further related in the present invention, it is characterised in that comprising as follows
Step,
Wherein:
R is selected from C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl or C1-6Alkoxy；
R1Selected from halogen；And
N is 0,1,2 or 3.
Logical formula (III) compound represented is further related in the present invention, for logical formula (IV) and its isomers general formula (IV-1)
With general formula (IV-2) compound represented, its stereoisomer or its pharmaceutically-acceptable salts:
Wherein:
R4Selected from hydrogen atom, C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy,
C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 5-8 member aryl and 5-8 unit's heteroaryl；The wherein C1-6Alkyl, C1-6Deuteroalkyl,
C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 5-8 member aryl and 5-8 member are miscellaneous
Aryl is optionally further selected from D-atom, C1-6Alkyl, C1-6Halogenated alkyl, halogen, amino, nitro, cyano, hydroxyl, C1-6Alkane
Oxygroup, C1-6Halogenated alkoxy and C1-6Replaced one or more substituent groups in hydroxyalkyl；It is preferred that hydrogen atom, C1-3Alkyl and
5-8 member aryl；The aryl that more preferable 5-6 member halogen replaces；
R and n is as described in logical formula (III).
The invention further relates to a kind of methods for preparing general formula (III-1) compound represented, it is characterised in that comprising as follows
Step,
Wherein:
R is selected from C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl or C1-6Alkoxy；
R1Selected from halogen；
R5Selected from hydrogen atom or C1-6Alkyl；And
N is 0,1,2 or 3.
The invention further relates to a kind of intermediates for preparing logical formula (IV) compound represented and its isomers, are general formula
(V) and its isomers general formula (V-1) and general formula (V-2) compound represented, its stereoisomer or its pharmaceutically-acceptable salts:
Wherein:
R5Selected from hydrogen atom, C1-6Alkyl, C1-6Deuteroalkyl and C1-6Halogenated alkyl；The wherein C1-6Alkyl, C1-6Deuterium
Substituted alkyl and C1-6Halogenated alkyl is optionally further by selected from one or more of D-atom, halogen, amino, cyano and hydroxyl
Replaced substituent group；It is preferred that hydrogen atom and C1-3Alkyl；More preferable hydrogen atom；
R and n is as described in logical formula (III).
The invention further relates to a kind of methods for preparing general formula (IV-1) compound represented, it is characterised in that includes following step
Suddenly,
Wherein:
R is selected from C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl or C1-6Alkoxy；
R1For halogen；
R5For hydrogen atom or C1-6Alkyl；And
N is 0,1,2 or 3.
The invention further relates to a kind of methods for preparing logical formula (I) compound represented, it is characterised in that it comprises the following steps,
Wherein:
R、R1With n as described in logical formula (IV).
The invention further relates to a kind of methods for preparing logical formula (I) compound represented, it is characterised in that it comprises the following steps,
Wherein:
R、R1、R5With n as described in logical formula (IV).
The invention further relates to a kind of methods for preparing logical formula (I) compound represented, it is characterised in that it comprises the following steps,
Wherein:
R、R1、R5With n as described in logical formula (V).
The invention further relates to a kind of formula (VI) compound represented logical as follows and its isomers general formulas (VI-1) and general formula
(VI-2) compound shown in, it is characterised in that logical formula (I) compound represented, its stereoisomer or its pharmaceutically-acceptable salts
It is the midbody compound for preparing compound shown in logical formula (VI) and its isomers general formula (VI-1) and general formula (VI-2),
Wherein:
Ra is selected from hydrogen atom, D-atom, C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6It is halogenated
Alkoxy, C3-8Naphthenic base, C3-8Halogenated cycloalkyl and C3-8Deuterated naphthenic base；It is preferred that C1-3Alkyl and C3-6Naphthenic base；
R is C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl, C1-6Alkoxy and C1-6Halogenated alkoxy；And
N is 0,1,2 or 3.
Logical formula (VI) compound represented and its isomers general formula (VI-1) and general formula are prepared the invention further relates to a kind of
(VI-2) intermediate of compound shown in, for shown in logical formula (VII) and its isomers general formula (VII-1) and general formula (VII-2)
Compound, its stereoisomer or its pharmaceutically-acceptable salts:
Wherein:
R, Ra and n is as described in logical formula (VI).
The invention further relates to a kind of methods for preparing general formula (VI-1) compound represented, it is characterised in that includes following step
Suddenly,
Wherein:
R, Ra and n is as described in logical formula (VI).
The invention further relates to a kind of methods for preparing general formula (VII-1) compound represented, it is characterised in that comprising as follows
Step,
Wherein:
R, Ra and n is as described in logical formula (VI).
The invention further relates to a kind of methods for preparing general formula (VI-1) compound represented, it is characterised in that includes following step
Suddenly,
Wherein:
R, Ra and n is as described in logical formula (VI).
The present invention also designs a kind of method for preparing general formula (VI-1) compound represented, it is characterised in that includes following step
Suddenly,
The invention further relates to a kind of methods for preparing general formula (VI-1) compound represented, it is characterised in that includes following step
Suddenly,
The invention further relates to a kind of methods for preparing general formula (VI-2) compound represented, it is characterised in that includes following step
Suddenly,
Compared with prior art, present invention has the advantage that
1, it avoids using hazardous agents；
2, the operation using post separation is avoided；
3, synthetic route greatly shortens, and greatly improves total recovery；
4, chiral induction or chiral oxidization are taken, highly selective has obtained target chiral centers；
5, technique is optimized, can satisfy industrial amplification demand.
Specific embodiment
It is described in detail: unless stated to the contrary, following that there is following contain with term in the specification and in the claims
Justice.
