CN108727347A - A kind of crystal form and preparation method thereof of Opioid Receptors (MOR) agonist - Google Patents
A kind of crystal form and preparation method thereof of Opioid Receptors (MOR) agonist Download PDFInfo
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- CN108727347A CN108727347A CN201810336092.9A CN201810336092A CN108727347A CN 108727347 A CN108727347 A CN 108727347A CN 201810336092 A CN201810336092 A CN 201810336092A CN 108727347 A CN108727347 A CN 108727347A
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- DJHGTASRHCFVNH-RYUDHWBXSA-N CCO[C@@H](CC1)c2ccccc2[C@H]1N Chemical compound CCO[C@@H](CC1)c2ccccc2[C@H]1N DJHGTASRHCFVNH-RYUDHWBXSA-N 0.000 description 1
- YUMLNLMFBWBKSK-OHSXHVKISA-N CCO[C@@H](CC1)c2ccccc2[C@H]1NCC[C@@]1(CC2(CCCC2)OCC1)c1ncccc1 Chemical compound CCO[C@@H](CC1)c2ccccc2[C@H]1NCC[C@@]1(CC2(CCCC2)OCC1)c1ncccc1 YUMLNLMFBWBKSK-OHSXHVKISA-N 0.000 description 1
- NVGSPCSQFOQQPW-OAHLLOKOSA-N O=CC[C@@]1(CC2(CCCC2)OCC1)c1ncccc1 Chemical compound O=CC[C@@]1(CC2(CCCC2)OCC1)c1ncccc1 NVGSPCSQFOQQPW-OAHLLOKOSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to a kind of crystal forms and preparation method thereof of Opioid Receptors (MOR) agonist.Specifically, the present invention relates to (1S, 4S) -4- ethyoxyls-N- (2- ((R) -9- (pyridine -2- bases) -6- oxaspiros [4.5] decyl- 9- yls) ethyl) -1,2, the A crystal forms and preparation method thereof of 3,4- naphthane -1- amine.The A crystal forms of formula (I) compound of the present invention have good stability of crystal form, and recrystallisation solvent low toxicity and low residue used, can be preferably applied to clinical treatment.
Description
Technical field
The present invention relates to (1S, 4S) -4- ethyoxyls-N- (2- ((R) -9- (pyridine -2- bases) -6- oxaspiros [4.5] decyl- 9-
Base) ethyl) -1,2,3,4- naphthane -1- amine A crystal forms and preparation method thereof, the application in pharmaceutical composition and the A
The use of crystal form, composition in preparing treatment and/or preventing to have the drug of related disorders with Opioid Receptors (MOR) agonist
On the way.
Background technology
Opiate receptor is a kind of important g protein coupled receptor (G protein coupled receptor, GPCR), is
The target spot that endogenous opiatepeptide and opioid drug combine, immune to nervous system after opiate receptor activation and internal system have
It is most strong at present and common central analgesia medicine to have adjustment effect, opioid drug.Endogenous opiatepeptide is in the mammalian body
The opioid activity substance naturally occurred, the endogenous opiatepeptide being currently known be roughly divided into enkephalins, endorphin, dynorphin and
New several classes of deltorphin delta (Pharmacol Rev 2007；59:88-123).There are its corresponding opiate receptor in central nervous system,
That is μ (MOR), δ (DOR), κ (KOR) receptor etc..MOR is the effect target of the opioid analgesics drug such as endogenous enkephalins and morphine
Point.
Opioid drug, which is used for a long time, will produce the side effects such as tolerance and respiration inhibition, constipation, and these side effect quilts
It proves closely related with the function of β-arrestin.It, can be based on the negativity β-of MOR in order to reduce the side effect of opioid drug
Arrestin preferences ligand design drugs make the side effect that β-arrestin are mediated reduce, enhance therapeutic effect, for this hair
For bright oxa- loop coil analog derivative in the research as MOR alternative medicines, the research of TrevenaInc companies finds aryl benzyl
Activity is poor (J.Med.Chem.2013,56,8019-8031) when the substitution of position, but WO2017063509 (number of patent application PCT/
CN2016/101064, applying date 2016-09-30) disclose that high activity, Emax are but shown after a kind of cyclization of aryl benzyl position is aobvious
Work improves, hERG is obviously improved, the MOR compounds of single configuration, shown in structure such as formula (I)：
The crystal form report of compound shown in formula (I) is had no at present, it is well known that the crystalline structure as medicinal active ingredient
Often influence the chemical stability of the drug, the difference of crystallization condition and condition of storage is likely to result in the crystal knot of compound
The variation of structure, sometimes can also be along with the crystal form for generating other forms.In general, unbodied drug products do not have well-regulated
Crystal structure, often poor with other defects, such as product stability, filtering is more difficult, easily lumps, poor fluidity etc..Therefore,
It is necessary to improve each side's surface properties of above-mentioned product.
