CN107522654A - New α aminoamide derivatives and its medical usage - Google Patents

New α aminoamide derivatives and its medical usage Download PDF

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CN107522654A
CN107522654A CN201610442910.4A CN201610442910A CN107522654A CN 107522654 A CN107522654 A CN 107522654A CN 201610442910 A CN201610442910 A CN 201610442910A CN 107522654 A CN107522654 A CN 107522654A
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ethyl acetate
hydrogen atom
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CN107522654B (en
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史卫国
李浩田
樊士勇
仲伯华
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Institute of Pharmacology and Toxicology of AMMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to new α aminoamide derivatives and its medical usage, specifically, the present invention relates to the α aminoamide derivatives shown in structural formula I or its pharmaceutically acceptable salt, contain pharmaceutical composition of these compounds as active component, and the purposes of the derivative or its pharmaceutically acceptable salt for preparing analgesic

Description

New alpha-aminoamide derivatives and its medical usage
Technical field
The present invention relates to new alpha-aminoamide derivatives or its pharmaceutically acceptable salt, contains these compound conducts The pharmaceutical composition of active component, and the use of the derivative or its pharmaceutically acceptable salt for preparing analgesic On the way.
Background technology
Neuropathic pain (Neuropathic pain) be by maincenter or periphery somatesthesia nervous system infringement or A kind of chronic ache caused by disease, it is mainly shown as spontaneous pain (rest pain and paroxysmal pain) and induction property pain (hyperalgia and allodynia) bitterly, feature are that the pain sensation is still persistently present, and has a strong impact on patient's after nervous system injury heals Daily life quality.
Neuropathic pain cause is extensive, and the incidence of disease is high, and pathomechanism is complicated, clinical at present to lack specific curative Thing, it is the problem for perplexing medical field always.It is estimated that neuralgia alleviation can exceed that 50% after only 1/4 patient medication, And cental system side effect is obvious.Traditional antalgesic such as opioid receptor agonist only just shows certain effect at high doses Fruit, and high dose have it is additive；Though NSAIDs is without additive, low to neuralgia efficiency, therapeutic purposes are not reached. Therefore the specific treatment medicine of urgent clinical needs highly effective and safe.
Ralfinamide is selective N av1.7 retarding agents, is shown on a variety of neuropathic pain animal models good Therapeutic effect, analgesic activity is 20 times of Gabapentin, 80 times of carbamazepine.II clinical trial phase results show its safety Property and tolerance it is good, without additive, 80-320mg/day dosage is administered orally to the equal table of various middle severe neurological source property pain Reveal the effect of notable.It is uniquely in the II phases effective specific neuropathic pain medicine of clinical proof.But Ralfinamide analgesic activities and target selectively need further to be improved.
Inventor herein's design has synthesized a series of new alpha-aminoamide derivatives as shown in structural formula I：
In structural formula I：
1.X1For nitrogen-atoms when, X2、X3For carbon atom, R1、R2、R3、R4、R5It is hydrogen atom, R is hydrogen atom or C1-C5's Straight chained alkyl or branched alkyl, the carbon atom being connected with R are configured as R types or S types.
2.X2For nitrogen-atoms when, X1、X3For carbon atom, R1、R2、R3、R4、R5It is hydrogen atom, R is hydrogen atom or C1-C5's Straight chained alkyl or branched alkyl, the carbon atom being connected with R are configured as R types or S types.
3.X3For nitrogen-atoms when, X1、X2For carbon atom, R1、R2、R3、R4、R5It is hydrogen atom, R is hydrogen atom or C1-C5's Straight chained alkyl or branched alkyl, the carbon atom being connected with R are configured as R types or S types.
4.X1、X2、X3When being carbon atom, R1、R2、R3、R4、R5Can be hydrogen atom, methoxyl group, ethoxy separately or together Base or halogen atom (F, Cl, Br), R are hydrogen atom or C1-C5Straight chained alkyl or branched alkyl, the configuration for the carbon atom being connected with R For R types or S types.
Biological evaluation result shows, target compound intraperitoneal injection and gastric infusion, in Mice Formalin mould Significant analgesic effect is shown in type, activity is higher than positive drug Ralfinamide.
Based on result above, the present invention is completed.
The content of the invention
The present invention provides pharmaceutically acceptable as the alpha-amido amides compound shown in structural formula I and its non-toxic Salt：
In structural formula I：X1For nitrogen-atoms when, X2、X3For carbon atom, R1、R2、R3、R4、R5It is hydrogen atom, R is hydrogen atom Or C1-C5Straight chained alkyl or branched alkyl, the carbon atom being connected with R is configured as R types or S types.X2For nitrogen-atoms when, X1、X3 For carbon atom, R1、R2、R3、R4、R5It is hydrogen atom, R is hydrogen atom or C1-C5Straight chained alkyl or branched alkyl, be connected with R Carbon atom be configured as R types or S types.X3For nitrogen-atoms when, X1、X2For carbon atom, R1、R2、R3、R4、R5It is hydrogen atom, R is Hydrogen atom or C1-C5Straight chained alkyl or branched alkyl, the carbon atom being connected with R is configured as R types or S types.X1、X2、X3It is During carbon atom, R1、R2、R3、R4、R5Can be hydrogen atom, methoxyl group, ethyoxyl or halogen atom (F, Cl, Br) separately or together, R For hydrogen atom or C1-C5Straight chained alkyl or branched alkyl, the carbon atom being connected with R is configured as R types or S types.
The present invention also provides the target compound shown in Formulas I a：
In structural formula Ia, link position of the oxygen atom on pyridine ring is ortho position, meta or para position, and R is hydrogen atom or C1- C5Straight chained alkyl or branched alkyl.
The present invention also provides the target compound shown in Formulas I b：
In structural formula Ib, link position of the oxygen atom on pyridine ring is ortho position, meta or para position, and R is hydrogen atom or C1- C5Straight chained alkyl or branched alkyl.
The present invention also provides the target compound shown in Formulas I c：
In structural formula Ic, R1、R2、R3、R4、R5Can be hydrogen atom, methoxyl group, ethyoxyl or halogen atom separately or together (F, Cl, Br), R are hydrogen atom or C1-C5Straight chained alkyl or branched alkyl, the carbon atom being connected with R is configured as R types or S Type.
The present invention also provides the target compound shown in Formulas I d：
In structural formula Id, R1、R2、R3、R4、R5Can be hydrogen atom, methoxyl group, ethyoxyl or halogen atom separately or together (F, Cl, Br), R are hydrogen atom or C1-C5Straight chained alkyl or branched alkyl, the carbon atom being connected with R is configured as R types or S Type.
The present invention is also provided containing the compound shown in Formulas I, Formulas I a, Formulas I b, Formulas I c, Formulas I d and its non-toxic pharmaceutically Acceptable salt is as active component, and the pharmaceutical composition that suitable excipients are formed.These pharmaceutical compositions can be Solution, tablet, capsule or injection；These pharmaceutical compositions can pass through injection administration or oral administration.
The present invention is also provided containing the compound shown in Formulas I, Formulas I a, Formulas I b, Formulas I c, Formulas I d and its non-toxic pharmaceutically Acceptable salt, and can pharmaceutically be connect containing the compound shown in Formulas I, Formulas I a, Formulas I b, Formulas I c, Formulas I d and its non-toxic Pharmaceutical composition purposes as antalgesic of the salt received as active component.