Term " alkyl " refers to saturated aliphatic hydrocarbons group, is the linear chain or branched chain group comprising 1 to 12 carbon atom, excellent
Select the alkyl containing 1 to 8 carbon atom；Low alkyl group more preferably containing 1 to 6 carbon atom, most preferably contains 1
To the low alkyl group of 3 carbon atoms；Non-limiting example include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group,
Tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl,
2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethyl butyrate
Base, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl
Amyl, 4- methyl amyl, 2,3- dimethylbutyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methyl
Hexyl, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 2,2- dimethyl amyl group, 3,3- dimethyl amyl group, 2- ethylpentyl,
3- ethylpentyl, n-octyl, 2,3- dimethylhexanyl, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 2,2- dimethyl oneself
Base, 3,3- dimethylhexanyl, 4,4- dimethylhexanyl, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- second
Base amyl, 2- methyl -3- ethylpentyl, n-nonyl, 2- methyl -2- ethylhexyl, 2- methyl -3- ethylhexyl, 2,2- diethyl
Base amyl, positive decyl, 3,3- diethylhexyl, 2,2- diethylhexyl and its various branched isomers etc..
Term " naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, cycloalkyl ring include 3 to
12 carbon atoms, preferably comprise 3 to 8 carbon atoms, more preferably include 3 to 6 carbon atoms.The non-limiting reality of monocyclic cycloalkyl
Example includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptyl three
Alkenyl, cyclooctyl etc..
Term " heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, and it includes 3 to 20 rings
Atom, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), but do not wrap
The loop section of-O-O- ,-O-S- or-S-S- are included, remaining annular atom is carbon.3 to 12 annular atoms are preferably comprised, wherein 1~4
It is hetero atom；It more preferably include 3 to 6 annular atoms.The non-limiting example of monocyclic heterocycles base includes pyrrolidinyl, imidazolidine
Base, tetrahydrofuran base, tetrahydro-thienyl, glyoxalidine base, dihydrofuryl, pyrazoline base, pyrrolin base, piperidyl,
Piperazinyl, morpholinyl, thio-morpholinyl, high piperazine base etc..
Term " aryl " refers to that 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle are (namely shared
The ring of adjacent carbon atoms pair) group, preferably 5 to 8 yuan, more preferable 5 to 6 yuan, such as phenyl and naphthalene；More preferable phenyl.
Term " heteroaryl " refers to the heteroaromatic system comprising 1 to 4 hetero atom, 5 to 14 annular atoms, and wherein hetero atom selects
From oxygen, sulphur and nitrogen.Heteroaryl is preferably 5 to 8 yuan, more preferably 5- or 6-membered, such as imidazole radicals, furyl, thienyl, thiazole
Base, pyrazolyl, oxazolyl, pyrrole radicals, tetrazole radical, pyridyl group, pyrimidine radicals, thiadiazoles, pyrazinyl 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, penta oxygen of ring
Base, cyclohexyloxy.
Term " halogenated alkyl " refers to the alkyl replaced by one or more halogens, and wherein alkyl is as defined above.
Term " halogenated alkoxy " refers to the alkoxy replaced by one or more halogens, and wherein alkoxy is as defined above.
Term " hydroxyalkyl " refers to the alkyl being optionally substituted by a hydroxyl group, and wherein alkyl is as defined above.
Term " hydroxyl " refers to-OH group.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " amino " refers to-NH2。
Term " cyano " refers to-CN.
Term " nitro " refers to-NO2。
Term " oxo base " refers to=O.
The different terms such as " X is selected from A, B or C ", " X is selected from A, B and C ", " X A, B or C ", " X A, B and C " are expressed
Identical meaning, i.e. expression X can be any one or a few in A, B, C.
" optional " or " optionally " mean event or environment described later can with but need not occur, which includes
The occasion that the event or environment occur or do not occur.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group "
But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom
Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this
Field technical staff, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take
Generation.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key
Fixed.
" pharmaceutical composition " indicate containing one or more compounds described herein or its physiologically/pharmaceutical salt or
The mixture and other components such as physiology/pharmaceutical carrier and excipient of pro-drug and other chemical constituents.Medicine
The purpose of compositions is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.
" officinal salt " refers to the salt of the compounds of this invention, has safety when this kind of salt is used in the mammalian body and has
Effect property, and there is due bioactivity.
Below with reference to embodiment, the present invention is described in further detail and completely, but the limitation present invention by no means, the present invention
Also it is not intended to be limited to the content of embodiment.
The compound of the present invention structure is determined by nuclear magnetic resonance (NMR) or/and LC-MS chromatography (LC-MS)
's.Nmr chemical displacement (δ) is provided with the unit of hundred a ten thousandths (ppm).The measurement of NMR is with Bruker AVANCE-400 core
Magnetic instrument, measurement solvent are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3) and deuterated chloroform (CDCl OD3) in be designated as
Tetramethylsilane (TMS).
The measurement of LC-MS chromatography LC-MS Agilent 1200Infinity Series mass spectrograph.The measurement of HPLC
Use Agilent 1200DAD high pressure liquid chromatograph (Sunfire 150 × 4.6mm of C18 chromatographic column) and Waters 2695-
2996 high pressure liquid chromatographs (Gimini 150 × 4.6mm of C18 chromatographic column).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and the specification that TLC is used is
0.15mm~0.20mm, the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.Column chromatography generally uses cigarette
200~300 mesh silica gel of platform Huanghai Sea silica gel is carrier.
Starting material in the embodiment of the present invention is known and can be commercially available, or can use or press
It is synthesized according to methods known in the art.
In the case where no specified otherwise, all reactions of the invention are under continuous magnetic agitation, in drying nitrogen
Or carried out under argon atmospher, solvent is dry solvent.
Analysis method parameter involved in the present invention:
1. liquid phase analysis method:
(1) chemical purity liquid phase analysis method:
Mobile phase A :+0.05% trifluoroacetic acid of water
Mobile phase B :+0.04% trifluoroacetic acid of acetonitrile
Chromatographic column: 5 μm of 4.6x 150mm of Agilent SBC-18
Gradient
| TIME(min) | A (%) | B (%) |
| 0 | 95 | 5 |
| 13 | 25 | 75 |
| 14 | 5 | 95 |
| 17 | 5 | 95 |
Column temperature: 40 DEG C
Flow velocity: 1mL/min
Detection wavelength: 254nm
(2) chiral purity liquid phase analysis method:
Chromatographic column: 5 μm of 4.6x 250mm of Daicel CHIRALPAK IC
Sample volume: 10 μ l
Mobile phase: n-hexane/isopropanol/diethylamine=70/30/0.1
Column temperature: 35 DEG C
Flow velocity: 0.8mL/min
Detection wavelength: 254nm
Sample preparation: 10% ethyl alcohol of 1.0mg/mL in methylene chloride, 20% n-hexane 70%.
