CN106278994B - Spiro-compound and its preparation method and application - Google Patents
Spiro-compound and its preparation method and application Download PDFInfo
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- CN106278994B CN106278994B CN201510272578.7A CN201510272578A CN106278994B CN 106278994 B CN106278994 B CN 106278994B CN 201510272578 A CN201510272578 A CN 201510272578A CN 106278994 B CN106278994 B CN 106278994B
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Abstract
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, disclose the spiro-compound and its preparation method and application of following general formula.Bioactivity screening the result shows that, such compound have monoamine transporter protein binding activity.Compound provided by the present invention has the potentiality using various diseases treatment, including but not limited to depression, attention deficit disorder, obesity, neuropathic pain etc..
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field.More particularly to a kind of loop coil series indicated by general formula I
Compound, preparation method, chiral separation method and the compound medical composition and its use.It is provided by the invention by
The compound and monoamine transport protein that general formula I is indicated have higher combination activity.It can be used for preparing prevention or treatment mind depression
The drug of the mental disorders such as disease.
Background technique
Depression is a kind of mental disease changed with emotion morbid state as cardinal symptom, is mainly shown as depressed, of few words
It is hypologia, it is serious to generate very strong introgression.Having more than 10% patients with depression has manic symptoms, is clinically diagnosed as
Bipolar disorders.In modern society, the disease incidence of depression is high.Root according to the statistics of the World Health Organization, depression at present
Illness rate in adult population is 10%-20%, it has also become the fourth-largest disease in the world, it is contemplated that be likely to become only to the year two thousand twenty
Inferior to the second largest disease of disease of cardiovascular system.Treating depression clinical demand is huge, new and effective anti-depression drug
Research becomes the hot spot that international the world of medicine attractes attention.
In recent years, clinically mainly there are following three kinds for treating the most common monoamine reuptake inhibitors of depression: 1.
Selective serotonin reuptake inhibitor (SSRI), such as the Five Golden Flowers Paxil of antidepressant
(Paroxetine), Prozac (Fluoxetine), Sertraline (Sertraline), Citalopram (Citalopram), fluorine volt
Sha Ming (Fluvoxamine), this kind of drug is by inhibiting SERT to the reuptake effect of 5-HT to increase synaptic cleft 5- hydroxyl
The concentration of tryptamines is to improve the symptom of patient.2. selective norepinephrine reuptake inhibitor, such as Reboxetine
(Reboxetine).3. the dual reuptake inhibitor of 5-HT and NE (SNRI), such as Duloxetine (Duloxetine), meter Na Pu
Human relations (Midalcipran), Venlafaxine (Venlafaxine) etc..Above-described monoamine reuptake inhibitors are due to side effect
It is small, more significant thus as treatment depression in the market the first-line drug of effect.
But have the defects that using SSRIs and SNRIs as the antidepressants of representative it is more, if onset time is slow, big portion
Divide double blind experiment to show that these antidepressants usually require normally play curative effect in 2-4 weeks, and has about 30%-40%
Patient do not benefit from the treatment of these drugs.In addition to onset time slowly other than, SSRI and SNRI there is also other defect, than
If they not can effectively improve the anhedonia of depressive patient, improve reward, excitation driving and goal-directed behavior, they are to suppression
The improvement of strongly fragrant Patients ' Cognitive ability is also slow and limited, and they easily lead to sex dysfunction.
Currently, the research and development of the triple reuptake inhibitors of 5-HT, NE, DA belongs to the hot fields of new drug development.
The major companies such as Merck, Lundbeck, Roche, Pfizer, Takeda competitively develop TRIs, and multiple projects enter clinical research.
However statistical data shows to share 17 candidate's TRIs new drugs in this field of depression and enter clinical experimental stage treating,
And 8 are in clinic II phase and the above stage, but such drug there is no successfully to list at present.
Summary of the invention
To solve the technical problems existing in the prior art, it is an object of the present invention to provide one kind to have monoamine
Transport protein combines active loop coil series compound, such compound can be used for treating the mental disorders such as depression.
It is a further object to provide a kind of volution compound indicated by hereafter general formula I and alloisomerisms
Body and its pharmaceutically acceptable salt, prodrug or its solvate.
Yet another object of the invention is that providing the preparation method of such compound.
Another purpose of the invention is that providing the chiral separation method of such compound.
Another purpose of the invention is that providing a kind of different containing the volution compound indicated by general formula I, its solid
The pharmaceutical composition of structure body and its pharmaceutically acceptable salt, prodrug or its solvate.
Yet another object of the invention is that providing by general formula I its stereoisomer of volution compound indicated and its medicine
The purposes of acceptable salt, prodrug or its solvate on.There is monoamine transport protein knot by the compound that general formula I is indicated
Activity is closed for mental disorders such as treatment depression.
To achieve the goals above, it is different to provide a kind of volution compound being represented by the following general formula I, its solid by the present invention
Structure body and its pharmaceutically acceptable salt, prodrug or its solvate.R1、R2、R3、R4, X, Y, m, n be defined as follows.
Wherein:
M is 0,1, or 2；
N is 1 or 2；
X, Y is each independently nitrogen or carbon, and one in X, Y be nitrogen another be carbon, when X or Y are carbon atom,
Substituent R2Or R3For hydrogen atom；When X or Y is nitrogen-atoms, substituent R2Or R3For hydrogen atom, (C1-C10) alkyl, (C3-C10)
Naphthenic base, (C1-C10) alkenyl, (C1-C10) alkynyl, (C1-C10) alkoxy, (C3-C10) cycloalkyloxy, aryl, miscellaneous alkyl, miscellaneous alkene
Base or miscellaneous alkynyl；
R1And R4It is halogen, trifluoromethyl, trifluoromethoxy, cyano, amino, nitro, (C each independently1-C10) alkyl,
(C3-C10) naphthenic base, (C1-C10) alkenyl, (C1-C10) alkynyl, (C1-C10) alkoxy, (C3-C10) cycloalkyloxy or R1And R4
It is formed together 5,6,7 yuan of naphthenic base or 6-10 member aryl.
In a preferred embodiment of the invention, wherein m and n is 1.X is nitrogen-atoms, and Y is carbon atom, R3Substituent group
For hydrogen atom.R2Substituent group is hydrogen atom, (C1-C10) alkyl.R1And R4It is halogen, trifluoromethyl, cyano, ammonia each independently
Base, nitro, (C1-C10) alkyl, (C3-C10) naphthenic base, (C1-C10) alkenyl, (C1-C10) alkynyl, (C1-C10) alkoxy, (C3-
C10) cycloalkyloxy or R1And R4It is formed together 5,6,7 yuan of naphthenic base or 6-10 member aryl.
In a preferred embodiment of the invention, wherein m and n is 1.X is nitrogen-atoms, and Y is carbon atom, R3Substituent group
For hydrogen atom.R2Substituent group is hydrogen atom, methyl or ethyl.R1And R4It is halogen, nitro, (C each independently1-C10) alkyl,
(C3-C10) naphthenic base, (C1-C10) alkenyl, (C1-C10) alkynyl, (C1-C10) alkoxy, (C3-C10) cycloalkyloxy or R1And R4
It is formed together 6-10 member aryl.
In a preferred embodiment of the invention, wherein m and n is 1.X is nitrogen-atoms, and Y is carbon atom, R3Substituent group
For hydrogen atom.R2Substituent group is hydrogen atom or methyl.R1And R4It is chlorine atom each independently, and is located at the position 3,4- of phenyl ring.
Or R1And R4It independently is hydrogen atom, nitro, (C1-C3) alkyl, (C3-C7) naphthenic base, (C1-C7) alkenyl, (C1-C5) alkynyl,
(C1-C7) alkoxy, (C3-C7) cycloalkyloxy or R1And R46 member ring aryl are formed together positioned at phenyl ring 3,4-.