The synthesis of target compound shown in Formulas I a or Ib is with terephthalaldehyde (I-1) or m-terephthal aldehyde (I-2) Beginning raw material, generated by reduction reaction to hydroxymethylbenzaldehyde (II-1) or m-terephthal aldehyde (II-2), II-1 or II-2 and N- Bromo-succinimide (NBS), triphenylphosphine (PPh3) generation is reacted to bromomethyl benzaldehyde (III-1) or a bromomethyl benzene first Aldehyde (III-2), III-1 or III-2 again with pyridone, K2CO3Or Cs2CO3, KI reaction generation contraposition substitution ether intermediate (IV-1) or meta substitution ether intermediate (IV-2), IV-1 or IV-2 again with alpha-amido amide hydrochloride, sodium cyanoborohydride, three Ethamine,Reduction amination occurs for type molecular sieve, obtains target product Ia or Ib.Synthetic route is as follows：
In structural formula Ia, link position of the oxygen atom on pyridine ring is ortho position, meta or para position, and R is hydrogen atom or C1- C5Straight chained alkyl or branched alkyl.
In structural formula Ib, link position of the oxygen atom on pyridine ring is ortho position, meta or para position, and R is hydrogen atom or C1- C5Straight chained alkyl or branched alkyl.
The synthesis of target compound shown in Formulas I c or Id is with terephthalaldehyde (I-1) or m-terephthal aldehyde (I-2) Beginning raw material, generated by reduction reaction to hydroxymethylbenzaldehyde (II-1) or m-terephthal aldehyde (II-2), II-1 or II-2 and N- Bromo-succinimide (NBS), triphenylphosphine (PPh3) generation is reacted to bromomethyl benzaldehyde (III-1) or a bromomethyl benzene first Aldehyde (III-2), III-1 or III-2 again with fortified phenol, K2CO3Or Cs2CO3, KI reaction generation contraposition substitution ether intermediate (IV-1) or meta substitution ether intermediate (IV-2), IV-1 or IV-2 again with alpha-amido amide hydrochloride, sodium cyanoborohydride, three Ethamine,Reduction amination occurs for type molecular sieve, obtains target product Ic or Id.Synthetic route is as follows：
In structural formula Ic, R1、R2、R3、R4、R5Can be that hydrogen atom, methoxyl group, ethyoxyl or halogen atom (F, Cl, Br), R are Hydrogen atom or C1-C5Straight chained alkyl or branched alkyl, the carbon atom being connected with R is configured as R types or S types.
In structural formula Id, R1、R2、R3、R4、R5Can be that hydrogen atom, methoxyl group, ethyoxyl or halogen atom (F, Cl, Br), R are Hydrogen atom or C1-C5Straight chained alkyl or branched alkyl, the carbon atom being connected with R is configured as R types or S types.
Embodiment
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited In following embodiments.One of skill in the art, can be with it is understood that on the premise of without departing substantially from the spirit and scope of the present invention Various change and modification are carried out to the present invention.
The synthesis of embodiment 1 (2S) -2- (4- (pyridine -2- oxygen methyl) benzyl) amino-propionamide (Ia-1)
The synthesis of 1.1 4- hydroxymethylbenzaldehydes (II-1)
A 500mL eggplant-shape bottle is taken, by 20g terephthalaldehydes (0.15mol；4.0equiv), 100ml ethanol and 150ml Tetrahydrofuran is sequentially added in bottle, and stirring and dissolving is uniform.It is disposable slowly toward addition 1.7g boron in bottle then under condition of ice bath Sodium hydride solid (9.3mmol；1.0equiv), more than 6h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction are reacted Process.After terephthalaldehyde raw material point is wholly absent, stop reaction, the 2mol/L hydrochloric acid solutions prepared in advance are added dropwise and are quenched Go out, regulation pH value then rotates reaction solution to dry to 4~5, it is residue obtained with water, ethyl acetate weight is molten and adds liquid separation and leaks In bucket.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate layer, is added saturated sodium-chloride water solution and is washed.With Afterwards, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Drier is filtered, weighs 60-100 mesh specifications silica white about 30g is added in filtrate, is rotated to drying sand, is carried out silica gel column chromatography separation, the eluent system of selection is petroleum ether: ethyl acetate =3: 1, the single aldehyde radical reduction reaction product of gained is collected, II-1 white solid 17.6g, yield is obtained：86.1%.
The synthesis of 1.2 4- bromomethyls benzaldehydes (III-1)
A 500mL eggplant-shape bottle is taken, peeling weighs the (0.073mol of 10.0g intermediate IIs -1；1.0equiv), add 150mL dichloromethane is dissolved, then adds 19.6g N- bromo-succinimide solids under agitation.Under subsequent condition of ice bath Add triphenylphosphine solid in four batches into eggplant-shape bottle, amount to 38.5g (0.146mol；2.0equiv), each batch interval half Hour, treat that triphenylphosphine finishes, remove ice bath, continue to react more than 3h, thin layer TLC point plates, uv analyzer at room temperature (254nm) monitors reaction process.After II-1 raw material points disappear substantially, stop reaction, reaction solution is poured into and fills 150ml cold water Beaker in, then aqueous phase organic phase mixed liquor is poured into separatory funnel and extracted, aqueous phase is extracted with 150ml dichloromethane, is merged Dichloromethane layer, add saturated sodium-chloride water solution and wash.Then, organic phase anhydrous sodium sulfate or anhydrous magnesium sulfate are dried Night.Drier is filtered, 60-100 mesh specification silica whites about 15g is weighed and adds in filtrate, rotates to drying sand, carries out silica gel column layer Analysis separation, the eluent system of selection is petroleum ether: ethyl acetate=99: 1, gained benzyl position alcoholic extract hydroxyl group bromo-reaction product is collected, III-1 white solid 8.5g, yield is obtained：58.0%.
The preparation of 1.3 4- (pyridine -2- oxygen methyl)-benzaldehyde (IV-1a)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.48g 2- hydroxyls Pyridine (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and 0.22g yellow solids are obtained IV-1a, yield：21.0%.
The preparation of 1.4 (2S) -2- (4- (pyridine -2- oxygen methyl) benzyl) amino-propionamide (Ia-1)
A 250mL eggplant-shape bottle is taken, weighs 0.34g L- alanimamides hydrochlorides (2.7mmol；1.0equiv)、0.13g Sodium cyanoborohydride (2.2mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 0.58g intermediate compound IV -1a (2.7mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is yellow-brown solid that the volume ratio of chloromethanes is gradually risen to the end-product Ia-1 5%), obtained in 50min by 0%, is added up to 0.24g, yield 30.6%.MS(ESI)m/z：(M+H+)285.2；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 8.17-8.38 (m, 2H), 7.01-7.46 (m, 8H), 5.17 (s, 2H), 3.54-3.72 (m, 2H), 3.00-3.02 (m, 1H), 1.13 (d, 3H, J=6.7Hz)
The synthesis of embodiment 2 (2S) -2- (4- (pyridine -3- oxygen methyl) benzyl) amino-propionamide (Ia-2)
The preparation of 2.1 4- (pyridine -3- oxygen methyl)-benzaldehyde (IV-1b)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.48g 3- hydroxyls Pyridine (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and 0.25g yellow solids are obtained IV-1b, yield：23.2%.