Invention content
The technical problem to be solved in the present invention is to provide one kind (1S, 4S) -4- ethyoxyls-N- (2- ((R) -9- (pyridine -2-
Base) -6- oxaspiros [4.5] decyl- 9- yls) ethyl) and -1,2,3,4- naphthane -1- amine (as shown in formula (I)) A crystal forms, the crystal form
Has good stability.
Technical scheme is as follows：
The A crystal forms of compound shown in a kind of formula (I) of present invention offer, it is characterised in that：Radiated using Cu-K α, obtain with
The X-ray powder diffraction collection that 2 θ angles of the angle of diffraction indicate, 2 angles θ of the angle of diffraction 6.01,6.09,11.23,11.33,
12.14, there is characteristic peak at 12.23,13.19,16.86,17.07,19.21,21.00,22.85,23.14 and 24.56, wherein
The error range of 2 θ of each characteristic peak is ± 0.2,
In one embodiment of the invention, 2 angles θ of the angle of diffraction 6.01,6.09,11.23,11.33,12.14,
12.23、12.46、13.19、16.05、16.54、16.86、17.07、18.32、18.83、19.21、21.00、21.63、
21.70, there is characteristic peak at 22.28,22.85,23.14,23.74,24.56,26.53 and 31.71, wherein 2 θ of each characteristic peak
Error range be ± 0.2.
In one embodiment of the invention, 2 angles θ of the angle of diffraction 6.01,6.09,8.43,11.23,11.33,
12.14、12.23、12.46、12.94、13.19、16.05、16.54、16.86、17.07、18.32、18.83、19.21、
21.00、21.63、21.70、22.28、22.85、23.14、23.74、24.56、25.12、26.53、27.50、27.87、
31.71, there is characteristic peak at 32.23,37.33 and 40.02, wherein the error range of 2 θ of each characteristic peak is ± 0.2.
In one embodiment of the invention, the A crystal forms of compound shown in a kind of formula (I) of present invention offer, feature
It is：Fusing point is 85 DEG C~98 DEG C, preferably 88.6 DEG C~92 DEG C, more preferably 90.23 DEG C.
The invention further relates to a kind of methods preparing A crystal forms, which is characterized in that the method includes：
(1) compound shown in formula (I) is dissolved in solvent, crystallization, is filtered, up to target A crystal forms after drying；
(2) compound shown in formula (I) is added in solvent, is beaten, filtering, up to target A crystal forms after drying；
The method of the crystallization is selected from volatilization crystallization, room temperature crystallization, cooling crystallization or crystal seed induction crystallization is added.
Solvent in method described in said program (1) is selected from esters, fat hydrocarbon, alcohols, ketone, nitrile or ethers；
The esters solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate；The alcohols solvent is selected from methanol, second
Alcohol, isopropanol, normal propyl alcohol, isoamyl alcohol or trifluoroethanol；The ketones solvent is selected from acetone, acetophenone, hexone
Or methyl pyrrolidone；The fat hydrocarbon solvent is selected from pentane, n-hexane or normal heptane；The alicyclic hydrocarbon type solvent is selected from ring
Pentane or hexamethylene；The nitrile solvents are selected from acetonitrile or propionitrile；The ether solvent is selected from tetrahydrofuran, ether, propylene glycol
Methyl ether or methyl tertiary butyl ether(MTBE).
Solvent in method described in said program (2) is selected from fat hydrocarbon, esters, ethers, alicyclic hydrocarbon type, halogenated hydrocarbons
The mixed solvent of class, nitrile, water or mixed solvent, preferably halogenated hydrocarbon, esters, nitrile or halogenated hydrocarbon and esters；
The arene is selected from benzene, toluene or dimethylbenzene；The halogenated hydrocarbon be selected from dichloromethane, chloroform, chlorobenzene or
Dichloro-benzenes；The mixed solvent of the halogenated hydrocarbon and the preferred dichloromethane of the mixed solvent of esters and ethyl acetate composition；It is described
Fat hydrocarbon solvent is selected from pentane, n-hexane or normal heptane；The esters solvent is selected from ethyl acetate, isopropyl acetate or acetic acid
Butyl ester；The alicyclic hydrocarbon type solvent is selected from pentamethylene or hexamethylene；The nitrile solvents are selected from acetonitrile or propionitrile；The ethers is molten
Agent is selected from tetrahydrofuran, ether, propylene glycol monomethyl ether or methyl tertiary butyl ether(MTBE).
The present invention further provides the pharmaceutical compositions of A crystal forms, it is characterised in that can pharmaceutically be connect comprising one or more
Carrier, diluent or the excipient received.
The present invention also provides the pharmaceutical compositions of A crystal forms, A crystal forms to swash with Opioid Receptors (MOR) in preparation treatment
Purposes in the drug for the relevant disease that dynamic agent mediates.
The relevant disease that MOR receptor stimulating agents of the present invention mediate is selected from pain, immune dysfunction, inflammation, oesophagus
Reflux, nerve and mental disease, uropoiesis and reproductive disease, angiocardiopathy and breathing problem, preferably pain.