Synthesis technology one
(1) synthetic route:
(2) synthesis step:
(1) preparation of compound HS-A
It is sequentially added in 3L reaction flask dimethyl disulfide (228g), acetic acid (290g), methylene chloride (1140mL), nitrogen
Protection, it is cooling.Temperature connects device for absorbing tail gas (lye absorption), sulfonyl is added dropwise into reaction system to -25 DEG C or so in reaction solution
Chlorine (1012g), completion of dropwise addition in 2.5 hours continue stirring 2 hours.Heating, is stirred overnight at room temperature.It will be in reaction solution with water pump
Methylene chloride and by-product chloroacetic chloride evaporate, and obtain yellow transparent concentrate.It is evaporated under reduced pressure concentrate with water pump, it is saturating to obtain yellow
Prescribed liquid 371.1g, yield 77.8%.
(2) preparation of compound HS-B
It sequentially adds SM2 (317.0g), N, N'- diisopropylethylamine (314.9g), toluene (6L), uses in 10L reaction flask
Reaction solution is cooled to -70~-75 DEG C by dry ice.HS-A (180.0g) is dissolved in toluene (200mL), is transferred in dropping funel,
It is added dropwise in reaction solution, adds again within 2.5 hours, continue stirring 1.5 hours, reaction terminates.Reaction solution is slowly ramped to -20 DEG C,
Water (3L) is added dropwise into reaction system, stirs, layering.Organic phase is washed with 1N hydrochloric acid (3L), then uses saturated sodium bicarbonate solution
(3L) washing, organic layer are dried, filtered with anhydrous sodium sulfate, are concentrated under reduced pressure to give Tan solid 319.5g, yield 81.1%.
(3) preparation of compound HS-C
It is sequentially added in 2L reaction flask HS-B (100g), toluene (1L), nitrogen protection, reaction solution is cooled to 0 DEG C with ice water.
2M vinylimidazolium chloride magnesium tetrahydrofuran solution (186.1mL) is slowly added dropwise in reaction solution, interior 0~5 DEG C of temperature is controlled.After adding
Stirring 1 hour, reaction terminates, and is added dropwise saturated ammonium chloride solution (100mL).Add 2N hydrochloric acid (200mL).Layering, water phase are used
Methyl tertiary butyl ether(MTBE) extraction, water layer retain.Merge organic phase, washed with water (300mL), is layered, merges all water phases, use dichloro
Three times, organic layer is dried, filtered the mixed extractant solvent of methane and methanol with anhydrous sodium sulfate, is concentrated under reduced pressure to give grease
27.0g, yield 96.6%.
(4) preparation of compound HS-D
It is sequentially added in 1L autoclave HS-C (29.4g), 7M methanolic ammonia solution (810mL) is warming up to 50 DEG C, insulated and stirred
48 hours, fully reacting.Reaction solution is down to room temperature, is concentrated under reduced pressure into no liquid outflow, adds methanol (50mL), continue to be concentrated
It is flowed out to no liquid, obtains grease 32.1g, yield 91.9%.
(5) preparation of compound HS-E
SM3 (48.7g) is added in 2L reaction flask, ethyl alcohol (500mL) stirs, and nitrogen protection, ice water is cooled to 0 DEG C.It will
HS-D (32.1g) is dissolved in ethyl alcohol (100mL), then is added dropwise in reaction solution, is added within 0.5 hour.It is added dropwise again into reaction system
Triethylamine (45.6g) adds for 0.5 hour, continues stirring 3 hours.Filtering, filter cake are beaten 10 minutes with 200mL methanol room temperature, mistake
Filter.Merge filtrate twice, is concentrated under reduced pressure, obtains brown solid 50.4g, yield 72.0%.
(6) preparation of compound HS-F
Potassium hydroxide (36.3g) is added in 500mL reaction flask, water (220mL) adds HS-E (50.4g), oil bath heating
To reflux, 15 hours are kept the temperature, fully reacting.It is cooled to room temperature, adjusts PH to 7.5~8.5 with 3N hydrochloric acid, solid, room temperature is precipitated
Stirring 1 hour.Filtering, filter cake are washed with water, and obtain khaki solid 34.2g, yield 67.9% after dry.
(7) preparation of compound HS-G
It is sequentially added in 500mL three-necked flask HS-F (14.5g), sodium chloride (10.9g), ethyl acetate (73mL), 6N salt
Sour (73mL), water (73mL), ice water are cooled to 0~10 DEG C.Sodium nitrite (4.1g) is dissolved in water, is slowly added dropwise to reaction flask
In, it adds within 0.5 hour, continues stirring 1.5 hours.Ice water is removed, stirring 2 hours is warmed to room temperature.Second is added into reaction system
Acetoacetic ester (200mL), stirring are filtered after ten minutes, and filter cake is washed with ethyl acetate.Filtrate layered, aqueous layer with ethyl acetate extraction
Once, merge organic layer.Organic layer washed once with saturated brine, and sodium sulphate dries, filters, and concentration obtains light yellow solid
15.6g, yield 99.3%.