The preparation of 2.2 (2S) -2- (4- (pyridine -3- oxygen methyl) benzyl) amino-propionamide (Ia-2)
A 250mL eggplant-shape bottle is taken, weighs 0.34g L- alanimamides hydrochlorides (2.7mmol；1.0equiv)、0.13g Sodium cyanoborohydride (2.2mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 0.58g intermediate compound IV -1b (2.7mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is yellow-brown solid that the volume ratio of chloromethanes is gradually risen to the end-product Ia-2 5%), obtained in 50min by 0%, is added up to 0.22g, yield 28.6%.MS(ESI)m/z：(M+H+)285.2；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 8.19-8.42 (m, 2H), 7.10-7.50 (m, 8H), 5.15 (s, 2H), 3.54-3.72 (m, 2H), 3.00-3.02 (m, 1H), 1.13 (d, 3H, J=6.7Hz)
The synthesis of embodiment 3 (2S) -2- (4- (pyridine -3- oxygen methyl) benzyl) amino-propionamide (Ia-3)
The preparation of 3.1 4- (pyridine -4- oxygen methyl)-benzaldehyde (IV-1c)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.48g 4- hydroxyls Pyridine (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and 0.21g yellow solids are obtained IV-1c, yield：19.8%.
The preparation of 3.2 (2S) -2- (4- (pyridine -4- oxygen methyl) benzyl) amino-propionamide (Ia-3)
A 250mL eggplant-shape bottle is taken, weighs 0.34g L- alanimamides hydrochlorides (2.7mmol；1.0equiv)、0.13g Sodium cyanoborohydride (2.2mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 0.58g intermediate compound IV -1c (2.7mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is yellow-brown solid that the volume ratio of chloromethanes is gradually risen to the end-product Ia-3 5%), obtained in 50min by 0%, is added up to 0.22g, yield 28.6%.MS(ESI)m/z：(M+H+)285.2；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 8.19-8.42 (m, 2H), 7.10-7.50 (m, 8H), 5.15 (s, 2H), 3.54-3.72 (m, 2H), 3.00-3.02 (m, 1H), 1.13 (d, 3H, J=6.7Hz)
The synthesis of embodiment 4 (2S) -2- (3- (pyridine -2- oxygen methyl) benzyl) amino-propionamide (Ib-1)
The preparation of 4.1 3- hydroxymethylbenzaldehydes (II-2)
A 500mL eggplant-shape bottle is taken, by 20g m-terephthal aldehydes (0.15mol；4.0equiv), 100ml ethanol and 150ml Tetrahydrofuran is sequentially added in bottle, and stirring and dissolving is uniform.It is disposable slowly toward addition 1.7g boron in bottle then under condition of ice bath Sodium hydride solid (9.3mmol；1.0equiv), more than 6h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction are reacted Process.After terephthalaldehyde raw material point is wholly absent, stop reaction, the 2mol/L hydrochloric acid solutions prepared in advance are added dropwise and are quenched Go out, regulation pH value then rotates reaction solution to dry to 4~5, it is residue obtained with water, ethyl acetate weight is molten and adds liquid separation and leaks In bucket.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate layer, is added saturated sodium-chloride water solution and is washed.With Afterwards, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Drier is filtered, weighs 60-100 mesh specifications silica white about 30g is added in filtrate, is rotated to drying sand, is carried out silica gel column chromatography separation, the eluent system of selection is petroleum ether: ethyl acetate =3: 1, the single aldehyde radical reduction reaction product of gained is collected, II-2 white solid 16.4g, yield is obtained：80.2%.
The preparation of 4.2 3- bromomethyls benzaldehydes (III-2)
A 500mL eggplant-shape bottle is taken, peeling weighs the (0.073mol of 10.0g intermediate IIs -2；1.0equiv), add 150mL dichloromethane dissolves 1b, then adds 19.6g N- bromo-succinimide solids under agitation.Under subsequent condition of ice bath Add triphenylphosphine solid in four batches into eggplant-shape bottle, amount to 38.5g (0.146mol；2.0equiv), each batch interval half Hour, treat that triphenylphosphine finishes, remove ice bath, continue to react more than 3h, thin layer TLC point plates, uv analyzer at room temperature (254nm) monitors reaction process.After II-2 raw material points disappear substantially, stop reaction, reaction solution is poured into and fills 150ml cold water Beaker in, then aqueous phase organic phase mixed liquor is poured into separatory funnel and extracted, aqueous phase is extracted with 150ml dichloromethane, is merged Dichloromethane layer, add saturated sodium-chloride water solution and wash.Then, organic phase anhydrous sodium sulfate or anhydrous magnesium sulfate are dried Night.Drier is filtered, 60-100 mesh specification silica whites about 15g is weighed and adds in filtrate, rotates to drying sand, carries out silica gel column layer Analysis separation, the eluent system of selection is petroleum ether: ethyl acetate=99: 1, gained benzyl position alcoholic extract hydroxyl group bromo-reaction product is collected, III-2 white solid 6.8g, yield is obtained：46.8%.
The preparation of 4.3 3- (pyridine -2- oxygen methyl)-benzaldehyde (IV-2a)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -2；1.0equiv), 0.48g 2- hydroxyls Pyridine (5.0mmol；1.0equiv), 2.5g cesium carbonates (7.5mmol；1.5equiv), 0.6g KIs (3.0mmol； 0.6equiv), 40mL DMFs are added in bottle, are stirred, and are subsequently heated to 40 DEG C of reactions overnight, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained to use 2mol/L The NaOH aqueous solution, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, merges second Ethyl acetate layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate. Drier is filtered, 60-100 mesh specification silica whites about 5g is weighed and adds in filtrate, rotates to drying sand, carries out silica gel column chromatography point From the eluent system of selection is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and 0.27g yellow is obtained Solid IV-2a, yield：25.2%.
The preparation of 4.4 (2S) -2- (3- (pyridine -2- oxygen methyl) benzyl) amino-propionamide (Ib-1)
A 250mL eggplant-shape bottle is taken, weighs 0.34g L- alanimamides hydrochlorides (2.7mmol；1.0equiv)、0.13g Sodium cyanoborohydride (2.2mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 0.58g intermediate compound IV -2a (2.7mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is yellow-brown solid that the volume ratio of chloromethanes is gradually risen to the end-product Ib-1 5%), obtained in 50min by 0%, is added up to 0.24g, yield 30.6%.MS(ESI)m/z：(M+H+)285.2；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 8.06-8.31 (m, 2H), 7.08-7.51 (m, 8H), 5.13 (s, 2H), 3.50-3.73 (m, 2H), 3.00-3.03 (m, 1H), 1.16 (d, 3H, J=6.7Hz)
The synthesis of embodiment 5 (2S) -2- (3- (pyridine -3- oxygen methyl) benzyl) amino-propionamide (Ib-2)
The preparation of 5.1 3- (pyridine -3- oxygen methyl)-benzaldehyde (IV-2b)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -2；1.0equiv), 0.48g 3- hydroxyls Pyridine (5.0mmol；1.0equiv), 2.5g cesium carbonates (7.5mmol；1.5equiv), 0.6g KIs (3.0mmol； 0.6equiv), 40mL DMFs are added in bottle, are stirred, and are subsequently heated to 40 DEG C of reactions overnight, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained to use 2mol/L The NaOH aqueous solution, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, merges second Ethyl acetate layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate. Drier is filtered, 60-100 mesh specification silica whites about 5g is weighed and adds in filtrate, rotates to drying sand, carries out silica gel column chromatography point From the eluent system of selection is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and 0.26g yellow is obtained Solid IV-2b, yield：24.0%.