The present invention also provides the pharmaceutical compositions of A crystal forms, A crystal forms to prepare prevention or treatment pain and pain related disorders
Drug in purposes.
Pain of the present invention is selected from pain, neuropathic pain, treatment of traumatic pain or inflammation caused by postoperative pain, cancer
Pain caused by disease.
Cancer of the present invention be selected from breast cancer, carcinoma of endometrium, cervical carcinoma, cutaneum carcinoma, prostate cancer, oophoroma,
Fallopian tube cneoplasms, ovarioncus, hemophilia and leukaemia.
The present invention also provides the pharmaceutical compositions of A crystal forms, A crystal forms to be used in preparing the drug of excitement or antagonism MOR receptors
On the way.
By X-ray powder diffraction collection (XRPD), differential scanning calorimetric analysis (DSC) to acquired formula (I) shownization
The A crystal forms for closing object carry out structure determination, crystal form research.
The method of A crystal forms recrystallization is not particularly limited, and can be carried out with common recrystallization operation method.For example, can
Anti-solvent crystallization is added after being dissolved in organic solvent with the compound shown in raw material formula (I), after the completion of crystallization, by being filtered dry
It is dry, you can to obtain required crystallization.
The method of crystallization of the present invention has volatilization crystallization, room temperature crystallization, cooling crystallization, addition crystal seed induction crystallization etc..
Starting material used in crystal form preparation method of the present invention can be compound shown in any form of formula (I), tool
Body form includes but not limited to：Amorphous, arbitrary crystal form etc..
Detailed description of the invention
In the description and claims of this application, unless otherwise stated, science used herein and skill
Art noun has the normally understood meaning of those skilled in the art institute.However, for a better understanding of the present invention, being provided below
The definition and explanation of part relational language.In addition, as the definition and explanation of term provided herein and people in the art
When the normally understood meaning of member institute is inconsistent, with the definition of term provided herein and it is construed to accurate.
" C of the present invention1-6Alkyl " indicates that the alkyl containing 1-6 carbon atom of linear chain or branched chain, specific example include
But it is not limited to：Methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tertiary butyl, n-pentyl, isopentyl, 2-
Methyl butyl, neopentyl, 1- ethyl propyls, n-hexyl, isohesyl, 3- methyl amyls, 2- methyl amyls, 1- methyl amyls, 3,
3- dimethylbutyls, 2,2- dimethylbutyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 1,3- dimethylbutyls, 2,3-
Dimethylbutyl, 2- ethyl-butyls, 1,2- dimethyl propyls etc..
" hydroxyl " of the present invention refers to the groups such as-OH.
" cyano " of the present invention refers to the groups such as-CN.
" ketones solvent " of the present invention refers to the compound that carbonyl (- C (O) -) is connected with two alkyl, according to molecule
The difference of middle alkyl, ketone can be divided into aliphatic ketone, alicyclic ketone, aromatic ketone, saturated ketone and beta-unsaturated ketone, and specific example includes but unlimited
In：Acetone, acetophenone, hexone or methyl pyrrolidone.
" esters solvent " of the present invention refers to the rudimentary organic acid and carbon atom quantity that carbon atom quantity is 1 to 4
For the conjugate of 1 to 6 lower alcohol, specific example includes but not limited to：Ethyl acetate, isopropyl acetate or butyl acetate.
" ether solvent " of the present invention refer to be 1 to 10 containing ehter bond-O- and carbon atom number chain compound
Or cyclic compound, specific example include but not limited to：Tetrahydrofuran, ether, propylene glycol monomethyl ether, methyl tertiary butyl ether(MTBE) or 1,4-
Dioxane.
" alcohols solvent " of the present invention refers to one or more " hydroxyl " substitution " C1-6One or more on alkyl "
Group derived from hydrogen atom, " hydroxyl " and " C1-6As defined hereinabove, specific example includes but not limited to alkyl "：First
Alcohol, ethyl alcohol, isopropanol, normal propyl alcohol, isoamyl alcohol or trifluoroethanol.
" nitrile solvents " of the present invention refer to one or more " cyano " substitution " C1-6One or more on alkyl "
Group derived from hydrogen atom, " cyano " and " C1-6As defined hereinabove, specific example includes but not limited to alkyl "：Second
Nitrile or propionitrile.
" fat hydrocarbon solvent " of the present invention refers to between carbon atom in aliphatic compound essential attribute, molecule
It is connected to chain carbon skeleton both ends and opens the hydrocarbon such as saturated fat hydro carbons that not cyclic and carbon atom number is 1-10,
Including alkane solvents, specific example includes but not limited to：Normal butane, pentane, n-hexane or normal heptane.
" alicyclic hydrocarbon type solvent " of the present invention refers to having cyclic annular carbon skeleton, and ring kin with aliphatic hydrocarbon
The hydrocarbon compound that atom number is 1-8, specific example include but not limited to：Pentamethylene or hexamethylene.