(8) preparation of compound HS-H
HS-G (15.5g) is added in 500mL three-necked flask, Isosorbide-5-Nitrae-dioxane (100mL), water (100mL) is warming up to 50
℃.The bromo- 4- fluoroaniline (11.7g) of 3- is added, 50~60 DEG C are stirred 10 minutes.Sodium bicarbonate (7.7g) is dissolved in water (100mL),
It is slowly added dropwise in reaction flask, controls interior 50~60 DEG C of temperature, add within 0.5 hour.Continue stirring 1 hour, fully reacting.Remove oil
Room temperature is down in bath, is added ethyl acetate (200mL), is stirred 10 minutes, layering.Aqueous layer with ethyl acetate extraction is primary, is associated with
Machine layer, salt water washed once, and sodium sulphate dries, filters, and concentration obtains khaki solid 22.0g, yield 88.3%.
(9) preparation of compound HS-I
HS-H (19.5g) is added in 500mL three-necked flask, ethyl acetate (300mL) is added carbonyl dimidazoles (11.7g),
Continue stirring 1 hour, fully reacting.1N hydrochloric acid (100mL) is added in reaction system, stirs 10 minutes, layering.Organic layer 1N
Salt acid elution, then be washed with brine once, sodium sulphate dries, filters, and concentration obtains pale yellowish brown solid 18.3g, yield
88.2%.
(10) preparation of compound HS-J
HS-I (18.3g) is added in three-necked flask, acetonitrile (500mL), cyclopropyl-sulfonylamide (12.8g), ferric acetyl acetonade
(3.0g).Reaction solution is warming up to 40~45 DEG C, stirs 15 minutes.It is added iodobenzene diacetate (17.1g), reaction solution is at 40~45 DEG C
Stirring 1 hour.Ferric acetyl acetonade (3.0g) is added into reaction solution again, iodobenzene diacetate (17.1g), continuation is stirred at 40~45 DEG C
It mixes 1 hour.Ferric acetyl acetonade (3.0g) is added into reaction solution again, iodobenzene diacetate (17.1g) continues to stir at 40~45 DEG C
1 hour.Ferric acetyl acetonade (3.0g) is added into reaction solution again, iodobenzene diacetate (17.1g) continues to stir 1 at 40~45 DEG C
Hour.Sample detection, raw material fully reacting.Reaction solution is concentrated into no liquid and oozes, and is added ethyl acetate (200mL), then successively
With 4N hydrochloric acid (180mL), saturated aqueous sodium carbonate (180mL), saturated brine (180mL) washing.Organic layer is dry with sodium sulphate
It is dry, it filters, concentration obtains 13.3g yellow solid, yield 56.8%.
(11) preparation of compound HS-K
HS-J (13.0g) is added in three mouthfuls of reaction flasks, tetrahydrofuran (130mL), stirring to solid is all dissolved, then uses ice
It is water-cooled to 0~10 DEG C.Sodium hydroxide (7.5g) is taken, adds water (100mL) to dissolve, sodium hydrate aqueous solution is added dropwise to reaction solution
In.It is added dropwise, reaction solution stirs 2 hours, fully reacting.Reaction liquid layer, aqueous layer with ethyl acetate (130mL) extraction.It closes
And organic phase, then 1N hydrochloric acid (130mL) successively is used, saturated brine (130mL) washing.Organic phase is dry with anhydrous sodium sulfate, mistake
Filter, concentration, obtains light yellow solid 11.9g.Ethyl acetate (40mL) is added in crude product, is warming up to reflux, adds methyl- tert
Butyl ether (40mL) is slowly cooled to room temperature, stirs 2 hours, and filtering, filter cake is washed with methyl tertiary butyl ether(MTBE).It is dry, obtain class
White solid 9.5g, yield 76.8%.
MS m/z(ESI):525.0,527.0(M,M+2).
1H NMR(400MHz,DMSO-d6, ppm) δ 11.44 (s, 1H), 8.92 (s, 1H), 7.18 (t, J=17.6Hz,
1H),7.12(dd,J1=2.7Hz, J2=2.7Hz, 1H), 6.77 (m, 1H), 6.55 (t, J=11.6Hz, 1H), 3.93 (m,
1H),3.80(m,3H),3.47(s,3H),2.64(m,1H),0.95(m,4H).
Detection chemistry and chiral purity: 99.2%.
Product chiral purity: S configuration: 99.8%, R configuration: 0.2%.
Synthesis technology two
(1) synthetic route:
(2) synthesis step:
(1) preparation of compound HS-1
Sodium hydroxide (24g) is added in 1000mL reaction flask, dehydrated alcohol (680mL), nitrogen protection, ice water cooling.It is past
SM1 (34.1g) is added in reaction system, then iodomethane (44.7g) is added dropwise into reaction system, adds within 1 hour, continues under ice water
Stirring 15 minutes or so, removes ice water, slowly restores to being stirred at room temperature 2 hours, and raw material fully reacting is filtered, filtrate decompression rotation
It is dry, obtain colourless liquid 21.9g, yield 80.0%.
(2) preparation of compound HS-2
It is sequentially added in 1000mL reaction flask raw material SM2 (32.5g), ethyl acetate (160mL), nitrogen protection, ice water is cold
But, HS-1 (18.3g) is dissolved with ethyl acetate (160mL), is added in reaction system by 5 DEG C or so of temperature in reaction solution.Control
0~10 DEG C of interior temperature is added dropwise triethylamine (30.4g) into reaction system, adds within 0.5 hour, continues stirring 2 hours, fully reacting.
It is added water (300mL), stirs, layering, water layer is extracted with ethyl acetate again.Combined ethyl acetate, salt water washing, is spin-dried for, and obtains
Sepia solid 34.6g, yield 79.7%.
(3) preparation of compound HS-3
Potassium hydroxide (33.7g) is added in 500mL reaction flask, water (200mL) adds HS-2 (43.3g), stirs 10 points
Clock.Reaction solution is warming up to reflux, keeps the temperature 15 hours, fully reacting.It is cooled to room temperature, is added ethyl acetate (200mL), water
(120mL).Stirring, layering, water layer are extracted with ethyl acetate once again.Combined ethyl acetate is washed with brine primary.It is spin-dried for,
Obtain Melon yellow color grease 31.4g, yield 72.5%.