The preparation of 5.2 (2S) -2- (3- (pyridine -3- oxygen methyl) benzyl) amino-propionamide (Ib-2)
A 250mL eggplant-shape bottle is taken, weighs 0.34g L- alanimamides hydrochlorides (2.7mmol；1.0equiv)、0.13g Sodium cyanoborohydride (2.2mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 0.58g intermediate compound IV -2b (2.7mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is yellow-brown solid that the volume ratio of chloromethanes is gradually risen to the end-product Ib-2 5%), obtained in 50min by 0%, is added up to 0.22g, yield 28.6%.MS(ESI)m/z：(M+H+)285.2；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.98-8.29 (m, 2H), 7.09-7.50 (m, 8H), 5.13 (s, 2H), 3.50-3.73 (m, 2H), 3.00-3.03 (m, 1H), 1.12 (d, 3H, J=6.7Hz).
The synthesis of embodiment 6 (2S) -2- (3- (pyridine -4- oxygen methyl) benzyl) amino-propionamide (Ib-3)
The preparation of 6.1 3- (pyridine -4- oxygen methyl)-benzaldehyde (IV-2c)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -2；1.0equiv), 0.48g 4- hydroxyls Pyridine (5.0mmol；1.0equiv), 2.5g cesium carbonates (7.5mmol；1.5equiv), 0.6g KIs (3.0mmol； 0.6equiv), 40mL DMFs are added in bottle, are stirred, and are subsequently heated to 40 DEG C of reactions overnight, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained to use 2mol/L The NaOH aqueous solution, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, merges second Ethyl acetate layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate. Drier is filtered, 60-100 mesh specification silica whites about 5g is weighed and adds in filtrate, rotates to drying sand, carries out silica gel column chromatography point From the eluent system of selection is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and 0.24g yellow is obtained Solid IV-2c, yield：22.2%.
The preparation of 6.2 (2S) -2- (3- (pyridine -4- oxygen methyl) benzyl) amino-propionamide (Ib-3)
A 250mL eggplant-shape bottle is taken, weighs 0.34g L- alanimamides hydrochlorides (2.7mmol；1.0equiv)、0.13g Sodium cyanoborohydride (2.2mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 0.58g intermediate compound IV -2c (2.7mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is yellow-brown solid that the volume ratio of chloromethanes is gradually risen to the end-product Ib-3 5%), obtained in 50min by 0%, is added up to 0.17g, yield 22.5%.MS(ESI)m/z：(M+H+)285.2；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.96-8.27 (m, 2H), 7.09-7.50 (m, 8H), 5.13 (s, 2H), 3.50-3.73 (m, 2H), 3.00-3.02 (m, 1H), 1.13 (d, 3H, J=6.7Hz).
The synthesis of embodiment 7 (2S) -2- (4- (2- fluorine Phenoxymethyl) benzyl) amino-propionamide (Ic-1)
The synthesis of 7.1 4- (2- fluorine Phenoxymethyl)-benzaldehyde (IV-3a)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.56g 2- fluorobenzene Phenol (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash.Then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is light yellow solid that 0.41g is obtained Body IV-3a, yield：35.8%.
The synthesis of 7.2 (2S) -2- (4- (2- fluorine Phenoxymethyl) benzyl) amino-propionamide (Ic-1)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.24g intermediate compound IV -3a (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-1 5%), obtained in 50min by 0%, is added up to 0.47g, yield 28.5%.MS(ESI)m/z：(M+H+)302.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.34-7.38 (m, 6H), 7.10 (s, 2H), 6.77-6.91 (m, 3H), 5.09 (s, 2H), 3.52-3.70 (m, 2H), 2.99- 3.01 (m, 1H), 1.13 (d, 3H, J=6.7Hz)
The synthesis of embodiment 8 (2S) -2- (4- (3- fluorine Phenoxymethyl) benzyl) amino-propionamide (Ic-2)
The synthesis of 8.1 4- (3- fluorine Phenoxymethyl)-benzaldehyde (IV-3b)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.56g 3- fluorobenzene Phenol (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is light yellow solid that 0.37g is obtained Body IV-3b, yield：32.4%.
The preparation of 8.2 (2S) -2- (4- (3- fluorine Phenoxymethyl) benzyl) amino-propionamide (Ic-2)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.24g intermediate compound IV -3b (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-2 5%), obtained in 50min by 0%, is added up to 0.49g, yield 30.1%.MS(ESI)m/z：(M+H+)302.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.31-7.35 (m, 6H), 7.02 (s, 2H), 6.81-6.93 (m, 3H), 5.12 (s, 2H), 3.45-3.60 (m, 2H), 2.89- 2.96 (m, 1H), 1.21 (d, 3H, J=6.7Hz)
The synthesis of embodiment 9 (2S) -2- (4- (4- fluorine Phenoxymethyl) benzyl) amino-propionamide (Ic-3)
The preparation of 9.1 4- (4- fluorine Phenoxymethyl)-benzaldehyde (IV-3c)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.56g 4- fluorobenzene Phenol (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is light yellow solid that 0.42g is obtained Body IV-3c, yield：36.1%.
The preparation of 9.2 (2S) -2- (4- (4- fluorine Phenoxymethyl) benzyl) amino-propionamide (Ic-3)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.24g intermediate compound IV -3c (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-3 5%), obtained in 50min by 0%, is added up to 0.37g, yield 22.5%.MS(ESI)m/z：(M+H+)302.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.30-7.65 (m, 6H), 7.18 (s, 2H), 6.84-7.00 (m, 3H), 5.12 (s, 2H), 3.45-3.60 (m, 2H), 2.89- 2.96 (m, 1H), 1.21 (d, 3H, J=6.7Hz)
The synthesis of embodiment 10 (2S) -2- (4- (2- chlorine Phenoxymethyl) benzyl) amino-propionamide (Ic-4)
The preparation of 10.1 4- (2- chlorine Phenoxymethyl)-benzaldehyde (IV-3d)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.64g 2- chlorobenzenes Phenol (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is light yellow solid that 0.63g is obtained Body IV-3d, yield：50.8%.
The preparation of 10.2 (2S) -2- (4- (2- chlorine Phenoxymethyl) benzyl) amino-propionamide (Ic-4)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.33g intermediate compound IV -3d (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-4 5%), obtained in 50min by 0%, is added up to 0.69g, yield 40.2%.MS(ESI)m/z：(M+H+)318.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.34-7.38 (m, 6H), 7.10 (s, 2H), 6.77-6.91 (m, 3H), 5.09 (s, 2H), 3.52-3.70 (m, 2H), 2.99- 3.01 (m, 1H), 1.13 (d, 3H, J=6.7Hz)
The synthesis of embodiment 11 (2S) -2- (4- (3- chlorine Phenoxymethyl) benzyl) amino-propionamide (Ic-5)
The preparation of 11.1 4- (3- chlorine Phenoxymethyl)-benzaldehyde (IV-3e)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.64g 3- chlorobenzenes Phenol (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is light yellow solid that 0.53g is obtained Body IV-3e, yield：42.9%.