In a preferred embodiment of the invention, wherein m and n is 1.X is carbon atom, and Y is nitrogen-atoms, R2Substituent group
For hydrogen atom.R3Substituent group is hydrogen atom, (C1-C10) alkyl.R1And R4It is halogen, trifluoromethyl, cyano, ammonia each independently
Base, nitro, (C1-C10) alkyl, (C3-C10) naphthenic base, (C1-C10) alkenyl, (C1-C10) alkynyl, (C1-C10) alkoxy, (C3-
C10) cycloalkyloxy or R1And R4It is formed together 5,6,7 yuan of naphthenic base or 6-10 member aryl.
In a preferred embodiment of the invention, wherein m and n is 1.X is carbon atom, and Y is nitrogen-atoms, R2Substituent group
For hydrogen atom.R3Substituent group is hydrogen atom, methyl or ethyl.R1And R4It is halogen, nitro, (C each independently1-C10) alkyl,
(C3-C10) naphthenic base, (C1-C10) alkenyl, (C1-C10) alkynyl, (C1-C10) alkoxy, (C3-C10) cycloalkyloxy or R1And R4
It is formed together or 6-10 member aryl.
In a preferred embodiment of the invention, wherein m and n is 1.X is carbon atom, and Y is nitrogen-atoms, R2Substituent group
For hydrogen atom.R3Substituent group is hydrogen atom or methyl.R1And R4It is chlorine atom each independently, and is located at the 3,4- of phenyl ring
Position.Or R1And R4It independently is hydrogen atom, nitro, (C1-C3) alkyl, (C3-C7) naphthenic base, (C1-C7) alkenyl, (C1-C5) alkynes
Base, (C1-C7) alkoxy, (C3-C7) cycloalkyloxy or R1And R46 member ring aryl are formed together positioned at phenyl ring 3,4-.
In a preferred embodiment of the invention, wherein X is carbon atom, and Y is that the typical compound of nitrogen-atoms is three-dimensional
Isomerization/optical is pure or has carried out the separation of diastereoisomer.
Some detailed descriptions of the invention:
Unless otherwise indicated, terminology used in the present invention alkyl refers to the saturation univalent alkyl of linear chain or branched chain, wherein alkane
Base can be optionally substituted by one or more substituents.The embodiment of alkyl includes but is not limited to methyl, ethyl, propyl
(including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), normal-butyl, isobutyl
Base, tert-butyl, such as (C1-C6) alkyl refers to linear saturation monovalent hydrocarbon with 1~6 carbon atom or have 3 to 6 carbon
The branch of atom is saturated monovalent hydrocarbon.
Unless otherwise mentioned, terminology used in the present invention " alkenyl " refer to the straight chain comprising one or more carbon-carbon double bonds or
Person's branch monovalent hydrocarbon.Alkenyl can be optionally substituted by one or more substituents.Term " alkenyl " also includes " cis-
(cis) " and " trans- (trans) " group of structure or those of ordinary skill in the art understood " E " and " Z " formula structure.
Unless otherwise mentioned, terminology used in the present invention " alkenyl " includes straight chain and branched-chain alkenyl.For example, (C2-C6) alkenyl alkenyl refers to
The straight chain unsaturation monovalent hydrocarbon of 2 to 6 carbon atoms or the branch unsaturation monovalent hydrocarbon of 3 to 6 carbon atoms.Embodiment
Including but not limited to vinyl, propylene 1- base, propylene 2- base, allyl, cyclobutenyl and 4- methyl butene base.
Unless otherwise mentioned, terminology used in the present invention " alkynyl " refer to the straight chain comprising one or more triple carbon-carbon bonds or
Person's branch monovalence alkynyl.Alkynyl can be optionally substituted by one or more substituents.Unless otherwise mentioned, term " alkynyl "
Including straight chain and branch alkynyl.For example, (C2-C6) alkynyl refers to the straight chain unsaturation monovalence alkynyl or 3 to 6 of 2 to 6 carbon atoms
The branch unsaturation monovalence alkynyl of a carbon atom.
Unless otherwise mentioned, terminology used in the present invention " naphthenic base " refers to the monovalent hydrocarbon of cyclic annular saturation bridge and/or non-bridge
Base can optionally be replaced by one or more substituent groups of the present invention.The embodiment of naphthenic base includes but is not limited to
Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, decahydro bitter edible plant base and Buddha's warrior attendant a heatable brick bed base.
Unless otherwise mentioned, terminology used in the present invention " miscellaneous alkyl ", " miscellaneous thiazolinyl " and " miscellaneous alkynyl " refer respectively to one
Or alkyl, alkenyl and alkynyl that multiple carbon atoms are replaced by hetero atom.
Unless otherwise mentioned, terminology used in the present invention " hetero atom " refers to other any originals other than carbon or hydrogen
Son.In some embodiments, term " hetero atom " refers to N, O, S, Si or P.In other embodiments, term " hetero atom "
Refer to N, O or S.
Unless otherwise mentioned, terminology used in the present invention " aryl " refers to monocyclic aryl and/or comprising at least one fragrance
The polycyclic monovalent aryl of hydrocarbon ring.The embodiment of aryl includes but is not limited to phenyl, naphthalene, anthryl, phenanthryl and xenyl.
Unless otherwise mentioned, terminology used in the present invention " aryl alkyl " or " aralkyl " refer to the list replaced with aryl
Valence alkyl.In some embodiments, alkyl and aryl are optionally substituted by one or more substituents.
Unless otherwise mentioned, terminology used in the present invention " pharmaceutically acceptable salt " refers to by pharmaceutically acceptable nothing
The salt that the acid of poison is prepared, including inorganic acid and organic acid.Suitable non-toxic acid includes inorganic and organic acid, but is not limited to,
Such as acetic acid, alginic acid, ortho-aminobenzoic acid, benzene sulfonic acid, benzoic acid, stick brain sulfonic acid, arrest rubber acid, vinyl sulfonic acid, formic acid, prolong
Fumarate, furancarboxylic acid, gluconic acid, glutamic acid, glucuronic acid, galacturonic acid, glycidic acid, hydrobromic acid, hydrochloric acid, cream
Acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, galactosaccharic acid, nitric acid, pa not acid (pamoic), pantothenic acid, benzene second
Acid, propionic acid, phosphoric acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid etc..
Unless otherwise mentioned, terminology used in the present invention " solvate " refers to compound or its salt provided by the invention also
Including with the solvent of stoichiometry or non-stoichiometry amount with non-covalent molecular separating force in conjunction with.When the solvent is water, this is molten
Agent compound is hydrate.
Unless otherwise mentioned, terminology used in the present invention " stereoisomer " includes that all enantiomerism/alloisomerisms are pure
And the enrichment of enantiomerism/alloisomerism the compounds of this invention.
Unless otherwise mentioned, terminology used in the present invention " alloisomerism is pure " indicates a solid comprising a kind of compound
The ingredient of isomers and other stereoisomers substantially free of the compound.For example, a kind of have a chiral centre
Compound the pure ingredient of alloisomerism by the enantiomer opposite substantially free of the compound.There are two in chirality for a kind of tool
The pure ingredient of the alloisomerism of the compound of the heart is by other diastereomers substantially free of the compound.
Another object according to the present invention, the present invention provides volution compounds, its stereoisomer and its pharmaceutically
The preparation method of acceptable salt, prodrug or its solvate, this method use following synthetic route: following synthetic route (I and
II):
Reaction step is as follows:
A) it using compound A as raw material, restores to obtain compound B through tetrahydrochysene lithium aluminium.
B) compound B is aoxidized by mCPBA and is generated compound C.
C) rearrangement reaction generation compound D occurs under triethyl aluminum effect for compound C.
D) compound D generation oxidation reaction in the case where wearing the effect of this Martin's oxidant obtains compound E.
E) compound E reaction 3+2 cycloaddition reaction under the effect of amine reagent obtains compound F.