(4) preparation of compound HS-4
HS-3 (40.0g) is added in 1000mL reaction flask, 6N hydrochloric acid (200mL), stirring adds sodium chloride (32.5g),
Ethyl acetate (200mL), water (200mL).Ice water is cooling, controls interior 0~10 DEG C of temperature, sodium nitrite in aqueous solution is added dropwise into system
(sodium nitrite 12.3g+ water 80mL), completion of dropwise addition in 1.5 hours continue stirring 2 hours, remove ice water, be stirred overnight at room temperature.It is past
Water (100mL) is added in reaction system, ethyl acetate (150mL) is layered, and water layer is extracted with ethyl acetate once again, merges second
Ethyl acetate layer is washed with brine, dry with anhydrous sodium sulfate, is spin-dried for, is obtained yellow solid 44.6g.Acetic acid second is added in crude product
Ester (44.6g), is warming up to reflux, then petroleum ether (135g) slowly is added dropwise, cooling, filters, a small amount of petroleum ether of filter cake, dries
It is dry, obtain light yellow solid 38.5g, yield 88.6%.
(5) preparation of compound HS-5
HS-4 (21.0g) is added in 1000mL reaction flask, water (135mL), Isosorbide-5-Nitrae-dioxane (135mL) stirs, and rises
Temperature.The bromo- 4- fluoroaniline (16.9g) of 3- is added into system to 60 DEG C or so for interior temperature rise.Insulated and stirred 10 minutes, toward reactant
Sodium bicarbonate aqueous solution (sodium bicarbonate 11.2g+ water 135mL) is added dropwise in system.It adds within 15 minutes, it is anti-to continue heat preservation at this temperature
0.5 hour is answered, fully reacting.It is cooled to room temperature, ethyl acetate (200mL) is added into reaction system, stir, layering, water layer
It is extracted with ethyl acetate again primary.Combined ethyl acetate layer, is washed with brine, and organic layer is dry with anhydrous sodium sulfate, is spin-dried for, obtains
To sepia grease 29.3g, yield 84.7%.
(6) preparation of compound HS-6
HS-5 (29.3g) is added in 500mL reaction flask, ethyl acetate (350mL), carbonyl dimidazoles (18.3g), room temperature is stirred
Mix reaction 1 hour, fully reacting.It is added 1N hydrochloric acid (350mL), stirring.Layering, organic layer washed once with 1N hydrochloric acid, then use
Salt water washed once, and anhydrous sodium sulfate is dry, is spin-dried for, obtains yellow-brown solid 35.2g.Ethyl alcohol (175mL) is added in the solid,
60 DEG C are warming up to, stirs 0.5 hour, is slowly cooled to room temperature, is filtered, it is dry with a little ethanol washing filter cake, obtain khaki
Solid 25.4g, yield 81.3%.
(7) preparation of compound HS-7
HS-6 (25.0g) is added in 500mL reaction flask, toluene (150mL), water (0.324g), L-TARTARIC ACID diethylester
(6.2g), nitrogen protection are warming up to 60 DEG C, are added tetra isopropyl titanium oxide (5.2g), insulation reaction 2 hours.It is cooled to room temperature,
It is added n,N-diisopropylethylamine (2.5g), then cumyl hydroperoxide is slowly added dropwise, add within 0.5 hour, it is small to continue stirring 2
When, 15% ammonium hydroxide 200ml is added, stirs 1 hour, filters, filter cake washing, drying obtains yellow-brown solid 22.5g.In solid
It is added ethyl acetate (45ml), heating, Quan Rong, then methyl tertiary butyl ether(MTBE) (135ml) is added dropwise, be cooled to room temperature, filter, obtain shallow
Yellow solid 18.9g, yield 72.8%.
(8) preparation of compound HS-8
HS-7 (18.0g) is added in reaction flask, acetonitrile (500mL), cyclopropyl-sulfonylamide (12.6g), ferric acetyl acetonade
(3.0g).Reaction solution is warming up to 40~45 DEG C, stirs 15 minutes.It is added iodobenzene diacetate (16.8g), reaction solution is at 40~45 DEG C
Stirring 1 hour.Ferric acetyl acetonade (3.0g) is added into reaction solution again, iodobenzene diacetate (16.8g), continuation is stirred at 40~45 DEG C
It mixes 1 hour.Ferric acetyl acetonade (3.0g) is added into reaction solution again, iodobenzene diacetate (16.8g) continues to stir at 40~45 DEG C
1 hour.Ferric acetyl acetonade (3.0g) is added into reaction solution again, iodobenzene diacetate (16.8g) continues to stir 1 at 40~45 DEG C
Hour.Sample detection, raw material fully reacting.Reaction solution is concentrated into no liquid and oozes, and is added ethyl acetate (200mL), then successively
With 4N hydrochloric acid (180mL), saturated aqueous sodium carbonate (180mL), saturated brine (180mL) washing.Organic layer is dry with sodium sulphate
It is dry, it filters, concentration obtains 18.2g yellow solid, yield 79.3%.
(9) preparation of compound HS-9
HS-8 (15.0g) is added in reaction flask, tetrahydrofuran (150mL), stirring to solid is all dissolved, then cold with ice water
But to 0~10 DEG C.Sodium hydroxide (8.7g) is taken, adds water (115mL) to dissolve, sodium hydrate aqueous solution is added dropwise in reaction solution.
It is added dropwise, reaction solution stirs 2 hours, fully reacting.Reaction liquid layer, aqueous layer with ethyl acetate (150mL) extraction.It is associated with
Machine phase, then washed with 1N hydrochloric acid (150mL), saturated brine (150mL) washing.Organic phase is dried, filtered with anhydrous sodium sulfate, dense
Contracting, obtains light yellow solid 13.7g.Ethyl acetate (45mL) is added in crude product, is warming up to reflux, adds methyl tertiary butyl ether(MTBE)
(45mL) is slowly cooled to room temperature, stirs 2 hours, and filtering, filter cake is washed with methyl tertiary butyl ether(MTBE).It is dry, it is solid to obtain off-white color
Body 10.1g, yield 70.6%.