The preparation of 11.2 (2S) -2- (4- (3- chlorine Phenoxymethyl) benzyl) amino-propionamide (Ic-5)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.33g intermediate compound IV -3e (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-5 5%), obtained in 50min by 0%, is added up to 0.59g, yield 34.3%.MS(ESI)m/z：(M+H+)318.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.31-7.35 (m, 6H), 7.02 (s, 2H), 6.81-6.93 (m, 3H), 5.12 (s, 2H), 3.45-3.60 (m, 2H), 2.89- 2.96 (m, 1H), 1.21 (d, 3H, J=6.7Hz)
The synthesis of embodiment 12 (2S) -2- (4- (4- chlorine Phenoxymethyl) benzyl) amino-propionamide (Ic-6)
The preparation of 12.1 4- (4- chlorine Phenoxymethyl)-benzaldehyde (IV-3f)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.64g 4- chlorobenzenes Phenol (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is light yellow solid that 0.63g is obtained Body IV-3f, yield：51.1%.
The preparation of 12.2 (2S) -2- (4- (4- chlorine Phenoxymethyl) benzyl) amino-propionamide (Ic-6)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.33g intermediate compound IV -3f (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-6 5%), obtained in 50min by 0%, is added up to 0.68g, yield 39.5%.MS(ESI)m/z：(M+H+)318.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.30-7.65 (m, 6H), 7.18 (s, 2H), 6.84-7.00 (m, 3H), 5.12 (s, 2H), 3.45-3.60 (m, 2H), 2.89- 2.96 (m, 1H), 1.21 (d, 3H, J=6.7Hz)
The synthesis of embodiment 13 (2S) -2- (4- (2- methoxyl groups Phenoxymethyl) benzyl) amino-propionamide (Ic-7)
The preparation of 13.1 4- (2- methoxyl groups Phenoxymethyl)-benzaldehyde (IV-3g)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.62g 2- methoxies Base phenol (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is light yellow solid that 0.52g is obtained Body IV-3g, yield：43.0%.
The preparation of 13.2 (2S) -2- (4- (2- methoxyl groups Phenoxymethyl) benzyl) amino-propionamide (Ic-7)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.31g intermediate compound IV -3g (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-7 5%), obtained in 50min by 0%, is added up to 0.50g, yield 29.5%.MS(ESI)m/z：(M+H+)314.2；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.34-7.35 (m, 4H), 7.00 (s, 1H), 6.83-6.94 (m, 4H), 5.00 (s, 2H), 3.34-3.68 (m, 5H), 2.97- 3.01 (m, 1H), 1.12 (d, 3H, J=6.7Hz)
The synthesis of embodiment 14 (2S) -2- (4- (3- methoxyl groups Phenoxymethyl) benzyl) amino-propionamide (Ic-8)
The preparation of 14.1 4- (4- methoxyl groups Phenoxymethyl)-benzaldehyde (IV-3h)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.62g 4- methoxies Base phenol (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is light yellow solid that 0.42g is obtained Body IV-1h, yield：34.1%.
The preparation of 14.2 (2S) -2- (4- (3- methoxyl groups Phenoxymethyl) benzyl) amino-propionamide (Ic-8)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.31g intermediate compound IV -3h (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-8 5%), obtained in 50min by 0%, is added up to 0.54g, yield 32.0%.MS(ESI)m/z：(M+H+)314.2；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.35-7.37 (m, 4H), 7.00 (s, 1H), 6.83-6.94 (m, 4H), 5.00 (s, 2H), 3.34-3.68 (m, 5H), 2.97- 3.01 (m, 1H), 1.11 (d, 3H, J=6.7Hz)
The synthesis of embodiment 15 (2S) -2- (4- (4- methoxyl groups Phenoxymethyl) benzyl) amino-propionamide (Ic-9)
The preparation of 15.1 4- (4- methoxyl groups Phenoxymethyl)-benzaldehyde (IV-3i)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.62g 4- methoxies Base phenol (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is light yellow solid that 0.42g is obtained Body IV-3i, yield：34.1%.
The preparation of 15.2 (2S) -2- (4- (4- methoxyl groups Phenoxymethyl) benzyl) amino-propionamide (Ic-9)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.31g intermediate compound IV -3i (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-9 5%), obtained in 50min by 0%, is added up to 0.46g, yield 27.0%.MS(ESI)m/z：(M+H+)314.2；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.35-7.36 (m, 4H), 7.00 (s, 1H), 6.83-6.94 (m, 4H), 5.00 (s, 2H), 3.34-3.68 (m, 5H), 2.97- 3.01 (m, 1H), 1.12 (d, 3H, J=6.7Hz)
The synthesis of embodiment 16 (2S) -2- (4- (2,3- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-10)
The preparation of 16.1 4- (2,3- difluoro Phenoxymethyl)-benzaldehyde (IV-3j)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.65g 2,3- bis- Fluorophenol (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is light yellow solid that 0.40g is obtained Body IV-3j, yield：32.0%.
The preparation of 16.2 (2S) -2- (4- (2,3- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-10)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.34g intermediate compound IV -3j (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-10 5%), obtained in 50min by 0%, is added up to 0.45g, yield 33.3%.MS(ESI)m/z：(M+H+)320.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.26-7.56 (m, 5H), 7.10 (s, 2H), 6.52-6.81 (m, 3H), 4.99 (s, 2H), 3.40-3.65 (m, 2H), 2.95- 3.07 (m, 1H), 1.20 (d, 3H, J=6.7Hz)
The synthesis of embodiment 17 (2S) -2- (4- (2,4- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-11)
The preparation of 17.1 4- (2,4- difluoro Phenoxymethyl)-benzaldehyde (IV-3k)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.65g 2,4- bis- Fluorophenol (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is light yellow solid that 0.39g is obtained Body IV-3k, yield：31.0%.
The preparation of 17.2 (2S) -2- (4- (2,4- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-11)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.34g intermediate compound IV -3k (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-11 5%), obtained in 50min by 0%, is added up to 0.46g, yield 34.0%.MS(ESI)m/z：(M+H+)320.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.26-7.56 (m, 5H), 7.12 (s, 1H), 6.52-6.81 (m, 3H), 4.99 (s, 2H), 3.40-3.65 (m, 2H), 2.95- 3.07 (m, 1H), 1.20 (d, 3H, J=6.7Hz)
The synthesis of embodiment 18 (2S) -2- (4- (3,4- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-12)
The preparation of 18.1 4- (3,4- difluoro Phenoxymethyl)-benzaldehyde (IV-3l)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.65g 3,4- bis- Fluorophenol (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is light yellow solid that 0.46g is obtained Body IV-3l, yield：36.5%.
The preparation of 18.2 (2S) -2- (4- (3,4- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-12)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.34g intermediate compound IV -3l (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-12 5%), obtained in 50min by 0%, is added up to 0.49g, yield 36.5%.MS(ESI)m/z：(M+H+)320.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 9.14 (s, 2H), 7.91 (s, 1H), 6.80-7.63 (m, 7H), 5.08 (s, 2H), 4.02-4.11 (m, 2H), 3.72-3.74 (m, 1H), 1.39 (d, 3H, J=6.7Hz)
The synthesis of embodiment 19 (2S) -2- (4- (3,5- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-13)
The preparation of 19.1 4- (3,5- difluoro Phenoxymethyl)-benzaldehyde (IV-3m)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.65g 3,5- bis- Fluorophenol (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is light yellow solid that 0.43g is obtained Body IV-3m, yield：34.1%.