F) compound F carries out reduction reaction as reducing agent using sodium borohydride and obtains compound G.
G) compound G reaction removing benzyl protecting group under hydrogen effect obtains compound H.
H) compound H progress amino Boc under the effect of Boc acid anhydrides protects to obtain compound I.
I) compound I wear this Martin's oxidant effect under occur oxidation reaction obtain compound J.
J) compound J obtains compound K with aryl halides generation nucleophilic substitution under that action of n-butyl lithium.
K) compound K restores to obtain target compound through tetrahydrochysene lithium aluminium.
L) using compound N as raw material, compound O is obtained under LDA effect.
M) allyl amine of N-Cbz protection carries out coupling reaction with compound O under 9-BBN effect and generates compound P.
N) compound P is aoxidized by mCPBA and is generated compound Q.
O) compound Q anti-raw ring-opening reaction under the action of borine generates compound R.
In the present invention, what the general formula I was indicated, the chiral separation method of the volution compound when Y is nitrogen-atoms,
Use following route:
Reaction step is as follows:
A) using compound F as raw material, through sodium borohydride reduction, this pair of of diastereo-isomerism of U-A~B is obtained through silica gel column chromatography
Body.
B) compound U-A~B respectively in the presence of the condensing agents such as DCC, DMAP and chiral mandelic acid occur esterification, obtain
To product in only one group can pass through column chromatograph separate diastereoisomer V-A~B.
C) compound V-A~B carries out ester hydrolysis reaction and obtains compound W-A~B.
D~f) compound W-A~B carries out debenzylation respectively, amino carries out Boc protection reaction, wears this Martin oxidation
Reaction obtains compound X-A~B.So far, quaternary carbon chiral resolution finishes.
G) it is each contented with aryl halides nucleophilic substitution reaction to occur for compound X-A~B in the presence of n-BuLi respectively
To 4 optically pure compound Y-A~D and Z-A~D.
H) compound Z-A~D generates target compound A-8A~D under the action of tetrahydrochysene lithium aluminium.
I) compound Y-A~D generates target compound A-9A~D in the case where few drops of concentrated hydrochloric acids act on.
Provided volution compound, its stereoisomer and its pharmaceutically acceptable salt, prodrug according to the present invention
Or its solvate, one of preferably following compound:
There is apparent monoamine to transport egg for a further object according to the present invention, volution compound provided by the invention
White combination activity, the ligand small molecule that can further prepare the monoamine transport protein of high inhibitory activity and preparation are for pre-
Prevent, delay or treat the drug of the diseases such as depression, attention deficit disorder, obesity, neuropathic pain.
Specific embodiment
Below with reference to embodiment, the present invention is further elaborated, and following implementation can only describe this by way of example
Invention.It is obvious that those of ordinary skill in the art can in the scope of the present invention and essence, to the present invention carry out it is various flexible and
Modification.It is to be understood that this invention is intended to cover the accommodation and modification that include in the appended claims.
Experiment and sample analysis instrument:
1HNMR and13CNMR is measured in 400 Nuclear Magnetic Resonance of Varian Mercury plus.
LS-MS is measured by Agilent 1100Series LC/MSD1946D type mass spectrograph.
Special chemical reagent is purchased from sigma, Alfa, Acros, the Reagent Companies such as An Naiji.General chemical reagent is purchased from state
Solution on Chemical Reagents in Shanghai company, medicine group is that domestic analysis is pure.
Primary solvent includes petroleum ether, and ethyl acetate, methylene chloride, methanol etc. is synthesis grade purchased from Chinese medicines group.
Column chromatography silica gel uses Haiyang Chemical Plant, Qingdao's chemistry pure silicon glue, generally 300-400 mesh.
TLC silica gel plate is the HSF-254 thin-layer chromatography prefabricated board of Yantai Chemical Manufacture.
Ultraviolet lamp is Shanghai Gu Cun electric light instrument plant ZF-1 type ultraviolet analysis instrument for three purposed.
Prepare embodiment (the embodiment of the present invention numbers same compound number)
Embodiment 1: compound A-1A~B 6- (3- methoxyphenyl)-1- methyl-1-azaspiro [4.5] decyl- 6- alcohol
Synthetic route:
Reaction step:
The preparation of LDA is carried out first.Diisopropylamine (9.8ml, 69.9mmol) is added in the anhydrous THF of 90ml, -78 DEG C
Lower addition n-BuLi 41ml (1.7N, 70mmol) adds rear system and is warming up to 0 DEG C of reaction 15min.Again by system as -78
At DEG C, LDA obtained is a faint yellow THF solution.DMPU 21ml is added in LDA, and is slowly dropped into compound N (hexamethylene
Ketone) (6ml, 57.9mmol) THF solution 50ml, react 2h at this temperature.Be slowly dropped into later trifluoro sulfonate (22g,
Rear system is added dropwise the reaction was continued at this temperature 9h in THF solution (60ml) 61.6mmol).After completion of the reaction, reaction solution
Direct silica gel mixed sample column chromatography (petroleum ether: ethyl acetate=20:1), obtains the grease 8.6g of a faint yellow viscosity very little.
Product is apt to deteriorate, carries out the reaction of next step at once.Yield: 55%
During prepare compound P, the allyl amine (3.48g, 0.02mol) that benzyl chloroformate is protected is dissolved in
In 68ml 9-BBN (0.5N, 0.03mol), after 3h is stirred at room temperature, compound O (5g, 0.02mol), NaOH are sequentially added
(2.27g, 0.06mmol), Pd (PPh3)4(0.17g, 0.18mmol), water (30ml), system N2Flow back 1.5h after displacement.Reaction
After, THF is evaporated off in diatomite filtering, and residue is dissolved in 150ml methylene chloride, organic phase washing, saturated common salt washing,
It is dry, it is spin-dried for.Residue silica gel column chromatography (petroleum ether: ethyl acetate=5:1), obtains a light yellow oil 5.2g.Grease
It is long placed in rear agglutination solid.Yield: 96%
MS(m/z):296[M+Na]+
1H NMR(400MHz,CDCl3)δ7.54-6.98(m,5H),5.41(s,1H),5.09(s,2H),5.01(s,1H),
3.17 (t, J=13.1,2H), 2.01-1.77 (m, 6H), 1.65-1.50 (m, 6H)
During prepare compound R, compound P (1.5g, 5.19mmol) is dissolved in 80ml anhydrous methylene chloride,
The dry ice bath is cooled to -78 DEG C, and BF is slowly added dropwise at this temperature3-Et2O (0.85ml, 6.92mmol) solution continues in this temperature
Lower reaction 3.5h.It after completion of the reaction, is alkalinity with sodium bicarbonate solution regulation system, organic phase is washed with a small amount of saturated common salt
It washs, anhydrous sodium sulfate is dry, is spin-dried for, residue silica gel column chromatography (petroleum ether: ethyl acetate=5:1) obtains a white solid
1.2g.Yield: 80%
MS(m/z):312[M+Na]+
During prepare compound S, raw material compound R (650mg, 2.25mmol) is dissolved in the anhydrous THF of 50ml,
Lithium Aluminium Hydride (305mg, 7.65mmol) is added under ice bath, adds rear system and is warming up to reflux.Reaction terminates after 3h, adds under ice bath
Enter ice water quenching reaction, add 15ml 20%NaOH solution, system gradually becomes to clarify after reacting 1min, there is blocks of solid
It generates.It filters at once.Filter cake methylene chloride: methanol=9:1 mixed solvent ultrasound simultaneously filters.Filtrate is evaporated off in merging filtrate,
The dilution of residue 100ml methylene chloride, a little saturated common salt water washing, anhydrous sodium sulfate are dry.Filtering, is spin-dried for.Product without
It is further processed and directly carries out next step reaction.Yield: 95%
MS(m/z):170[M+H]+
During prepare compound T, compound S (330mg, 1.95mmol) is dissolved in 50ml anhydrous methylene chloride
In, it is added under ice bath and wears this Martin's oxidant (1.24g, 2.92mmol).The system of adding is gradually heated to room temperature reaction 2h.Reaction
After, saturation NaHSO is added under ice bath3Quenching reaction adds 2ml20%NaOH aqueous solution regulation system as alkalinity.Two
Chloromethanes extracts (100ml), separates organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, obtains
One red oil.Since the compound adsorbs very seriously on silica gel, column chromatographic purifying can not be passed through.Therefore product without
It is further purified and directly carries out next step reaction.