" aromatic hydrocarbon solvent " of the present invention refers to the conjugated system with closed hoop in molecule, п electron numbers symbol
It closes the carbocyclic compound of Huckel's rule and its general name of derivative, specific example includes but not limited to：Benzene, toluene, isopropyl
Benzene or dimethylbenzene.
" halogenated hydrocarbon solvent " of the present invention refers on one or more " halogen atoms " substitution alkyl or aryl
Group derived from one or more hydrogen atoms, specific example include but not limited to：Chloromethanes, dichloromethane, chloroform, four chlorinations
Carbon, chloroform, chlorobenzene or dichloro-benzenes.
" mixed solvent " of the present invention refers to that one or more different types of organic solvents mix according to a certain percentage
The solvent that solvent or organic solvent made of conjunction mix according to a certain percentage with water；The mixed solvent is preferably halogenated
The mixed solvent of hydrocarbon solvent and esters；The halogenated hydrocarbon solvent and the mixed solvent of esters are preferably dichloromethane and acetic acid
The mixed solvent of ethyl ester.
" X-ray powder diffraction collection or XRPD " of the present invention refers to according to bragg's formula 2d sin θs=n λ
(in formula, λ is the wavelength of X-ray,The series n of diffraction is any positive integer, generally takes first-order diffraction peak, n=
1), when X-ray is incident on a certain of crystal or partial crystals sample with sweep angle θ (complementary angle of incidence angle, also known as Bragg angle)
When on the atomic plane with d lattice plane spacing, Bragg equation can be met, to measure this group of X-ray powder diffraction
Figure.
" differential scanning calorimetric analysis or DSC " of the present invention refers to measuring sample in sample heating or thermostatic process
Temperature difference, differential heat flow between product and reference substance are obtained with characterizing all physical changes related with fuel factor and chemical change
The transformation information of sample.
" 2 θ or 2 θ angles " of the present invention refer to the angle of diffraction, and θ is Bragg angle, and unit is ° or degree the error model of 2 θ
It is ± 0.1~± 0.5, preferably ± 0.1~± 0.3 to enclose, more preferably ± 0.2.
" interplanar distance or interplanar distance (d values) " of the present invention refers to the company that space lattice selects 3 irrelevancy rows
Unit vector a, b, the c of two neighboring lattice point are tied, dot matrix is divided into juxtaposed parallelepiped unit, referred to as crystal face by them
Spacing.Space lattice is divided according to determining parallelepiped unit line, obtains a set of rectilinear grid, referred to as space lattice or
Lattice.Dot matrix and lattice are the periodicity for the Points And lines reflection crystal structure for using geometry respectively, different crystal faces, interplanar distance
(the distance between two i.e. adjacent parallel crystal faces) is different；Unit isOr angstrom.
The invention further relates to include the A crystal forms of formula (I) compound represented, and optional one or more medicinal loads
The pharmaceutical composition of body and/or diluent.Pharmaceutically acceptable any dosage form can be made in described pharmaceutical composition.For example,
The A crystal forms or pharmaceutical preparation of the present invention can be formulated as tablet, capsule, pill, granule, solution, suspension, syrup
Agent, injection (including injection, injection sterile powder and concentrated solution for injection), suppository, inhalant or spray.
In addition, pharmaceutical composition of the present invention can also with any suitable administering mode, such as oral, parenteral,
The modes such as rectum, transpulmonary or local administration are applied to the patient or subject for needing this treatment.When for being administered orally, institute
It states pharmaceutical composition and can be made into oral preparation, such as oral solid formulation, such as tablet, capsule, pill, granule；Or, mouth
Take liquid preparation, such as oral solution, oral suspensions, syrup.When oral preparation is made, the pharmaceutical preparation may be used also
Including suitable filler, adhesive, disintegrant, lubricant etc..When for parenteral administration, the pharmaceutical preparation can be made into
Injection, including injection, injection sterile powder and concentrated solution for injection.When injection is made, described pharmaceutical composition
The conventional method in existing pharmaceutical field can be used to be produced.It, can not in the pharmaceutical preparation when preparing injection
Additives are added, suitable additives can also be added according to the property of drug.When for rectally, the pharmaceutical preparation can
Suppository etc. is made.When for transpulmonary administration, the pharmaceutical preparation can be made into inhalant or spray etc..In certain preferred implementations
In scheme, A crystal forms of the invention are to treat and/or prevention effective dose is present in pharmaceutical composition or drug.Certain preferred
Embodiment in, A crystal forms of the invention are present in the form of unit dose in pharmaceutical composition or drug.
The A crystal forms of formula (I) compound of the present invention can be used for preparing treatment related with Opioid Receptors (MOR) agonist
Purposes in disease medicament.Therefore, the application further relates to, and the A crystal forms of formula (I) compound of the present invention are used to prepare the use of drug
On the way, the drug is used to treat the purposes in the drug of disease related with Opioid Receptors (MOR) agonist.This
Outside, the application further relates to, a method of inhibiting disease related with Opioid Receptors (MOR) agonist comprising
To subject in need's application treatment and/or the A crystal forms or this hair of the formula (I) compound of the present invention of prevention effective dose
Bright pharmaceutical composition.