The preparation of 19.2 (2S) -2- (4- (3,5- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-13)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.34g intermediate compound IV -3m (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-13 5%), obtained in 50min by 0%, is added up to 0.50g, yield 37.2%.MS(ESI)m/z：(M+H+)320.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 9.13 (s, 2H), 7.88 (s, 1H), 6.80-7.60 (m, 7H), 5.08 (s, 2H), 4.02-4.11 (m, 2H), 3.72-3.74 (m, 1H), 1.36 (d, 3H, J=6.7Hz)
The synthesis of embodiment 20 (2S) -2- (4- (2,6- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-14)
The preparation of 20.1 4- (2,6- difluoro Phenoxymethyl)-benzaldehyde (IV-3n)
A 250mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -1；1.0equiv), 0.65g 2,6- bis- Fluorophenol (5.0mmol；1.0equiv), 2.1g potassium carbonate (15.0mmol；3.0equiv), 0.6g KIs (3.0mmol； 0.6equiv), 60mL acetone is added in bottle, is stirred, and is subsequently heated to 58 DEG C of back flow reaction 24h, thin layer TLC point plates, purple Outer analysis instrument (254nm) monitors reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained water-soluble with 2mol/L NaOH Liquid, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, combined ethyl acetate Layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate.Filter dry Drying prescription, weigh 60-100 mesh specification silica whites about 5g and add in filtrate, rotate to drying sand, carry out silica gel column chromatography separation, choosing The eluent system selected is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is light yellow solid that 0.37g is obtained Body IV-3n, yield：29.8%.
The preparation of 20.2 (2S) -2- (4- (2,6- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-14)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.34g intermediate compound IV -3n (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-14 5%), obtained in 50min by 0%, is added up to 0.43g, yield 31.8%.MS(ESI)m/z：(M+H+)320.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 8.90 (s, 2H), 7.85 (s, 1H), 6.89-7.65 (m, 7H), 5.08 (s, 2H), 4.02-4.11 (m, 2H), 3.72-3.74 (m, 1H), 1.36 (d, 3H, J=6.7Hz)
The synthesis of embodiment 21 (2R) -2- (4- (2,3- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-15)
A 250mL eggplant-shape bottle is taken, weighs 0.68g D- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.34g intermediate compound IV -3j (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-15 5%), obtained in 50min by 0%, is added up to 0.45g, yield 33.3%.MS(ESI)m/z：(M+H+)320.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 1H-NMR (400MHz, DMSO-d6)：7.26-7.56 (m, 5H), 7.10 (s, 2H), 6.52-6.81 (m, 3H), 4.99 (s, 2H), 3.40-3.65 (m, 2H), 2.95-3.07 (m, 1H), 1.20 (d, 3H, J=6.7Hz)
The synthesis of embodiment 22 (2R) -2- (4- (2,4- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-16)
A 250mL eggplant-shape bottle is taken, weighs 0.68g D- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.34g intermediate compound IV -3k (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-16 5%), obtained in 50min by 0%, is added up to 0.46g, yield 34.0%.MS(ESI)m/z：(M+H+)320.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.26-7.56 (m, 5H), 7.12 (s, 1H), 6.52-6.81 (m, 3H), 4.99 (s, 2H), 3.40-3.65 (m, 2H), 2.95- 3.07 (m, 1H), 1.20 (d, 3H, J=6.7Hz)
The synthesis of embodiment 23 (2R) -2- (4- (3,4- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-17)
A 250mL eggplant-shape bottle is taken, weighs 0.68g D- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.34g intermediate compound IV -3l (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-17 5%), obtained in 50min by 0%, is added up to 0.49g, yield 36.5%.MS(ESI)m/z：(M+H+)320.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 9.14 (s, 2H), 7.91 (s, 1H), 6.80-7.63 (m, 7H), 5.08 (s, 2H), 4.02-4.11 (m, 2H), 3.72-3.74 (m, 1H), 1.39 (d, 3H, J=6.7Hz)
The synthesis of embodiment 24 (2R) -2- (4- (3,5- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-18)
A 250mL eggplant-shape bottle is taken, weighs 0.68g D- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.34g intermediate compound IV -3m (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-18 5%), obtained in 50min by 0%, is added up to 0.50g, yield 37.2%.MS(ESI)m/z：(M+H+)320.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 9.13 (s, 2H), 7.88 (s, 1H), 6.80-7.60 (m, 7H), 5.08 (s, 2H), 4.02-4.11 (m, 2H), 3.72-3.74 (m, 1H), 1.36 (d, 3H, J=6.7Hz)
The synthesis of embodiment 25 (2R) -2- (4- (2,6- difluoro Phenoxymethyl) benzyl) amino-propionamide (Ic-19)
A 250mL eggplant-shape bottle is taken, weighs 0.68g D- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.34g intermediate compound IV -3n (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Question response filters solution after terminating, with Reaction solution is rotated to dry afterwards, it is residue obtained with water, ethyl acetate weight is molten and adds in separatory funnel.The isometric acetic acid of aqueous phase Ethyl ester extracts 2 to 3 times, combined ethyl acetate layer, adds saturated sodium-chloride water solution and washes.Then, organic phase anhydrous sodium sulfate Or anhydrous magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, is rotated to dry Sand processed, silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and two It is white solid that the volume ratio of chloromethanes is gradually risen to the end-product Ic-19 5%), obtained in 50min by 0%, is added up to 0.43g, yield 31.8%.MS(ESI)m/z：(M+H+)320.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 8.90 (s, 2H), 7.85 (s, 1H), 6.89-7.65 (m, 7H), 5.08 (s, 2H), 4.02-4.11 (m, 2H), 3.72-3.74 (m, 1H), 1.36 (d, 3H, J=6.7Hz)
The synthesis of embodiment 26 (2S) -2- (3- (2- fluorine Phenoxymethyl) benzyl) amino-propionamide (Id-1)
The preparation of 26.3 3- (2- fluorine Phenoxymethyl)-benzaldehyde (IV-4a)
A 150mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -2；1.0equiv), 0.56g 2- fluorobenzene Phenol (5.0mmol；1.0equiv), 2.5g cesium carbonates (7.5mmol；1.5equiv), 0.6g KIs (3.0mmol； 0.6equiv), 40mL DMFs are added in bottle, are stirred, and are subsequently heated to 40 DEG C of reactions overnight, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained to use 2mol/L The NaOH aqueous solution, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, merges second Ethyl acetate layer, add saturated sodium-chloride water solution and wash.Then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate. Drier is filtered, 60-100 mesh specification silica whites about 5g is weighed and adds in filtrate, rotates to drying sand, carries out silica gel column chromatography point From the eluent system of selection is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is pale yellow that 0.36g is obtained Color solid IV-4a, yield：28.7%.