MS(m/z):168[M+H]+
During preparing target compound A-1A~B, raw material Meta Bromo Anisole (0.38ml, 2.99mmol) is dissolved in
In the anhydrous THF of 10ml, n-BuLi 1.25ml (2.4N, 2.99mmol) is added dropwise at -78 DEG C, system reacts 1h at such a temperature.
Continue the 5ml anhydrous THF solution that compound T (110mg, 0.66mmol) is added dropwise, in reacting 2h at this temperature after being added dropwise.Instead
After answering, saturated aqueous ammonium chloride quenching reaction is added dropwise under ice bath.The extraction of 100ml ethyl acetate, organic phase washing, saturation
Salt washing, anhydrous sodium sulfate are dry.Filtering, is spin-dried for, and product TLC shows that there are two products.It is a pair of of diastereoisomer.This
There is no points of primary and secondary from TLC for two isomers.Their RfAlthough value relatively can still separate.We define pole
Property it is lesser be A-1A, polarity it is biggish be A-1B.Residue prepares silica gel plate separation (methylene chloride: methanol=15:1) and obtains
The sterling of A-1A and A-1B.A-1A is 50mg, A-1B 30mg.It is all colorless and transparent oily object.Total recovery: 45%
MS(m/z):276[M+H]+
A-1A:1H NMR(400MHz,CDCl3) δ 7.70-7.68 (m, 1H), 7.56 (d, J=8,2H), 7.32-7.26
(m,1H),6.89-6.87(m,1H),3.92(s,3H),3.75(brs,1H),3.09-3.02(m,1H),2.81-2.72(m,
1H),2.38-2.30(m,2H),2.10(s,3H),2.05-1.93(m,6H),1.80-1.59(m,1H).
A-1B:1H NMR(400MHz,CDCl3)δ7.45-7.30(m,2H),7.27-7.23(brs,1H,),6.92-6.88
(m,1H),3.86(s,3H),3.71(s,1H),3.05(brs,3H),2.75-2.65(m,1H),2.59-2.49(m,1H),
2.41-2.20(m,2H),2.10-1.91(m,6H),1.69-1.46(m,1H).。
Embodiment 2: compound A-26- (3,4- dichlorophenyl)-1- methyl-1-azaspiro [4.5] decyl- 6- alcohol
Synthetic technology route only replaces Meta Bromo Anisole with 3,4-, bis- chloroiodobenzone referring to described in embodiment 1, total to receive
Rate: 6.1%.
MS(m/z):314[M+H]+
Embodiment 3: compound A-31- methyl -6- (naphthalene -2- base) -1- azaspiro [4.5] decyl- 6- alcohol
Synthetic technology route only replaces Meta Bromo Anisole with 2- bromonaphthalene, total recovery referring to described in embodiment 1:
6.3%.
MS(m/z):296[M+H]+
Embodiment 4: compound A-4A~B 6- (3- methoxyphenyl) -2- methyl -2- azaspiro [4.5] decyl- 6- alcohol
Synthetic route:
Reaction step:
During prepare compound B, take three mouthfuls of reaction flasks of the drying of a 250ml, with syringe be added 100ml without
Lithium Aluminium Hydride (3.25g, 85.6mmol) is added under ice bath in water tetrahydrofuran.After stirring 5min, compound A (1- is added dropwise under ice bath
Cyclohexene -1- acetic acid) (8g, 57.1mmol) tetrahydrofuran solution 50ml, the system of adding be raised to room temperature reaction 15min after heat up
To back flow reaction 3h.After completion of the reaction, it is slowly added under ice bath water (30ml), 20%NaOH (30ml), diatomite filtering, filtrate
It is spin-dried for, the dilution of 200ml methylene chloride, the washing of organic phase saturated sodium-chloride, anhydrous sodium sulfate is dry.Filtering, organic phase are spin-dried for.?
One light yellow oil 6.48g.Product does not carry out next step reaction directly after further treatment.Yield: 90%
MS(m/z):127[M+H]+
1H NMR(400MHz,CDCl3) δ 5.52 (bs, 1H), 3.59 (t, J=6.3Hz, 2H), 2.22 (t, J=6.2Hz,
2H),2.02-1.91(m,2H),1.95-1.88(m,2H),1.68-1.53(4H).
During prepare compound C, compound B (7.5g, 59.5mmol) is dissolved in 250ml anhydrous methylene chloride
In, mCPBA (23.2g, 134.4mmol) is added under ice bath, system is warming up to room temperature reaction 2h after ice bath 15min.End of reaction
15%NaOH (150ml) is added afterwards, generates a large amount of white solids in system.Diatomite filtering, separates organic phase for filtrate, organic
Saturated common salt water washing is mutually used, anhydrous sodium sulfate is dried, filtered, drained, residue silica gel column chromatography (petroleum ether: ethyl acetate
=5:1~2:1), obtain a light yellow oil 7.01g.Yield: 83%
MS(m/z):143[M+H]+
1H NMR(400MHz,CDCl3) δ 3.82-3.62 (m, 2H), 3.15 (d, J=3.2Hz, 1H), 2.62 (brs, 1H),
1.98-1.68(m,4H),1.46-1.15(m,6H).
During prepare compound D, compound C (5g, 35.2mmol) is dissolved in 300ml anhydrous tetrahydro furan ,-
AlEt is slowly added dropwise at 78 DEG C3(2N, 88ml) warms naturally to ambient temperature overnight after being added dropwise.System is used after completion of the reaction
15%NaOH (100ml) is quenched, and tetrahydrofuran is removed in rotation, and residue is diluted with 150ml methylene chloride, the washing of organic phase saturated common salt
It washs, anhydrous sodium sulfate is dry.Organic phase filtering, is spin-dried for, obtains a light yellow oil.Residue silica gel column chromatography (petroleum ether: second
Acetoacetic ester=5:1), obtain a colorless oil 1.18g.Yield: 30%
MS(m/z):135[M+Na]+
1H NMR(400MHz,CDCl3)δ4.90(s,1H),4.75(s,1H),4.08-4.05(m,1H),2.42-2.36
(m, 1H), 2.05-2.01 (m, 2H), 1.84-1.75 (m, 1H), 1.69-1.65 (m, 1H), 1.56 (d, J=4.5Hz, 1H),
1.51-1.27(m,3H).
During prepare compound E, compound D (100mg, 0.89mmol) is dissolved in 20ml anhydrous methylene chloride
In, Dess-Martin oxidant (568mg, 1.34mmol) is added under ice bath.System is warming up to room temperature after reacting 0.5h under ice bath
React 1.5h.Reaction solution is spin-dried under ice bath after completion of the reaction, 20ml anhydrous ether is added, there are a large amount of white solids in system,
Filtering.It is spin-dried under filtrate ice bath.Do not carry out next step reaction rapidly after further treatment.