MS m/z(ESI):525.0,527.0(M,M+2).
1H NMR(400MHz,DMSO-d6, ppm) δ 11.44 (s, 1H), 8.92 (s, 1H), 7.18 (t, J=17.6Hz,
1H),7.12(dd,J1=2.7Hz, J2=2.7Hz, 1H), 6.77 (m, 1H), 6.55 (t, J=11.6Hz, 1H), 3.93 (m,
1H),3.80(m,3H),3.47(s,3H),2.64(m,1H),0.95(m,4H).
Product chemical purity: 98.3%.
Product chiral purity: S configuration: 99.8%, R configuration: 0.2%.
Synthesis technology three
(1) synthetic route:
(2) synthesis step
(1) preparation of compound HS-I
It sequentially adds in 10L reaction flask SM1 (104.0g), pyridine (63.3g), tetrahydrofuran (2L), will be reacted with dry ice
Liquid is cooled to -70~-75 DEG C.HS-A (60.0g) is dissolved in tetrahydrofuran (60mL), is transferred in dropping funel, then be added dropwise to
It in reaction solution, adds within 2.5 hours, continues stirring 1.5 hours, reaction terminates.Reaction solution is slowly ramped to -20 DEG C, toward reactant
Water (1L) is added dropwise in system, stirs, layering.Organic phase is washed with 1N hydrochloric acid (1L), then is washed with saturated sodium bicarbonate solution (1L),
Organic layer is dried, filtered with anhydrous sodium sulfate, is concentrated under reduced pressure to give light yellow oil 120.4g, yield 93.3%.
(2) preparation of compound HS-II
It is sequentially added in 2L reaction flask HS-I (100g), toluene (1L), nitrogen protection, reaction solution is cooled to 0 DEG C with ice water.
2M vinylimidazolium chloride magnesium tetrahydrofuran solution (186.1mL) is slowly added dropwise in reaction solution, interior 0~5 DEG C of temperature is controlled.After adding
Stirring 1 hour, reaction terminates, and is added dropwise saturated ammonium chloride solution (100mL).Add 2N hydrochloric acid (200mL).Layering, water phase are used
Methyl tertiary butyl ether(MTBE) extraction, water layer retain.Merge organic phase, washed with water (300mL), is layered, merges all water phases, use dichloro
Three times, organic layer is dried, filtered the mixed extractant solvent of methane and methanol with anhydrous sodium sulfate, is concentrated under reduced pressure to give brown oil
Object 25.3g, yield 90.6%.
(3) preparation of compound HS-III
It is sequentially added in 1L autoclave HS-II (25.0g), 7M methanolic ammonia solution (750mL) is warming up to 50 DEG C, heat preservation is stirred
48 hours are mixed, fully reacting.Reaction solution is down to room temperature, is concentrated under reduced pressure into no liquid outflow, adds methanol (50mL), continues dense
It is reduced to no liquid outflow, obtains 27.9g brown oil, yield 93.9%.
(4) preparation of compound HS-IV
SM2 (22.7g) is added in 2L reaction flask, methanol (250mL) stirs, and nitrogen protection, ice water is cooled to 0 DEG C.It will
HS-III (15.0g) is dissolved in ethyl alcohol (50mL), then is added dropwise in reaction solution, is added within 0.5 hour.It is added dropwise again into reaction system
Triethylamine (21.2g) adds for 0.5 hour, continues stirring 3 hours.Filtering, filter cake are beaten 10 minutes with 100mL methanol room temperature, mistake
Filter.Merge filtrate twice, is concentrated under reduced pressure, obtains brown solid 23.1g, yield 70.6%.
(5) preparation of compound HS-V
Potassium hydroxide (16.6g) is added in 500mL reaction flask, water (100mL) adds HS-IV (23.1g), and oil bath adds
Heat keeps the temperature 15 hours, fully reacting to flowing back.It is cooled to room temperature, adjusts PH to 7.5~8.5 with 3N hydrochloric acid, solid, room is precipitated
Temperature stirring 1 hour.Filtering, filter cake are washed with water, and obtain yellow solid 14.1g, yield 61.2% after dry.
(6) preparation of compound HS-VI
It is sequentially added in 500mL three-necked flask HS-V (14.0g), sodium chloride (10.5g), ethyl acetate (70mL), 6N salt
Sour (70mL), water (70mL), ice water are cooled to 0~10 DEG C.Sodium nitrite (4.0g) is dissolved in water, is slowly added dropwise to reaction flask
In, it adds within 0.5 hour, continues stirring 1.5 hours.Ice water is removed, stirring 2 hours is warmed to room temperature.Second is added into reaction system
Acetoacetic ester (200mL), stirring are filtered after ten minutes, and filter cake is washed with ethyl acetate.Filtrate layered, aqueous layer with ethyl acetate extraction
Once, merge organic layer.Organic layer washed once with saturated brine, and sodium sulphate dries, filters, and concentration obtains yellow solid
14.9g, yield 98.2%.
(7) preparation of compound HS-VII
HS-VI (14.9g) is added in 500mL three-necked flask, Isosorbide-5-Nitrae-dioxane (100mL), water (100mL) is warming up to
50℃.The bromo- 4- fluoroaniline (11.4g) of 3- is added, 50~60 DEG C are stirred 10 minutes.Sodium bicarbonate (7.7g) is dissolved in water
(100mL), is slowly added dropwise in reaction flask, controls interior 50~60 DEG C of temperature, adds within 0.5 hour.Continue stirring 1 hour, has reacted
Entirely.Oil bath is removed, room temperature is down to, is added ethyl acetate (200mL), is stirred 10 minutes, layering.Aqueous layer with ethyl acetate extraction one
It is secondary, merge organic layer, salt water washed once, and sodium sulphate dries, filters, and concentration obtains yellow solid 21.5g, yield 89.7%.