The preparation of 26.4 (2S) -2- (3- (2- fluorine Phenoxymethyl) benzyl) amino-propionamide (Id-1)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.24g intermediate compound IV -4a (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Then by reacting liquid filtering and it is evaporated, institute Obtain the residue 2mol/L NaOH aqueous solution, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted with isometric ethyl acetate Take 2 to 3 times, combined ethyl acetate layer, add saturated sodium-chloride water solution and wash, then, organic phase anhydrous sodium sulfate or anhydrous Magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, rotate to drying sand, Silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and dichloromethane It is white solid that the volume ratio of alkane is gradually risen to the end-product Id-1 5%), obtained in 50min by 0%, adds up to 0.47g, Yield 28.5%.MS(ESI)m/z：(M+H+)302.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)：7.34- 7.38 (m, 6H), 7.10 (s, 2H), 6.77-6.91 (m, 3H), 5.09 (s, 2H), 3.52-3.70 (m, 2H), 2.99-3.01 (m, 1H), 1.13 (d, 3H, J=6.7Hz)
The synthesis of embodiment 27 (2S) -2- (3- (3- fluorine Phenoxymethyl) benzyl) amino-propionamide (Id-2)
The preparation of 27.1 3- (3- fluorine Phenoxymethyl)-benzaldehyde (IV-4b)
A 150mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -2；1.0equiv), 0.56g 3- fluorobenzene Phenol (5.0mmol；1.0equiv), 2.5g cesium carbonates (7.5mmol；1.5equiv), 0.6g KIs (3.0mmol； 0.6equiv), 40mL DMFs are added in bottle, are stirred, and are subsequently heated to 40 DEG C of reactions overnight, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained to use 2mol/L The NaOH aqueous solution, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, merges second Ethyl acetate layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate. Drier is filtered, 60-100 mesh specification silica whites about 5g is weighed and adds in filtrate, rotates to drying sand, carries out silica gel column chromatography point From the eluent system of selection is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is pale yellow that 0.37g is obtained Color solid IV-4b, yield：30.0%.
The preparation of 27.2 (2S) -2- (3- (3- fluorine Phenoxymethyl) benzyl) amino-propionamide (Id-2)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.24g intermediate compound IV -4b (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Then by reacting liquid filtering and it is evaporated, institute Obtain the residue 2mol/L NaOH aqueous solution, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted with isometric ethyl acetate Take 2 to 3 times, combined ethyl acetate layer, add saturated sodium-chloride water solution and wash, then, organic phase anhydrous sodium sulfate or anhydrous Magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, rotate to drying sand, Silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and dichloromethane It is white solid that the volume ratio of alkane is gradually risen to the end-product Id-2 5%), obtained in 50min by 0%, adds up to 0.49g, Yield 30.1%.MS(ESI)m/z：(M+H+)302.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)：7.36- 7.39 (m, 6H), 7.12 (s, 2H), 6.77-6.91 (m, 3H), 5.09 (s, 2H), 3.52-3.70 (m, 2H), 2.99-3.01 (m, 1H), 1.13 (d, 3H, J=6.7Hz)
The synthesis of embodiment 28 (2S) -2- (3- (4- fluorine Phenoxymethyl) benzyl) amino-propionamide (Id-3)
The preparation of 28.1 3- (4- fluorine Phenoxymethyl)-benzaldehyde (IV-4c)
A 150mL eggplant-shape bottle is taken, weighs (the 5.0mmol of 1.0g intermediate IIIs -2；1.0equiv), 0.56g 4- fluorobenzene Phenol (5.0mmol；1.0equiv), 2.5g cesium carbonates (7.5mmol；1.5equiv), 0.6g KIs (3.0mmol； 0.6equiv), 40mL DMFs are added in bottle, are stirred, and are subsequently heated to 40 DEG C of reactions overnight, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Then by reacting liquid filtering and it is evaporated, it is residue obtained to use 2mol/L The NaOH aqueous solution, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted 2 to 3 times with isometric ethyl acetate, merges second Ethyl acetate layer, add saturated sodium-chloride water solution and wash, then, organic phase is dried overnight with anhydrous sodium sulfate or anhydrous magnesium sulfate. Drier is filtered, 60-100 mesh specification silica whites about 5g is weighed and adds in filtrate, rotates to drying sand, carries out silica gel column chromatography point From the eluent system of selection is petroleum ether: ethyl acetate=10: 1, gained is collected into ether reaction product, and it is pale yellow that 0.39g is obtained Color solid IV-4c, yield：31.2%.
The preparation of 28.2 (2S) -2- (3- (4- fluorine Phenoxymethyl) benzyl) amino-propionamide (Id-3)
A 250mL eggplant-shape bottle is taken, weighs 0.68g L- alanimamides hydrochlorides (5.4mmol；1.0equiv)、0.26g Sodium cyanoborohydride (4.3mmol；0.8equiv)、Type molecular sieve, 0.5ml triethylamines and 50ml methanol are added in bottle, Reaction 20min is stirred at room temperature, is then rapidly added 1.24g intermediate compound IV -4c (5.4mmol；1.0equiv), be heated to 40 DEG C after Continuous reaction 12h, thin layer TLC point plates, uv analyzer (254nm) monitoring reaction process.Then by reacting liquid filtering and it is evaporated, institute Obtain the residue 2mol/L NaOH aqueous solution, ethyl acetate weight is molten and adds in separatory funnel.Aqueous phase is extracted with isometric ethyl acetate Take 2 to 3 times, combined ethyl acetate layer, add saturated sodium-chloride water solution and wash, then, organic phase anhydrous sodium sulfate or anhydrous Magnesium sulfate is dried overnight.Drier is filtered, 60-100 mesh specification silica whites about 4g is weighed and adds in filtrate, rotate to drying sand, Silica gel column chromatography separation is carried out, the eluent system of selection is dichloromethane: methanol (uses linear gradient elution method, methanol and dichloromethane It is yellow-brown solid that the volume ratio of alkane is gradually risen to the end-product Id-3 5%), obtained in 50min by 0%, is added up to 0.37g, yield 22.5%.MS(ESI)m/z：(M+H+)302.1；Proton nmr spectra：1H-NMR (400MHz, DMSO-d6)： 7.35-7.38 (m, 6H), 7.10 (s, 2H), 6.77-6.91 (m, 3H), 5.09 (s, 2H), 3.53-3.74 (m, 2H), 3.09- 3.21 (m, 1H), 1.13 (d, 3H, J=6.7Hz)
The analgesic activity of the Mice Formalin model evaluation intraperitoneal administration (10mg/kg) of embodiment 29
ICR (CD-1) male mice (body weight is in 22~25g) is randomly divided into blank group, positive group, test compound group, Every group 6, according to 10mg/kg dosage, it is put into PVC inspection boxes and adapts to after intraperitoneal injection.The left back pin of mouse is given after 30min 20 μ L 2.7% formalin solution is subcutaneously injected in the palm, and it is put back in PVC inspection boxes rapidly and observed, and records late phase response (15-30min, II phase) mouse licks the time for licking injection of formalin sole.