In certain preferred aspects, the disease is related with Opioid Receptors (MOR) agonist
Disease is selected from pain.
Advantageous effect of the invention
Compared with prior art, technical scheme of the present invention has the following advantages：
Research has shown that the A crystal form dissolubilities of compound shown in formula (I) prepared by the present invention are excellent, purity is higher, in light
According to, under conditions of high temperature, high humidity crystal form do not change through XRPD detections, stability of crystal form it is good；HPLC purity variation it is small,
Chemical stability is high；The A crystal forms of compound shown in the formula (I) that technical solution of the present invention obtains disclosure satisfy that production and transport storage
Medicinal requirements, stable processing technique repeat controllably, can adapt in industrialized production.
Description of the drawings
Fig. 1 is the XRPD collection of illustrative plates of compound A crystal forms shown in formula (I).
Fig. 2 is the DSC collection of illustrative plates of compound A crystal forms shown in formula (I).
Fig. 3 is the TGA collection of illustrative plates of compound A crystal forms shown in formula (I).
Fig. 4 is the unbodied XRPD collection of illustrative plates of compound shown in formula (I).
Specific implementation mode
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is merely to illustrate the skill of the present invention
Art scheme, and non-limiting the spirit and scope of the invention.
Test the test condition of instrument：
1, differential scanning calorimeter (Differential Scanning Calorimeter, DSC)
Instrument model：Mettler Toledo DSC 3+ STARe System
Purge gass：Nitrogen
Heating rate：10.0℃/min
Temperature range：20-350℃
2, X-ray powder diffraction spectrum (X-ray Powder Diffraction, XRPD)
Instrument model：Rigaku UltimaIV X-ray powder diffraction instrument
Ray：Monochromatic Cu-K alpha rays
Scan mode：The θ of θ/2, scanning range：3-45°
Voltage：40kV, electric current：40mA
3, thermogravimetric analyzer (Thermogravimetric Analysis, TGA)
Instrument model：Mettler Toledo TGA2 STARe System
Purge gass：Nitrogen
Heating rate：10.0℃/min
Temperature range：20-250℃
Comparative example 1 (1S, 4S) -4- ethyoxyls-N- (2- ((R) -9- (pyridine -2- bases) -6- oxaspiros [4.5] decyl- 9- yls)
Ethyl) -1,2,3,4- naphthane -1- amine (compound 19 amorphous) preparation
The first step
(S) -1,2,3,4- naphthanes -1- t-butyl carbamates 11a
By (S) -1,2,3,4- tetrahydrochysenes-naphthalidine 10a (3g, 20.41mmol, using " Angewandte Chemie-
International Edition, 45 (28), method disclosed in 4641-4644,2006 " are prepared) it is dissolved in 100mL bis-
In chloromethanes, triethylamine (5.7mL, 40.82mmol) is added, di-tert-butyl dicarbonic acid ester (4.9g, 22.45mmol) is added, stirs
Mix reaction 12 hours.Reaction solution uses water (100mL), saturated sodium bicarbonate solution to wash (100mL) successively, the anhydrous sulphur of organic phase
Sour sodium drying, filtering, filtrate decompression concentration obtain crude title product 11a (5.6g, pale yellow oil), product is without pure
Change and directly carries out the next step.
MS m/z(ESI):248.3[M+1]
Second step
(S) -4- carbonyls -1,2,3,4- naphthanes -1- t-butyl carbamates 11b
By crude product (S) -1,2,3,4- naphthane -1- t-butyl carbamates 11a (5.6g, 20.41mmol) are dissolved in
90mL acetone and water (V/V=2:1) in the mixed solvent is added magnesium sulfate (5.5g, 45.66mmol), height is slowly added under stirring
Potassium manganate (7.22g, 45.66mmol) is stirred to react 12 hours.Reaction solution is concentrated under reduced pressure, with silica gel column chromatography with n-hexane
It is residue obtained by eluent with ethyl acetate, obtains title product 11b (3.1g, off-white powder), yield：52%.
MS m/z(ESI):262.3[M+1]
Third walks
(1S, 4S) -4- hydroxyl -1,2,3,4- naphthane -1- t-butyl carbamates 14a
By (S) -4- carbonyls -1,2,3,4- naphthane -1- t-butyl carbamates 11b (100mg, 0.883mmol) dissolvings
In 5mL toluene, it is cooled to 0 DEG C, (R) -2- methyl-CBS- oxazaborolidines (0.1ml, 0.076mmol) are added, is stirred 5 minutes,
Borine Dimethyl sulfide (0.88ml, 0.76mmol) is added, is stirred to react 2 hours.50ml saturated nacl aqueous solutions are added to be quenched instead
It answers, is extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase washs (30mL × 3), nothing with saturated nacl aqueous solution
Aqueous sodium persulfate is dried, filtering, filtrate decompression concentration, residual using dichloromethane and methanol as eluent gained with thin-layered chromatography
Excess obtains title product 14a (60mg, white solid), yield 60%.