(8) preparation of compound HS-VIII
HS-VII (21.5g) is added in 500mL three-necked flask, carbonyl dimidazoles are added in ethyl acetate (300mL)
(12.9g) continues stirring 1 hour, fully reacting.1N hydrochloric acid (200mL) is added in reaction system, stirs 10 minutes, layering.Have
Machine layer 1N salt acid elution, then be washed with brine once, sodium sulphate dries, filters, and concentration obtains yellow solid 20.1g, yield
87.7%.
(9) preparation of compound HS-IX
HS-VIII (18.3g) is added in three-necked flask, acetonitrile (500mL), cyclopropyl-sulfonylamide (12.8g), ferric acetyl acetonade
(3.0g).Reaction solution is warming up to 40~45 DEG C, stirs 15 minutes.It is added iodobenzene diacetate (17.1g), reaction solution is at 40~45 DEG C
Stirring 1 hour.Ferric acetyl acetonade (3.0g) is added into reaction solution again, iodobenzene diacetate (17.1g), continuation is stirred at 40~45 DEG C
It mixes 1 hour.Ferric acetyl acetonade (3.0g) is added into reaction solution again, iodobenzene diacetate (17.1g) continues to stir at 40~45 DEG C
1 hour.Ferric acetyl acetonade (3.0g) is added into reaction solution again, iodobenzene diacetate (17.1g) continues to stir 1 at 40~45 DEG C
Hour.Sample detection, raw material fully reacting.Reaction solution is concentrated into no liquid and oozes, and is added ethyl acetate (200mL), then successively
With 4N hydrochloric acid (180mL), saturated aqueous sodium carbonate (180mL), saturated brine (180mL) washing.Organic layer is dry with sodium sulphate
It is dry, it filters, concentration obtains 14.5g yellow solid, yield 62.2%.
(10) preparation of compound HS-X
HS-IX (13.0g) is added in three mouthfuls of reaction flasks, tetrahydrofuran (130mL), stirring to solid is all dissolved, then is used
Ice water is cooled to 0~10 DEG C.Sodium hydroxide (7.5g) is taken, adds water (100mL) to dissolve, sodium hydrate aqueous solution is added dropwise to reaction
In liquid.It is added dropwise, reaction solution stirs 2 hours, fully reacting.Reaction liquid layer, aqueous layer with ethyl acetate (130mL) extraction.
Merge organic phase, then successively uses 1N hydrochloric acid (130mL), saturated brine (130mL) washing.Organic phase is dry with anhydrous sodium sulfate,
Filtering, concentration, obtains light yellow solid 11.9g.Ethyl acetate (40mL) is added in crude product, is warming up to reflux, adds methyl
Tertbutyl ether (40mL) is slowly cooled to room temperature, stirs 2 hours, and filtering, filter cake is washed with methyl tertiary butyl ether(MTBE).It is dry, it obtains
Off-white powder 9.8g, yield 79.2%.
MS m/z(ESI):525.0,527.0(M,M+2).
Product chemical purity: 98.4%.
Product chiral purity: S configuration: 0.05%, R configuration: 99.95%.
Synthesis technology four
Synthesis technology:
In patent PCT/CN2017/079585, following synthetic route is disclosed, route is longer, and gross production rate is lower, and
Final step takes chiral column to prepare, and is not suitable for amplification.
Final goal compound Q/HS-K/HS-9 synthesis, from same raw material C/SM3/SM2, through process above road
Line comparison, table specific as follows:
As seen from the above table, compared with the existing technology, the step of general line, greatly reduces process route 1 and 2, and total recovery is big
It is big to improve, and each reaction condition is mild, is suitble to amplification.
Claims (20)
1. a kind of logical formula (I) and its isomers general formula (I-1) compound represented, its stereoisomer or its is pharmaceutically acceptable
Salt:
Wherein:
R is selected from hydrogen atom, D-atom, alkyl, deuteroalkyl, halogenated alkyl or alkoxy；And
N is 0,1,2 or 3.
2. a kind of intermediate for preparing logical formula (I) compound represented according to claim 1, for logical formula (II) and its
Isomers general formula (II-1) and general formula (II-2) compound represented, its stereoisomer or its pharmaceutically-acceptable salts:
Wherein:
R is selected from C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl or C1-6Alkoxy；And
N is 0,1,2 or 3.
3. a kind of method for preparing logical formula (I) compound represented described in claim 1, it is characterised in that include following step
Suddenly,
Wherein:
R and n are as described in claim 1.
4. a kind of intermediate for preparing logical formula (II) compound represented according to claim 2 and its isomers, is
Logical formula (III) and its isomers general formula (III-1) and general formula (III-2) compound represented, its stereoisomer or its pharmacy
Upper acceptable salt:
Wherein:
R is selected from C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl or C1-6Alkoxy；
R1Selected from C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, halogen, amino ,-
(CH2)xNR2R3、-(CH2)xC(O)NR2R3、-(CH2)xNR2C(O)R3With-(CH2)xNR2S(O)mR3；
R2And R3It is identical or different, and it is each independently selected from hydrogen atom, D-atom, C1-6Alkyl, C1-6Deuteroalkyl, C1-6It is halogenated
Alkyl, hydroxyl, amino, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 5-8 member aryl and 5-8 unit's heteroaryl, wherein the C1-6Alkane
Base, C1-6Deuteroalkyl, C1-6Halogenated alkyl, C3-8Naphthenic base, 5-8 circle heterocyclic ring base, 5-8 member aryl and 5-8 unit's heteroaryl optionally into
One step is selected from D-atom, C1-8Alkyl, halogen, hydroxyl, amino, nitro, cyano, C1-6Alkoxy, C1-6Hydroxyalkyl, C3-8Cycloalkanes
Replaced one or more substituent groups in base, 3-8 circle heterocyclic ring base, 5-8 member aryl and 5-8 unit's heteroaryl；
N is 0,1,2 or 3；
X is 0,1,2 or 3；And
M is 0,1 or 2.
5. a kind of method for preparing general formula as claimed in claim 2 (II-1) compound represented, it is characterised in that comprising as follows
Step,
Wherein:
R is selected from C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl or C1-6Alkoxy；
R1Selected from halogen；And
N is 0,1,2 or 3.