During prepare compound F, by compound E (30mg, 0.27mmol), N- benzyl -1- methoxyl group-N- ((three
Methylsilyl) methyl) methylamine (70 μ l, 0.27mmol) is dissolved in 10ml anhydrous methylene chloride, be added under ice bath TFA (2 μ l,
0.03mmol), 1h recession is reacted under ice bath and removes ice bath, and system warms naturally to room temperature reaction overnight.After completion of the reaction in system
Saturated sodium bicarbonate solution is added and adjusts PH to 11, methylene chloride extracts (100ml*2), organic phase saturated common salt water washing, nothing
Aqueous sodium persulfate is dry.Organic phase filtering, is spin-dried for, it is yellowish to obtain one for residue silica gel column chromatography (petroleum ether: ether=5:1~3:1)
Color grease 26mg.Yield: 40%
MS(m/z):244[M+H]+
1H NMR(400MHz,CDCl3)δ7.34-7.24(m,5H),3.61(s,2H),2.87-2.84(m,1H),2.69-
2.63(m,1H),2.54-2.46(m,2H),2.44-2.30(m,3H),1.92-1.76(m,4H),1.74-1.64(m,2H),
1.63-1.55(m,1H).
During prepare compound G, compound F (1.3g, 5.33mmol) is dissolved in 100ml anhydrous methanol, ice
Bath is lower to be added sodium borohydride (200mg, 5.29mmol), adds rear system and is warming up to room temperature reaction overnight.After completion of the reaction by first
Alcohol is evaporated off, and residue 100ml methylene chloride dilution, organic phase is washed with saturated sodium bicarbonate solution, washes, saturated common salt washing
It washs, anhydrous sodium sulfate is dry.Organic phase filtering, is spin-dried for, obtains a light yellow oil.
MS(m/z):246[M+H]+
During prepare compound H, compound G (450mg, 1.84mmol) is dissolved in 20ml anhydrous methanol, is added
Enter the palladium dydroxide of catalytic amount, system reacts at room temperature overnight under 3MPa hydrogen atmospheric pressure.After completion of the reaction, diatomite filters,
Filtrate, which is directly evaporated, carries out next step reaction.
MS(m/z):156[M+H]+
During prepare compound I, compound H (36mg, 0.23mmol) is dissolved in THF/H2The mixing of O=1:1
In solution (5ml), it is added with stirring Boc2O (50.6mg, 0.23mmol), NaOH (11mg, 0.28mmol), it is stirred at room temperature
Night.After completion of the reaction, THF, the dilution of residue 50ml methylene chloride, organic phase washing, saturated common salt water washing, anhydrous sulphur is evaporated off
Sour sodium is dry.Organic phase filtering, is spin-dried for, obtains a light yellow oil.Residue silica gel column chromatography (petroleum ether: ethyl acetate=
2:1), a colorless oil 52mg is obtained.Yield: 90%
MS(m/z):278[M+Na]+
During prepare compound J, compound I (100mg, 0.39mmol) is dissolved in 20ml anhydrous methylene chloride
In, it is added with stirring pyridine (63 μ l, 0.78mmol), is added under ice bath and wears this Martin's oxidant (249mg, 0.59mmol), added
Complete system is gradually heated to room temperature reaction 2h.After completion of the reaction, saturation NaHSO is added under ice bath3Quenching reaction adds 2ml
20%NaOH aqueous solution regulation system is alkalinity.Methylene chloride extracts (100ml), separates organic phase, organic phase saturated salt solution
Washing, anhydrous sodium sulfate are dry.Filtering, is spin-dried for.Residue silica gel column chromatography (petroleum ether: ethyl acetate=5:1), it is yellowish to obtain one
Color grease 85mg.Yield: 86%
MS(m/z):276[M+Na]+
1H NMR(400MHz,CDCl3)δ3.73-3.67(m,1H),3.42-3.24(m,2H),3.20-3.00(m,1H),
2.46-2.34(m,2H),2.34-2.13(m,1H),1.95-1.52(m,7H),1.42-1.36(m,9H).
During prepare compound K, Meta Bromo Anisole (370mg, 1.98mmol) is dissolved in the anhydrous THF of 15ml ,-
N-BuLi 0.82ml (2.4N, 1.98mmol) is added dropwise at 78 DEG C, system reacts 1h at such a temperature.Continue that compound J is added dropwise
The 5ml anhydrous THF solution of (100mg, 0.40mmol), in reacting 2h at this temperature after being added dropwise.After completion of the reaction, under ice bath
Saturated aqueous ammonium chloride quenching reaction is added dropwise.Ethyl acetate extracts (100ml), organic phase washing, and saturated common salt washing is anhydrous
Sodium sulphate is dry.Filtering, is spin-dried for, and product TLC shows that there are two the diastereoisomers being kept completely separate.We are lesser by polarity
It is named as K-A, it is biggish to be named as K-B.Column chromatography for separation obtains K-A 65mg, K-B 26mg.It is white foam solid.
Total recovery: 59%
MS(m/z):384[M+Na]+
K-A:1H NMR(400MHz,CDCl3)δ7.21-7.14(m,1H),7.12-7.63(m,2H),6.78-6.72(m,
1H),3.75(s,3H),3.36-3.14(m,2H),3.02-2.94(m,1H),2.60-2.45(m,2H),2.23-2.05(m,
2H),1.96-1.75(m,2H),1.70-1.56(m,3H),1.46-1.28(m,11H).
K-B:1H NMR(400MHz,CDCl3)δ7.22-7.16(m,1H),7.11-7.02(m,2H),6.82-6.77(m,
1H),3.73(s,3H),3.50-3.43(m,1H),2.98-2.90(m,1H),2.77-2.68(m,1H),2.49-2.42(m,
1H),2.34-2.24(m,1H),1.95-1.84(m,1H),1.79-1.68(m,3H),1.58-1.46(m,3H),1.43-1.36
(m,2H),1.34-1.24(m,9H).
During preparing target compound A-4A~B, by compound K-A (58mg, 0.16mmol) be dissolved in 10ml without
In water THF, Lithium Aluminium Hydride (19mg, 0.48mmol) is added under ice bath, adds rear system and is warming up to reflux.Reaction terminates after 3h,
Ice water quenching reaction is added under ice bath, adds 2ml 20%NaOH solution, system gradually becomes to clarify after reacting 1min, there is block
Shape solid generates.It filters at once.Filter cake methylene chloride: methanol=9:1 mixed solvent ultrasound simultaneously filters.Merging filtrate steams
Except filtrate, the dilution of residue 50ml methylene chloride, a little saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for.It is residual
Excess prepares silica gel plate separation (methylene chloride: methanol=15:1) and obtains final product.It is total for a white foam solid A-4A
42mg.Yield: 90%.The synthesis of compound A-4B is using K-B as raw material, and operation and processing are as the synthesis of A-4A.
MS(m/z):276[M+H]+
A-4A:1H NMR(400MHz,CDCl3)δ7.35-7.28(m,1H),7.20(s,1H),7.12-7.08(m,1H),
6.88-6.83(m,1H),3.82(s,3H),3.53-3.48(m,1H),3.25-3.17(m,1H),2.93-2.87(m,1H),
2.61-2.52(m,1H),2.40(s,3H),2.06-1.89(m,3H),1.85-1.68(m,5H),1.60-1.52(m,1H),
1.44-1.32(m,1H).
A-4B:1H NMR(400MHz,CDCl3)δ7.34-7.28(m,1H),7.16-7.11(m,2H),6.88-6.84(m,
1H),3.82(s,3H),3.36-3.18(m,4H),2.38(s,3H),2.30-2.19(m,1H),2.16-2.03(m,2H),
2.01-1.93(m,2H),1.84-1.73(m,2H),1.66-1.49(m,3H),1.42-1.30(m,1H).。
Embodiment 5: compound A-5A~B 2- methyl -6- (tolyl) -2- azaspiro [4.5] decyl- 6- alcohol
Synthetic technology route only replaces Meta Bromo Anisole with 3- methyl benzyl bromine, total recovery referring to described in embodiment 4:
3.2%.