MS m/z(ESI):208.3[M-55]
4th step
(1S, 4S) -4- ethyoxyl -1,2,3,4- naphthane -1- t-butyl carbamates 19a
By crude product (1S) -4- hydroxyls -1,2,3,4- naphthane -1- t-butyl carbamates 14a (850mg, 3.23mmol),
Silver oxide (76mg, 0.33mmol) and iodoethane (1.3mL, 16.15mmol) are dissolved in dichloromethane (30mL), are stirred to react
48 hours.Filtering, filtrate decompression concentration, obtains crude title product 19a (800mg, yellow oil), product is straight without further purification
Tap into row the next step.
MS m/z(ESI):236.1[M-55]
5th step
(1S, 4S) -4- ethyoxyl -1,2,3,4- naphthane -1- amine 19b
Crude Compound 19a (698mg, 2.4mmol) is dissolved in 4mL dichloromethane, 8mL 4M hydrogen chloride is added
Isosorbide-5-Nitrae-dioxane solution is stirred to react 2 hours.Reaction solution is concentrated under reduced pressure, and ethyl acetate is beaten (30mL), filtering, and filter cake is molten
In dichloromethane and methanol (20mL, V:V=5:1) in the mixed solvent, it is 7 to adjust reaction solution pH with saturated sodium bicarbonate solution
~8, reaction solution is concentrated under reduced pressure, with dichloromethane and methanol (V:V=5:1) mixed solvent washing (30mL × 2), is filtered, filter
Liquid is concentrated under reduced pressure, and obtains crude title product 19b (310mg, yellow liquid), product directly carries out the next step without further purification.
MS m/z(ESI):191.1[M+1]
6th step
(1S, 4S) -4- ethyoxyls-N- (2- ((R) -9- (pyridine -2- bases) -6- oxaspiros [4.5] decane -9- bases) second
Base) -1,2,3,4- tetrahydrochysenes
Naphthalene -1- amine 19
By (R) -2- (9- (pyridine -2- bases) -6- oxaspiros [4.5] decane -9- bases) acetaldehyde 5a (500mg, 1.85mmol,
It is prepared using method disclosed in patent application " WO2012129495 "), crude Compound 19b (310mg, 1.85mmol) is molten
Solution is stirred to react 40 minutes in dichloroethanes (30mL), and sodium triacetoxy borohydride (980mg, 4.63mmol) is added, stirs
Mix reaction 2 hours.Saturated sodium bicarbonate solution (30mL × 3) is used successively, washs (30mL × 3) with saturated nacl aqueous solution, has
Machine is mutually dried with anhydrous sodium sulfate, filtering, filtrate decompression concentration, pure using dichloromethane and methanol as eluant, eluent with thin-layered chromatography
Change gained residue, obtains title product 19 (280mg, clear yellow viscous solid), yield：35%.
It is amorphous to detect the clear yellow viscous solid through XRPD, which sees Fig. 4.
Embodiment 1
By (1S, 4S) -4- ethyoxyls-N- (2- ((R) -9- (pyridine -2- bases) -6- oxaspiros [4.5] decyl- 9- yls) second
Base) -1,2,3,4- naphthane -1- amine (100mg) are placed in a reaction flask, ethyl acetate (0.1mL) is added into reaction bulb, from 25
It DEG C is rapidly heated to 50 DEG C and to make it dissolve, after being kept for a period of time, slow cooling is to 5 DEG C, and filtering, dry, yield 80% should
The XRPD collection of illustrative plates of crystallized sample is shown in that Fig. 1, DSC spectrograms are shown in that Fig. 2, initial fusion temperature are 88.67 DEG C, and peak value is about 90.23 DEG C,
Its characteristic peak positions is as shown in the table：
Table 1, A crystal form characteristic peaks
Embodiment 2
By (1S, 4S) -4- ethyoxyls-N- (2- ((R) -9- (pyridine -2- bases) -6- oxaspiros [4.5] decyl- 9- yls) second
Base) -1,2,3,4- naphthane -1- amine (100mg) are placed in a reaction flask, and ethyl alcohol (0.1mL) is added, is rapidly heated from 25 DEG C to 50
It DEG C makes it dissolve, after being kept for a period of time, slow cooling is to 25 DEG C, if being precipitated without crystal, can add a small amount of crystal seed induction
Crystallization, then slow cooling filter to 5 DEG C, are dry, yield 70%.Sample is characterized in 6.08 through X-ray powder diffraction,
11.02,12.01,12.21,17.11,18.38,18.81,19.19,20.94,22.26,22.79,24.61,27.52 and
There is characteristic peak at 37.34, determines that product is A crystal forms.