6. intermediate according to claim 4, for logical formula (IV) and its isomers general formula (IV-1) and general formula (IV-2)
Compound represented, its stereoisomer or its pharmaceutically-acceptable salts:
Wherein:
R5Selected from hydrogen atom, C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C3-8Ring
Alkyl, 3-8 circle heterocyclic ring base, 5-8 member aryl and 5-8 unit's heteroaryl；The wherein C1-6Alkyl, C1-6Deuteroalkyl, C1-6It is halogenated
Alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 5-8 member aryl and 5-8 unit's heteroaryl are optional
Further it is selected from D-atom, C1-6Alkyl, C1-6Halogenated alkyl, halogen, amino, nitro, cyano, hydroxyl, C1-6Alkoxy, C1-6
Halogenated alkoxy and C1-6Replaced one or more substituent groups in hydroxyalkyl；It is preferred that hydrogen atom, C1-6Alkyl and 5-8 member virtue
Base；The aryl that more preferable 5-6 member halogen replaces；
R and n are as claimed in claim 3.
7. a kind of method for preparing general formula as claimed in claim 4 (III-1) compound represented, it is characterised in that comprising as follows
Step,
Wherein:
R is selected from C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl or C1-6Alkoxy；
R1Selected from halogen；
R5Selected from hydrogen atom or C1-6Alkyl；And
N is 0,1,2 or 3.
8. a kind of intermediate for preparing logical formula (IV) compound represented according to claim 6 and its isomers, is
Logical formula (V) and its isomers general formula (V-1) and general formula (V-2) compound represented, its stereoisomer or its can pharmaceutically connect
By salt:
Wherein:
R5Selected from hydrogen atom, C1-6Alkyl, C1-6Deuteroalkyl and C1-6Halogenated alkyl；The wherein C1-6Alkyl, C1-6Deuterated alkane
Base and C1-6Halogenated alkyl is optionally further replaced by the one or more in D-atom, halogen, amino, cyano and hydroxyl
Replaced base；It is preferred that hydrogen atom and C1-6Alkyl；More preferable hydrogen atom；
R and n are as claimed in claim 3.
9. a kind of method for preparing general formula as claimed in claim 4 (IV-1) compound represented, it is characterised in that comprising as follows
Step,
Wherein:
R is selected from C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl or C1-6Alkoxy；
R1For halogen；
R5For hydrogen atom or C1-6Alkyl；And
N is 0,1,2 or 3.
10. a kind of method for preparing logical formula (I) compound represented described in claim 1, it is characterised in that include following step
Suddenly,
Wherein:
R、R1It is as claimed in claim 4 with n.
11. a kind of method for preparing logical formula (I) compound represented described in claim 1, it is characterised in that include following step
Suddenly,
Wherein:
R、R1、R5It is as claimed in claim 6 with n.
12. a kind of method for preparing logical formula (I) compound represented described in claim 1, it is characterised in that include following step
Suddenly,
Wherein:
R、R1、R5It is as claimed in claim 8 with n.
13. chemical combination shown in a kind of formula (VI) compound represented logical as follows and its isomers general formula (VI-1) and general formula (VI-2)
Object, it is characterised in that logical formula (I) compound represented, its stereoisomer or its pharmaceutically-acceptable salts are to prepare logical formula (VI)
And its midbody compound of compound shown in isomers general formula (VI-1) and general formula (VI-2),
Wherein:
Ra is selected from hydrogen atom, D-atom, C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Haloalkoxy
Base, C3-8Naphthenic base, C3-8Halogenated cycloalkyl and C3-8Deuterated naphthenic base；It is preferred that C1-3Alkyl and C3-6Naphthenic base；
R is C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl, C1-6Alkoxy and C1-6Halogenated alkoxy；And
N is 0,1,2 or 3.
14. it is a kind of prepare logical formula (VI) compound represented according to claim 13 and its isomers general formula (VI-1) and
The intermediate of compound shown in general formula (VI-2), for logical formula (VII) and its isomers general formula (VII-1) and general formula (VII-2)
Compound represented, its stereoisomer or its pharmaceutically-acceptable salts:
Wherein:
R, Ra and n are as claimed in claim 13.
15. a kind of method for preparing general formula described in claim 13 (VI-1) compound represented, it is characterised in that comprising such as
Lower step,
Wherein:
R, Ra and n are as claimed in claim 13.
16. a kind of method for preparing general formula described in claim 14 (VII-1) compound represented, it is characterised in that comprising such as
Lower step,
Wherein:
R, Ra and n are as claimed in claim 13.
17. a kind of method for preparing general formula described in claim 13 (VI-1) compound represented, it is characterised in that comprising such as
Lower step,
Wherein:
R, Ra and n are as claimed in claim 13.
18. a kind of method for preparing general formula described in claim 13 (VI-1) compound represented, it is characterised in that comprising such as
Lower step,
19. a kind of method for preparing general formula described in claim 13 (VI-1) compound represented, it is characterised in that comprising such as
Lower step,
20. a kind of method for preparing general formula described in claim 13 (VI-2) compound represented, it is characterised in that comprising such as
Lower step,
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| CN201711399639 | 2017-12-22 | ||
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112679394A (en) * | 2020-12-31 | 2021-04-20 | 武汉工程大学 | Preparation method of styrene monomer containing chiral sulfoxide |
| CN112979513A (en) * | 2021-02-07 | 2021-06-18 | 武汉工程大学 | Chiral sulfoxide containing styrene monomer and preparation method thereof |
-
2018
- 2018-12-21 CN CN201811568105.1A patent/CN109956914A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112679394A (en) * | 2020-12-31 | 2021-04-20 | 武汉工程大学 | Preparation method of styrene monomer containing chiral sulfoxide |
| CN112979513A (en) * | 2021-02-07 | 2021-06-18 | 武汉工程大学 | Chiral sulfoxide containing styrene monomer and preparation method thereof |
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