MS(m/z):260[M+H]+
A-5A:1H NMR(400MHz,CDCl3)δ7.39(s,1H),7.36-7.32(m,1H),7.27-7.22(m,1H),
7.13-7.09(m,1H),3.49-3.45(m,1H),3.17-3.11(m,1H),2.88-2.83(m,1H),2.56-2.49(m,
1H),2.36(s,3H),2.34(s,3H),2.08-1.92(m,2H),1.86-1.65(m,6H),1.56-1.48(m,1H),
1.42-1.30(m,1H).
A-5B:1H NMR(400MHz,CDCl3)δ7.40-7.35(m,2H),7.29-7.25(m,1H),7.14-7.11(m,
1H),3.72-3.22(m,1H),3.12-3.04(m,2H),2.38(s,3H),2.31-2.26(m,4H),2.10-1.95(m,
4H),1.85-1.60(m,4H),1.54-1.44(m,1H),1.44-1.34(m,1H).。
Embodiment 6: compound A-66- (3- fluorophenyl) -2- methyl -2- azaspiro [4.5] decyl- 6- alcohol
Synthetic technology route only replaces Meta Bromo Anisole with 3- methyl benzyl bromine, total recovery referring to described in embodiment 4:
3.5%.
MS(m/z):264[M+H]+
A-6A:1H NMR(400MHz,CDCl3)δ7.38-7.28(m,3H),7.04-6.96(m,1H),3.16-3.08(m,
1H),2.98-2.88(m,1H),2.70-2.62(m,1H),2.52-2.40(m,1H),2.31(s,3H),2.00-1.88(m,
3H),1.80-1.58(m,4H),1.50-1.38(m,1H),1.32-1.22(m,2H).
A-6B:1H NMR(400MHz,CDCl3)δ7.41-7.32(m,3H),7.07-6.98(m,1H),3.31-3.20(m,
3H),2.42(s,3H),2.28-2.18(m,1H),2.13-2.00(m,4H),1.84-1.76(m,2H),1.70-1.60(m,
3H),1.44-1.32(m,1H).。
Embodiment 7: compound A-7A~B 2- methyl -6- (3- (trifluoromethyl) phenyl) -2- azaspiro [4.5] decyl- 6-
Alcohol
Synthetic technology route only replaces Meta Bromo Anisole with 3- methyl benzyl bromine, total recovery referring to described in embodiment 4:
3.2%.
MS(m/z):314[M+H]+
A-7A:1H NMR(400MHz,CDCl3)δ7.87(s,1H),7.83-7.79(m,1H),7.59-7.55(m,1H),
7.52-7.47(m,1H),2.99-2.92(m,1H),2.82-2.74(m,1H),2.59-2.54(m,1H),2.45-2.38(m,
1H),2.24(s,3H),2.07-2.00(m,1H),1.93-1.89(m,2H),1.83-1.68(m,4H),1.64-1.48(m,
3H).
A-7B:1H NMR(400MHz,CDCl3)δ7.89(s,1H),7.80-7.77(m,1H),7.61-7.56(m,1H),
7.55-7.49(m,1H),3.15-3.01(m,3H),2.32-2.22(m,4H),2.08-1.94(m,4H),1.85-1.76(m,
2H),1.68-1.56(m,3H),1.46-1.36(m,1H).。
Embodiment 8: compound A-8A~D 2- methyl -6- (naphthalene -2- base) -2- azaspiro [4.5] decyl- 6- alcohol
Chiral resolution route:
During prepare compound U-A~B, compound F (1.3g, 5.33mmol) is dissolved in 100ml anhydrous methanol
In, sodium borohydride (200mg, 5.29mmol) is added under ice bath, adds rear system and is warming up to room temperature reaction overnight.After completion of the reaction
Methanol is evaporated off, residue 100ml methylene chloride dilution, organic phase is washed with saturated sodium bicarbonate solution, is washed, saturated common salt
Water washing, anhydrous sodium sulfate are dry.Organic phase filtering, is spin-dried for, obtains a light yellow oil.Product TLC analysis finds have on plate
Two RfThe very close point of value, for a pair of of diastereoisomer.We are defined as U-A for polarity is lesser, and polarity is biggish
For U-B.Product silica gel column chromatography (methylene chloride: methanol=100:1~50:1~20:1), obtains U-A 480mg, U-B 450mg.
Total recovery: 75%
MS(m/z):246[M+H]+
U-A 1H NMR(400MHz,CDCl3)δ7.39-7.21(m,5H),3.58-3.56(m,2H),3.55-3.52(m,
1H),3.09-3.01(m,1H),2.22-2.81(m,1H),2.21-2.01(m,3H),1.79-1.76(m,1H),1.75-1.62
(m,1H),1.58-1.50(m,1H),1.49-1.40(m,2H),1.38-1.15(m,5H).
U-B 1H NMR(400MHz,CDCl3)δ7.39-7.21(m,5H),3.61-3.52(m,2H),3.39-3.26(m,
1H),3.21-3.16(m,1H),3.01-2.92(m,1H),2.21-2.01(m,2H),1.95-1.90(m,2H),1.70-1.52
(m,3H),1.50-1.20(m,6H).
During prepare compound V-A~B, by compound U-B (85mg, 0.35mmol), S-2- methoxyl group -2- benzene
Guanidine-acetic acid (65mg, 0.39mmol) is dissolved in 15ml anhydrous methylene chloride, and DCC (143mg, 0.69mmol) is added under ice bath,
DMAP (10mg, cat), system is gradually warmed to room temperature overnight.System is diluted with 100ml methylene chloride after completion of the reaction, 20ml
Saturated sodium bicarbonate washing, saturated common salt water washing, anhydrous sodium sulfate are dried, filtered, are spin-dried for.There are two R on TLC display boardf
It is worth point that is close but can separating, is a pair of of diastereoisomer, it is W-A that it is lesser, which to define polarity, for we, and polarity is biggish to be
W-B, residue silica gel column chromatography (methylene chloride: methanol=50:1) obtain the sterling of W-A and W-B.
MS(m/z):394[M+H]+
During prepare compound W-A~B, compound V-A (500mg, 1.27mmol) is dissolved in THF/CH3OH/
H2In the 50ml mixed solution of O=1:1:1, it is added with stirring 20%NaOH solution 5ml, system reacts 1h at room temperature.Reaction
After, system is extracted with 200ml ethyl acetate, organic phase washing, saturated common salt washing.Anhydrous sodium sulfate is dry.Filtering, rotation
Do to obtain W-A 310mg.For colorless and transparent oily object.Yield: 95%.Product directly carries out next step reaction without processing.W-B's
Preparation is as the preparation of W-A.Obtain a clear, colorless grease.Yield: 96%
MS(m/z):246[M+H]+
W-A and W-B spectrogram is overlapped.
1H NMR(400MHz,CDCl3)δ7.39-7.21(m,5H),3.61-3.52(m,2H),3.39-3.26(m,1H),
3.21-3.16(m,1H),3.01-2.92(m,1H),2.21-2.01(m,2H),1.95-1.90(m,2H),1.70-1.52(m,
3H),1.50-1.20(m,6H).
During prepare compound X-A~B, method therefor is similar with the method for 4 the inside of embodiment, to compound W-
A or W-B carries out debenzylation protection, Boc protection on nitrogen, wears the 3 steps reaction such as this Martin oxidation and respectively obtains compound X-A or X-B.
MS(m/z):276[M+Na]+
X-A and X-B spectrogram is overlapped.
1H NMR(400MHz,CDCl3)δ3.73-3.67(m,1H),3.42-3.24(m,2H),3.20-3.00(m,1H),
2.46-2.34(m,2H),2.34-2.13(m,1H),1.95-1.52(m,7H),1.42-1.36(m,9H).