Embodiment 3
By (1S, 4S) -4- ethyoxyls-N- (2- ((R) -9- (pyridine -2- bases) -6- oxaspiros [4.5] decyl- 9- yls) second
Base) -1,2,3,4- naphthane -1- amine (10mg) are placed in a reaction flask, acetophenone (0.5mL) is added.Reaction bulb is placed in ventilation
It is volatilized in cupboard, collects the solid in sample bottle.Sample is characterized in 5.97 through X-ray powder diffraction, 6.07,11.25,12.13,
13.16、16.08、16.59、16.84、17.16、18.30、18.80、19.22、20.98、21.65、21.92、22.25、
22.84, there is characteristic peak at 23.18,23.72,24.53,25.11,26.56,27.49,27.84,31.68,32.21 and 37.28,
Determine that product is A crystal forms.
Embodiment 4
By (1S, 4S) -4- ethyoxyls-N- (2- ((R) -9- (pyridine -2- bases) -6- oxaspiros [4.5] decyl- 9- yls) second
Base) -1,2,3,4- naphthane -1- amine (100mg) are placed in a reaction flask, and acetonitrile (0.1mL) is added, is rapidly heated from 25 DEG C to 50
It DEG C makes it dissolve, after being kept for a period of time, slow cooling is to 25 DEG C, if being precipitated without crystal, can add a small amount of crystal seed induction
Crystallization, then slow cooling filter to 5 DEG C, are dry, yield 70%.Sample is characterized in 6.05 through X-ray powder diffraction,
11.24、11.89、12.14、12.24、12.98、13.18、16.05、16.79、17.22、18.35、18.85、19.25、
20.94, have at 21.58,21.87,22.27,22.76,22.89,24.59,27.51,27.85,31.69,32.31 and 37.32
Characteristic peak determines that product is A crystal forms.
Embodiment 5
By (1S, 4S) -4- ethyoxyls-N- (2- ((R) -9- (pyridine -2- bases) -6- oxaspiros [4.5] decyl- 9- yls) second
Base) -1,2,3,4- naphthane -1- amine (10mg) are placed in a reaction flask, and n-hexane (0.1mL) is added, it is beaten 48 hours at room temperature,
Filtering, drying.Sample is characterized through X-ray powder diffraction, determines that product is A crystal forms.
Embodiment 6
By (1S, 4S) -4- ethyoxyls-N- (2- ((R) -9- (pyridine -2- bases) -6- oxaspiros [4.5] decyl- 9- yls) second
Base) -1,2,3,4- naphthane -1- amine (10mg) are placed in a reaction flask, and propylene glycol monomethyl ether (0.5mL) is added, volatilizes at room temperature, it receives
Collect solid.Sample is characterized through X-ray powder diffraction, determines that product is A crystal forms.
Embodiment 7, A crystal form influence factor study on the stability
The A crystal form samples openings of the gained of embodiment 1 are divided into placements, investigation illumination (4500Lux), high temperature (40 DEG C, 60
DEG C), under the conditions of high humidity (RH75%, RH90%) sample stability, it is 5 days and 10 days to investigate sample time, and HPLC detects pure
Degree result see the table below.
Test result：
Table 2, high temperature experimental result
The expression of short-term "-" does not detect.
Table 3, high humidity experimental result
The expression of short-term "-" does not detect.
Table 4, illumination experiment result
The expression of short-term "-" does not detect.
Conclusion (of pressure testing)
It is shown by the study on the stability result of table 2, table 3, table 4：
For crystal form A of the present invention under the conditions of illumination, high humidity, high temperature opening are placed, temperature is higher, the time is longer, crystal form color
It changes, impurity and enantiomter impurity increase；Light application time is longer, and impurity and enantiomter impurity increase；In height
Crystal form is more stable under the conditions of wet；XRPD detections crystal form under the conditions of illumination, high humidity, high temperature opening are placed does not change,
Illustrate that the A stability of crystal form of the present invention is good.
Embodiment 8, A crystal forms are long-term, accelerated stability is investigated
The crystal form A samples of 1 gained of embodiment are protected from light, seals and divides placement, investigates at long-term (25 DEG C, 60%RH) and adds
The stability of sample under fast (40 DEG C, 75%RH), it is 0.5 month, 1 month, 2 months, 3 months to investigate sample time, XRPD inspections
Survey whether crystal form changes.
Experimental result：
The stability (HPLC purity) of table 5, A crystal form samples
Conclusion (of pressure testing)：
The crystal form A of the gained of embodiment 1 is being protected from light, seal, long-term (25 DEG C, 60%RH), acceleration (40 DEG C, 75%
RH it places 3 months and has good stability under the conditions of), while the XRPD peak types of A crystal forms do not change, stable crystal form.
Claims (9)
1. the A crystal forms of compound shown in formula (I), it is characterised in that：It is radiated using Cu-K α, obtains indicating with 2 θ angles of the angle of diffraction
X-ray powder diffraction collection, 2 angles θ of the angle of diffraction 6.01,6.09,11.23,11.33,12.14,12.23,13.19,
16.86, there is characteristic peak at 17.07,19.21,21.00,22.85,23.14 and 24.56, wherein the error of 2 θ of each characteristic peak
Ranging from ± 0.2,
2. A crystal forms according to claim 1, which is characterized in that 2 angles θ of the angle of diffraction 6.01,6.09,11.23,
11.33、12.14、12.23、12.46、13.19、16.05、16.54、16.86、17.07、18.32、18.83、19.21、
21.00, there is characteristic peak at 21.63,21.70,22.28,22.85,23.14,23.74,24.56,26.53 and 31.71, wherein
The error range of 2 θ of each characteristic peak is ± 0.2.