After experiment terminates, the average value of each group mouse II phase pain reaction times is calculated.Positive drug group and target product group II phase pain inhibiting rates can be obtained by below equation：
Medicine pain inhibiting rate (%)=(m- medicine group pain reaction time during blank group pain reaction)/distilled water group Pain reaction time × 100%
The intraperitoneal administration of table 1 (10mg/kg) experimental result
As seen from the results in Table 1, under 10mg/kg dosage, all compounds show certain analgesic activities, wherein changing Compound Ib-2, Ic-2, Ic-4, Ic-7, Ic-8, Id-1, Id-2 intraperitoneal administration analgesic activities are significantly higher than positive drug Ralfinamide.
The analgesic activity of the Mice Formalin model evaluation gastric infusion (5mg/kg) of embodiment 30
Mouse is randomly divided into blank group, positive group, test compound group, every group 6, according to 5mg/kg dosage, gavage It is put into PVC inspection boxes and adapts to after administration.The formalin that 20 μ L2.7% are subcutaneously injected after 1 hour to the left back sole of mouse is molten Liquid, it is put back in PVC inspection boxes rapidly and observed, record late phase response (15-30min, II phase) mouse, which licks, licks injection formal The time of woods sole.
The gastric infusion of table 2 (5mg/kg) experimental result
Medicine II phase reaction time (second)
Blank group 120.0±18.6
Ib-2 80.3±11.1
Ic-4 78.3±13.6
Ic-8 90.3±12.7
Id-2 76.3±10.4
Ralfinamide 117.3±10.3
As seen from the results in Table 2, under 5mg/kg dosage, compound Ib-2, Ic-4, Ic-8, Id-2 the II phase reaction times Shortening more obvious than blank group, positive drug Ralfinamide analgesic effect are substantially ineffective under 5mg/kg dosage.
The analgesic activity of the Mice Formalin model evaluation intraperitoneal administration (2mg/kg) of embodiment 31
ICR (CD-1) male mice (body weight is in 22~25g) is randomly divided into blank group, positive group, test compound group, Every group 6, according to 2mg/kg dosage, it is put into PVC inspection boxes and adapts to after intraperitoneal injection.The left back pin of mouse is given after 30min 20 μ L 2.7% formalin solution is subcutaneously injected in the palm, and it is put back in PVC inspection boxes rapidly and observed, and records late phase response (15-30min, II phase) mouse licks the time for licking injection of formalin sole.
The intraperitoneal administration of table 3 (2mg/kg) experimental result
Medicine II phase reaction time (second)
Blank group 125.3±16.4
Ib-2 58.7±11.7
Ic-4 79.7±13.4
Ic-8 69.7±12.1
Id-2 81.7±15.1
Ralfinamide 129.3±14.8
As seen from the results in Table 3, under 2mg/kg dosage, compound Ib-2, Ic-4, Ic-8, Id-2 the II phase reaction times Shortening more obvious than blank group, positive drug Ralfinamide analgesic effect do not show analgesic activity under 2mg/kg dosage.
The evaluation that embodiment 32 is acted on Nav1.7 channel blockings
This experiment is based on patch clamp technique, evaluates compound on cell model in vitro and the selectivity of Nav1.7 passages is pressed down Ability processed, test concentrations are 10 μM.
The evaluation result of the Nav1.7 channel blockings of table 4 effect
Medicine Inactivate state Nav1.7 passage inhibiting rates
Ralfinamide 66±5
Ib-2 34±1
Ic-4 40±4
Ic-8 25±3
Id-2 49±2
As seen from the results in Table 4, compound Ib-2, Ic-4, Ic-8, Id-2 are equal to Nav1.7 selective inhibitory in vitro Less than positive drug Ralfinamide, show that its mechanism of action is different from Ralfinamide, Nav1.7 may not be that it acts on target Mark.
The evaluation that embodiment 33 is acted on Nav1.8 channel blockings
This experiment is based on patch clamp technique, further choosing of the evaluation compound to Nav1.8 passages on cell model in vitro Selecting property rejection ability, test concentrations are 10 μM.
The evaluation result of the Nav1.8 channel blockings of table 5 effect
As seen from the results in Table 5, compound Ic-8 shows stronger inhibitory activity, other compounds pair to Nav1.8 Nav1.8 activity is weaker.

Claims (7)

1. compound and its non-toxic pharmaceutically acceptable salt shown in structural formula I：
In structural formula I：
1.X1For nitrogen-atoms when, X2、X3For carbon atom, R1、R2、R3、R4、R5It is hydrogen atom, R is hydrogen atom or C1-C5Straight chain Alkyl or branched alkyl, the carbon atom being connected with R are configured as R types or S types.
2.X2For nitrogen-atoms when, X1、X3For carbon atom, R1、R2、R3、R4、R5It is hydrogen atom, R is hydrogen atom or C1-C5Straight chain Alkyl or branched alkyl, the carbon atom being connected with R are configured as R types or S types.
3.X3For nitrogen-atoms when, X1、X2For carbon atom, R1、R2、R3、R4、R5It is hydrogen atom, R is hydrogen atom or C1-C5Straight chain Alkyl or branched alkyl, the carbon atom being connected with R are configured as R types or S types.
4.X1、X2、X3When being carbon atom, R1、R2、R3、R4、R5Can be separately or together hydrogen atom, methoxyl group, ethyoxyl or Halogen atom (F, Cl, Br), R are hydrogen atom or C1-C5Straight chained alkyl or branched alkyl, the carbon atom being connected with R is configured as R Type or S types.
2. compound according to claim 1, its architectural feature is shown in Formulas I a：
In structural formula I a, link position of the oxygen atom on pyridine ring is ortho position, meta or para position, and R is hydrogen atom or C1-C5's Straight chained alkyl or branched alkyl.
3. compound according to claim 1, its architectural feature is shown in Formulas I b：
In structural formula I b, link position of the oxygen atom on pyridine ring is ortho position, meta or para position, and R is hydrogen atom or C1-C5's Straight chained alkyl or branched alkyl.
4. compound according to claim 1, its architectural feature is shown in Formulas I c：
In structural formula I c, R1、R2、R3、R4、R5Can be separately or together hydrogen atom, methoxyl group, ethyoxyl or halogen atom (F, Cl, Br), R is hydrogen atom or C1-C5Straight chained alkyl or branched alkyl, the carbon atom being connected with R is configured as R types or S types.
5. compound according to claim 1, its architectural feature is shown in Formulas I d：
In structural formula I d, R1、R2、R3、R4、R5Can be separately or together hydrogen atom, methoxyl group, ethyoxyl or halogen atom (F, Cl, Br), R is hydrogen atom or C1-C5Straight chained alkyl or branched alkyl, the carbon atom being connected with R is configured as R types or S types.
6. contain compound described in claim any one of 1-5 and its non-toxic pharmaceutically acceptable salt as activity into Point, and the pharmaceutical composition that suitable excipients are formed.These pharmaceutical compositions can be solution, tablet, capsule or note Penetrate agent；These pharmaceutical compositions can pass through injection administration or oral administration.
7. compound and its non-toxic pharmaceutically acceptable salt described in claim any one of 1-5, and wanted containing having the right Ask the pharmaceutical composition conduct of compound and its non-toxic pharmaceutically acceptable salt as active component described in any one of 1-5 The purposes of antalgesic.
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CN111233790A (en) * 2020-03-13 2020-06-05 上海应用技术大学 Acylhydrazone neuraminidase inhibitor and preparation method and application thereof
CN112716927A (en) * 2020-10-12 2021-04-30 复旦大学 Alpha-amino amide compound and preparation method and application thereof

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