During prepare compound Z-A~D, it is anhydrous that raw material 2- bromonaphthalene (492mg, 2.38mmol) is dissolved in 15ml
In THF, n-BuLi 0.98ml (2.4N, 2.38mmol) is added dropwise at -78 DEG C, system reacts 1h at such a temperature.Continue to be added dropwise
The 5ml anhydrous THF solution of X-A (120mg, 0.48mmol), in reacting 2h at this temperature after being added dropwise.After completion of the reaction, ice
Bath is lower to be added dropwise saturated aqueous ammonium chloride quenching reaction.The extraction of 100ml ethyl acetate, organic phase washing, saturated common salt washing, nothing
Aqueous sodium persulfate is dry.Filtering, is spin-dried for, and product TLC shows that there are two products.They are a pair of of diastereoisomers.We define
The lesser compound of polarity is Z-A, and biggish polarity is Z-C.Residue silica gel column chromatography (petroleum ether: ethyl acetate=20:1)
This pair of diastereoisomer is separated.Z-A 55mg, Z-C 52mg.It is white powdery solids.Total recovery: 55%
A pair of of diastereoisomer is also obtained in the reaction of 2- bromonaphthalene using X-B as raw material in the same way.We define pole
Property lesser compound be Z-B, biggish polarity is Z-D, opens Z-B and Z-D points through column chromatography.It is that white powder is solid
Body.Total recovery: 62%
MS(m/z):405[M+Na]+
NMR data Z-A and Z-B spectrogram is overlapped, and Z-C and Z-D are overlapped.
Z-A:1H NMR(400MHz,CDCl3)δ8.03-8.01(m,1H),7.89-7.78(m,3H),7.70-7.66(m,
1H),7.51-7.47(m,2H),3.42-3.32(m,2H),3.08-3.00(m,1H),2.64-2.54(m,1H),2.49-2.40
(m,1H),2.23-2.14(m,1H),2.01-1.85(m,2H),1.78-1.70(m,4H),1.62-1.52(m,3H),1.29
(s,9H).
Z-C:1H NMR(400MHz,CDCl3)δ8.01-7.99(m,1H),7.88-7.79(m,3H),7.71-7.67(m,
1H),7.51-7.48(m,2H),3.65-3.57(m,1H),3.15-3.07(m,2H),2.76-2.64(m,1H),2.57-2.48
(m,1H),2.06-1.97(m,1H),1.93-1.83(m,2H),1.82-1.68(m,5H),1.684-1.52(m,2H),1.32
(s,9H).
During preparing target compound A-8A~D, by compound Z-A (61mg, 0.16mmol) be dissolved in 10ml without
In water THF, Lithium Aluminium Hydride (19mg, 0.48mmol) is added under ice bath, adds rear system and is warming up to reflux.Reaction terminates after 3h,
Ice water quenching reaction is added under ice bath, adds 2ml 20%NaOH solution, system gradually becomes to clarify after reacting 1min, there is block
Shape solid generates.It filters at once.Filter cake methylene chloride: methanol=9:1 mixed solvent ultrasound simultaneously filters.Merging filtrate steams
Except filtrate, the dilution of residue 50ml methylene chloride, a little saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for.It is residual
Excess prepares silica gel plate separation (methylene chloride: methanol=15:1) and obtains final product.It is total for a white foam solid A-8A
42mg.Yield: 90%.The synthesis of A-8B~C is as the synthesis of A-8A.
MS(m/z):296[M+H]+
It NMR data A-8A and is overlapped with A-8B spectrogram, A-8C and A-8D are overlapped.
A-8A:1H NMR(400MHz,CDCl3)δ8.03-8.02(m,1H),7.93-7.86(m,3H),7.77-7.73(m,
1H),7.58-7.55(m,2H),3.71-3.66(m,1H),3.30-3.22(m,1H),2.98-2.90(m,1H),2.75-2.66
(m,1H),2.32(s,3H),2.24-2.18(m,1H),2.13-1.09(m,2H),2.06-1.99(m,1H),1.92-1.80
(m,4H),1.72-1.64(m,2H).
A-8C:1H NMR(400MHz,CDCl3)δ8.04-8.02(brs,1H),7.88-7.82(m,3H),7.69-7.65
(m,1H),7.54-7.51(m,2H),3.36-3.24(m,2H),3.20-3.12(m,1H),2.46-2.38(m,1H),2.23
(s,3H),2.18-2.00(m,5H),1.86-1.76(m,2H),1.72-1.62(m,2H).。
Embodiment 9: compound A-9A~D 6- (3,4- dichlorophenyl) -2- methyl -2- azaspiro [4.5] decyl- 6- alcohol
Chiral resolution route:
The synthesis of X-A~B is referring to described in embodiment 8.
During prepare compound Y-A~D, by raw material 3, bis- chloroiodobenzone of 4- (650mg, 2.38mmol) is dissolved in 15ml
In anhydrous THF, n-BuLi 0.98ml (2.4N, 2.38mmol) is added dropwise at -78 DEG C, system reacts 1h at such a temperature.Continue
The 5ml anhydrous THF solution of X-A (120mg, 0.48mmol) is added dropwise, in reacting 2h at this temperature after being added dropwise.End of reaction
Afterwards, saturated aqueous ammonium chloride quenching reaction is added dropwise under ice bath.The extraction of 100ml ethyl acetate, organic phase washing, saturated salt solution
It washes, anhydrous sodium sulfate is dry.Filtering, is spin-dried for, and product TLC shows that there are two products.They are a pair of of diastereoisomers.We
The definition lesser compound of polarity is Y-A, and biggish polarity is Y-C.Residue silica gel column chromatography (petroleum ether: ethyl acetate=
20:1) this pair of diastereoisomer is separated.Y-A 45mg, Y-C 43mg.It is white powdery solids.Total recovery:
55%
It is reacted in the same way as raw material with bis- chloroiodobenzone of 3,4- using X-B and also obtains a pair of of diastereoisomer.We
The definition lesser compound of polarity is Y-B, and biggish polarity is Y-D, opens Y-B and Y-D points through column chromatography.It is white powder
Shape solid.Total recovery: 62%
MS(m/z):422[M+H]+
NMR data Y-A and Y-B spectrogram is overlapped, and Y-C and Y-D are overlapped.
Y-A:1H NMR(600MHz,CDCl3)δ7.71(s,1H),7.38-7.36(m,1H),7.34-7.31(m,1H),
3.29-3.25(m,2H),3.09-3.03(m,1H),2.62-2.56(brs,1H),2.26-2.19(m,1H),2.12-2.05
(m,1H),2.02-1.89(m,2H),1.83-1.75(m,1H),1.74-1.63(m,3H),1.55-1.47(m,2H),1.46-
1.42(m,1H),1.38(s,9H).
Y-C:1H NMR(600MHz,CDCl3)δ7.73(m,1H),7.54-7.48(m,2H),3.52-3.45(m,1H),
2.98-2.92(m,1H),2.75-2.65(m,1H),2.45-2.38(m,1H),2.36-2.30(m,1H),1.95-1.70(m,
4H),1.58-1.48(m,3H),1.45-1.38(m,1H),1.35(s,4H),1.32-1.28(m,1H),1.25(s,5H).
During synthesising target compound A-9A~D, raw material Y-A (100mg, 0.25mmol) is dissolved in 10ml acetic acid
In ethyl ester, 3 drop concentrated hydrochloric acids are added dropwise.React on room temperature reaction 3d.After completion of the reaction, 20%NaOH solution regulation system is used under ice bath
For alkalinity, ethyl acetate extracts (100ml), organic phase saturated common salt water washing, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for.It is remaining
Object prepares silica gel plate separation (methylene chloride: methanol=15:1) and obtains a white foam solid 68mg (A-9A).Yield: 92%
A-9B~D is in kind synthesized by Y-B~D respectively.Wherein A-9B is white powdery solids, A-9C and A-9D
For colorless oil.
MS(m/z):300[M+H]+
It NMR data A-9A and is overlapped with A-9B spectrogram, A-9C and A-9D are overlapped.