3. A crystal forms according to claim 2, which is characterized in that 2 angles θ of the angle of diffraction 6.01,6.09,8.43,
11.23、11.33、12.14、12.23、12.46、12.94、13.19、16.05、16.54、16.86、17.07、18.32、
18.83、19.21、21.00、21.63、21.70、22.28、22.85、23.14、23.74、24.56、25.12、26.53、
27.50, there is characteristic peak at 27.87,31.71,32.23,37.33 and 40.02, wherein the error range of 2 θ of each characteristic peak is
±0.2。
4. a kind of method preparing the A crystal forms as described in any one of claim 1-3, which is characterized in that the method includes：
(1) compound shown in formula (I) is dissolved in solvent, crystallization, is filtered, up to target A crystal forms, the crystallization side after drying
Crystal seed induction crystallization is added in the preferred room temperature crystallization of method, cooling crystallization, volatilization crystallization；
(2) compound shown in formula (I) is added in solvent, is beaten, filtering, up to target A crystal forms after drying.
5. method as claimed in claim 4, which is characterized in that solvent in the method (1) be selected from esters, fat hydrocarbon,
Alcohols, ketone, nitrile or ethers；
The esters solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate；The alcohols solvent be selected from methanol, ethyl alcohol,
Isopropanol, normal propyl alcohol, isoamyl alcohol or trifluoroethanol；The ketones solvent is selected from acetone, acetophenone, hexone or first
Base pyrrolidones；The fat hydrocarbon solvent is selected from pentane, n-hexane or normal heptane；The alicyclic hydrocarbon type solvent is selected from pentamethylene
Or hexamethylene；The nitrile solvents are selected from acetonitrile or propionitrile；The ether solvent is selected from tetrahydrofuran, ether, propylene glycol monomethyl ether
Or methyl tertiary butyl ether(MTBE).
6. method as claimed in claim 4, which is characterized in that solvent in the method (2) be selected from fat hydrocarbon, esters,
Ethers, alicyclic hydrocarbon type, halogenated hydrocarbon, nitrile, water or mixed solvent, preferably halogenated hydrocarbon, esters, nitrile or halogenated hydrocarbon and ester
The mixed solvent of class；
The arene is selected from benzene, toluene or dimethylbenzene；The halogenated hydrocarbon is selected from dichloromethane, chloroform, chlorobenzene or dichloro
Benzene；The mixed solvent of the halogenated hydrocarbon and the preferred dichloromethane of the mixed solvent of esters and ethyl acetate composition；The fat
Hydrocarbon solvent is selected from pentane, n-hexane or normal heptane；The esters solvent is selected from ethyl acetate, isopropyl acetate or acetic acid fourth
Ester；The alicyclic hydrocarbon type solvent is selected from pentamethylene or hexamethylene；The nitrile solvents are selected from acetonitrile or propionitrile；The ether solvent
Selected from tetrahydrofuran, ether, propylene glycol monomethyl ether or methyl tertiary butyl ether(MTBE).
7. the pharmaceutical composition containing any one of the claim 1-3 A crystal forms, it is characterised in that include one or more medicines
Acceptable carrier, diluent or excipient on.
8. the pharmaceutical composition containing A crystal forms described in claim 1-3 any one of them A crystal forms, claim 7 is controlled in preparation
Treat the purposes in the drug of the relevant disease mediated with Opioid Receptors (MOR) agonist.
9. purposes according to claim 8, wherein the relevant disease that the MOR receptor stimulating agents mediate is selected from pain, exempts from
Epidemic disease dysfunction, inflammation, esophageal reflux, nerve and mental disease, uropoiesis and reproductive disease, angiocardiopathy and respiratory tract disease
Disease, preferably pain.
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| CN111303097B (en) * | 2018-12-12 | 2022-09-30 | 天津尚德药缘科技股份有限公司 | Crystal form C of michelia lactone fumarate dimethylamine and preparation method thereof |
| CN113227096A (en) * | 2019-01-25 | 2021-08-06 | 江苏恒瑞医药股份有限公司 | Crystal form of 1,2, 3-triazole [1,5-a ] pyrazine derivative and preparation method thereof |
| CN113227096B (en) * | 2019-01-25 | 2022-04-12 | 江苏恒瑞医药股份有限公司 | Crystal form of 1,2, 3-triazole [1,5-a ] pyrazine derivative and preparation method thereof |
| CN111662284A (en) * | 2019-03-06 | 2020-09-15 | 上海海雁医药科技有限公司 | Biheterocyclic substituted oxaspiro derivative, preparation method and medical application thereof |
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