A-9A:1H NMR(400MHz,CDCl3)δ7.66-7.65(m,1H),7.42-7.38(m,1H),7.34-7.31(m,
1H),2.88-2.74(m,3H),2.54-2.40(m,1H),2.12-1.99(m,2H),1.94-1.84(m,1H),1.80-1.73
(m,1H),1.70-1.56(m,4H),1.48-1.38(m,2H).
A-9C:1H NMR(400MHz,CDCl3)δ7.65-7.63(m,1H),7.39-7.37(m,2H),3.24-3.20(m,
1H),2.69-2.61(m,1H),2.44-2.36(m,1H),2.34-2.29(m,1H),2.22-2.11(m,2H),1.90-1.81
(m,1H),1.79-1.69(m,1H),1.64-1.56(m,4H),1.51-1.45(m,2H).。
Experimental example 10: the monoamine binding protein combination determination of activity of volution compound:
This part biological activity test is completed in French Cerap company.Compound is tested respectively under 10 μM and 1 μM of concentration
At Dopamine Transporter (DAT), norepinephrine transporter (NET), the Percentage bound on serotonin transporter (SERT).
Gained compound activity is as shown in table 1:
Table 1: the Percentage bound that compound is transported on body protein at three
By screening on a molecular scale, it is found that part of compounds shows medium or higher monoamine transporter egg
White combination activity, further to study the ligand small molecule of the possible high inhibitory activity of monoamine transporter albumen, preparation has
The original new drug of the diseases such as alleviation, treatment depression, attention deficit disorder, obesity, neuropathic pain provides valuable
Information.
Claims (13)
1. a kind of spiro-compound being represented by the following general formula I, its stereoisomer and its pharmaceutically acceptable salt,
Wherein: R1、R2、R3、R4, X, Y be defined as follows:
X, Y is each independently nitrogen or carbon, and one in X, Y be nitrogen another be carbon, when X or Y are carbon atom, replace
Base R2Or R3For hydrogen atom；When X or Y is nitrogen-atoms, substituent R2Or R3For hydrogen atom, C1-C10Alkyl, C3-C10Naphthenic base；
R1And R4It is halogen, trifluoromethyl, trifluoromethoxy, cyano, amino, nitro, C each independently1-C10Alkyl, C3-C10
Naphthenic base or R1And R4It is formed together 6 to 10 yuan of aryl.
2. spiro-compound as claimed in claim 1, which is characterized in that when X or Y is nitrogen-atoms, substituent R2Or R3For hydrogen original
Son.
3. spiro-compound as claimed in claim 1, which is characterized in that when X or Y is nitrogen-atoms, substituent R2Or R3For C1-C10
Alkyl.
4. spiro-compound as claimed in claim 1, which is characterized in that when X or Y is nitrogen-atoms, substituent R2Or R3For methyl or
Ethyl.
5. spiro-compound as claimed in claim 1, which is characterized in that R1And R4It is halogen.
6. spiro-compound as claimed in claim 5, which is characterized in that R1And R4It is chlorine atom, and is located at 3,4 of phenyl ring.
7. spiro-compound as claimed in claim 1, which is characterized in that R1And R4Positioned at 3,4 of phenyl ring and it is formed together 6 yuan of virtues
Base.
8. spiro-compound as claimed in claim 1, which is characterized in that wherein compound be alloisomerism it is pure or carried out it is non-right
Reflect the separation of isomers.
9. spiro-compound as described in claim 1, its stereoisomer and its pharmaceutically acceptable salt, feature exist
In " pharmaceutically acceptable salt " refers to the salt being prepared by pharmaceutically acceptable nontoxic acid, described nontoxic
Acid include acetic acid, alginic acid, ortho-aminobenzoic acid, benzene sulfonic acid, benzoic acid, camphorsulfonic acid, arrest rubber acid, vinyl sulfonic acid, formic acid,
Fumaric acid, furancarboxylic acid, gluconic acid, glutamic acid, glucuronic acid, galacturonic acid, glycidic acid, hydrobromic acid, hydrochloric acid, cream
Acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, galactosaccharic acid, nitric acid, pa not acid (pamoic), pantothenic acid, benzene second
Acid, propionic acid, phosphoric acid, salicylic acid, stearic acid, succinic acid, sulfuric acid or tartaric acid；
Wherein the compound is selected from following compound:
10. a kind of spiro compounds compositions including claim 1: wherein the compound has monoamine transport protein
Have in conjunction with activity, wherein the monoamine transport protein is selected from serotonin transporter (SERT), dopamine transporter
(DAT), one of norepinephrine transporter (NET) or multiple protein.
11. the volution compound that a kind of general formula I described in claim 1 is indicated, its stereoisomer and its can pharmaceutically connect
The salt production process received, which is characterized in that this method uses following synthetic route (I and II):
Reaction step is as follows:
A) it using compound A as raw material, restores to obtain compound B through tetrahydrochysene lithium aluminium；
B) compound B is aoxidized by mCPBA and is generated compound C；
C) rearrangement reaction generation compound D occurs under triethyl aluminum effect for compound C；
D) compound D generation oxidation reaction in the case where wearing the effect of this Martin's oxidant obtains compound E；
E) compound E and N- (methoxy)-N- (trimethyl silicane ylmethyl) benzyl amine carries out 3+2 cycloaddition reaction
Close object F；
F) compound F carries out reduction reaction as reducing agent using sodium borohydride and obtains compound G；
G) compound G reaction removing benzyl protecting group under hydrogen effect obtains compound H；
H) compound H progress amino Boc under the effect of Boc acid anhydrides protects to obtain compound I；
I) compound I generation oxidation reaction in the case where wearing the effect of this Martin's oxidant obtains compound J；
J) compound J obtains compound K with aryl halides generation nucleophilic substitution under that action of n-butyl lithium；
K) compound K restores to obtain target compound through tetrahydrochysene lithium aluminium；
L) using compound N as raw material, compound O is obtained under LDA effect；
M) allyl amine of N-Cbz protection carries out coupling reaction with compound O under 9-BBN effect and generates compound P；
N) compound P is aoxidized by mCPBA and is generated compound Q；
O) compound Q anti-raw ring-opening reaction under the action of borine generates compound R；
P) compound R is through LiAlH4Reduction obtains compound S；
Q) compound S generation oxidation reaction in the case where wearing the effect of this Martin's oxidant obtains compound T；
R) compound T obtains target compound with aryl halides generation nucleophilic substitution under that action of n-butyl lithium.
What 12. a kind of general formula I described in claim 1 was indicated, the chiral resolution side of the volution compound when Y is nitrogen-atoms
Method, which is characterized in that use following route:
Reaction step is as follows:
A) using compound F as raw material, through sodium borohydride reduction, this pair of of diastereoisomer of U-A~B is obtained through silica gel column chromatography；
B) with chiral mandelic acid esterification occurs for compound U-A~B in the presence of condensing agent DCC and DMAP respectively, obtains
Only have one group can chromatograph by column in product and separates diastereoisomer V-A~B；
C) compound V-A~B obtains compound W-A~B in NaOH aqueous solution ester hydrolysis reaction；
D~f) compound W-A~B carries out catalytic hydrogenation debenzylation respectively, amino is reacted with the progress Boc protection of boc acid anhydrides,
It wears this Martin's oxidation reaction and obtains compound X-A~B；
G) with bis- chloroiodobenzone of 3,4- or 2- bromonaphthalene occurs for compound X-A~B affine replace anti-in the presence of n-BuLi respectively
4 optically pure compound Y-A~D and Z-A~D should respectively be obtained；
H) compound Z-A~D generates target compound A-8A~D under the action of tetrahydrochysene lithium aluminium；
I) compound Y-A~D generates target compound A-9A~D in the case where few drops of concentrated hydrochloric acids act on.
13. any volution compound is in preparation for preventing, diagnosing or treating depression, note in claim 1~9
Purposes in meaning power defect obstacle, obesity or neuropathic pain drug.
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