CN108047199B - A kind of thiazole spirocyclopropane skeleton object and its crystal and preparation method - Google Patents
A kind of thiazole spirocyclopropane skeleton object and its crystal and preparation method Download PDFInfo
- Publication number
- CN108047199B CN108047199B CN201711388943.6A CN201711388943A CN108047199B CN 108047199 B CN108047199 B CN 108047199B CN 201711388943 A CN201711388943 A CN 201711388943A CN 108047199 B CN108047199 B CN 108047199B
- Authority
- CN
- China
- Prior art keywords
- crystal
- preparation
- compound
- spirocyclopropane
- thiazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a kind of thiazole spirocyclopropane skeleton object and its crystal and preparation method, structural formula are as follows:
Description
Technical field
The invention belongs to organic synthesis fields, and in particular to a kind of thiazole spirocyclopropane skeleton object and its crystal and preparation side
Method.
Background technique
Thiazole spirocyclopropane skeleton is widely present in natural products, in synthetic drug, and correlative study shows to contain the skeleton
Compound have a variety of important bioactivity and pharmaceutical activity, be with a wide range of applications.
For same compound, it will usually there are two types of or a variety of different crystalline states, and different crystal forms is then
It would generally show different bioavilabilities, dissolution rate, rate of dissolution, stability, fusing point, color, filtrability, density and stream
Dynamic property etc..Therefore, it develops dissolubility and the better crystal form of stability has very important significance.
Summary of the invention
The technical problems to be solved by the invention are as follows: how a kind of new thiazole spirocyclopropane skeleton object and its crystal are provided
And preparation method.
The technical solution of the present invention is as follows: a kind of compound, shown in structural formula such as formula (1):
Formula (1) compound the preparation method is as follows: taking (5R, 6R, 7R) -6-benzyl-6-chloro-7- (4-
Chlorophenyl) -2-phenyl-6,7-dihydro-5H-pyrano [2,3-d] thiazol-5-ol, using acetonitrile as solvent,
1,8- diazabicylo, 11 carbon -7- alkene is added as catalyst, reacts at room temperature to obtain the final product.
Further, the molar ratio of 1,8- diazabicylo, 11 carbon -7- alkene and acetonitrile is 5 ︰ 95.
A kind of crystal of formula (1) compound, the crystal form of the crystal are orthorhombic system, space group P212121, cell parameter
For9.1647 (3),13.1993 (4),17.5575 (4), α/°: 90, β/°: 90, γ/°: 90, unit cell volume
For 2123.90 (11), the fusing point of crystal form is 143-147 DEG C.
The preparation method of the crystal of formula (1) compound, the compound of modus ponens (1), in petroleum ether-ethyl acetate system often
Temperature volatilization crystallizes to obtain the final product, wherein in petroleum ether-ethyl acetate system, petroleum ether content is 80-90%v/v.
Application of the crystal of formula (1) compound or formula (1) compound in antibacterial.
Compared with prior art, the invention has the following advantages:
Present invention obtains a kind of new compounds, with thiazole spirocyclopropane skeleton structure, the experimental results showed that, it should
New compound all has preliminary resist to Escherichia coli, pseudomonas aeruginosa, enterococcus faecalis and staphylococcus aureus etc.
Bacterium activity.
Detailed description of the invention
Fig. 1 is the molecule stereo structure figure of the compounds of this invention.
Specific embodiment
The preparation of 1 compound of embodiment
The synthetic route of the compound is as follows:
In reaction tube, (5R, 6R, 7R) -6-benzyl-6-chloro-7- (4-chlorophenyl)-is sequentially added
2-phenyl-6,7-dihydro-5H-pyrano [2,3-d] thiazol-5-ol (1a), the DBU of solvent acetonitrile and catalytic amount
(1,8- diazabicylo, 11 carbon -7- alkene), is stirred at room temperature, is monitored and is reacted with TLC method, after complete reaction that reaction solution is dense
Contracting, obtains final product (2a) with silica gel column separating purification (PE:EA=35:1).
Method particularly includes:
Take (5R, 6R, 7R) -6-benzyl-6-chloro-7- (4-chlorophenyl) -2-phenyl-6,7-
Using acetonitrile as solvent 5mol%DBU is added, at room temperature instead in dihydro-5H-pyrano [2,3-d] thiazol-5-ol (1a)
It answers, to which reaction dissolvent after reaction, is removed under reduced pressure, silicagel column on residue, petroleum ether: ethyl acetate=35:1 is eluted, thin
Layer tracking, merges eluent, removes solvent, gained purified is up to formula (1) final product (2a).
The preparation of 2 compound crystal form of embodiment
Formula (1) compound prepared by Example 1 delays under room temperature in petroleum ether-ethyl acetate (90%:10%v/v)
Slow vaporization crystallization, obtains the monocrystalline of formula (1), ee value > 99%.
Formula (1) compound prepared by Example 1, at 25 DEG C, in petroleum ether-ethyl acetate (80%:20%v/v)
Slowly volatilization crystallization, obtains the monocrystalline of formula (1), ee value > 99% under room temperature.
3 structure detection of embodiment
Formula (1) compound represented prepared by Example 1 carries out nuclear magnetic resonance and Mass Spectrometer Method, as a result as follows:
1H NMR(400MHz,DMSO-d6):δ(ppm):9.28(s,1H),8.22–8.14(m,2H),7.74–7.67(m,
1H),7.58–7.52(m,2H),7.38–7.30(m,5H),7.27–7.23(m,2H),6.95–6.89(m,2H),3.76(s,
1H), 3.70 (d, J=14.8Hz, 1H), 3.56 (d, J=14.8Hz, 1H)
13C NMR(100MHz,DMSO-d6):δ(ppm):198.5,193.7,188.1,138.5,135.5,132.5,
131.8,130.9,129.6,128.8,128.3,126.6,125.0,51.4,49.4,43.7,29.8.
HRMS(ESI):m/z calculated for C25H19NO2SNa+:420.1034,found:420.1035.
The monocrystalline that Example 2 obtains carries out single crystal diffraction, and crystal structural data is as shown in table 1 below:
The single crystal diffraction data of 1 formula of table (1) compound
The compound molecule stereochemical structure finally confirmed is as shown in Figure 1.
Test example 1, antibacterial activity research
Using the antibacterial activity of each compound of equimultiple Dilution.The crystal of the invention of equivalent will be accurately weighed first
It uses 2ml DMSO to dissolve respectively with lavo-ofloxacin, does 10 concentration gradients respectively by equimultiple dilution method, each gradient is to MH
1ml is added in culture dish and contains drug solns, and is mixed with 14ml MH solid medium, is made into the different culture dish of drug containing.Then it uses
The bacterium solution that bacteria containing amount is 106 is inoculated on culture dish by the punch in 27 holes, is put into 37 DEG C of constant incubator, cultivates 18-
For 24 hours, whether observation inoculation position has bacterial growth, to judge its fungistatic effect.The results are shown in Table 1:
The measurement of the antibacterial activity MIC (mg/ml) of the crystal of the invention of table 2
Note: the above-mentioned bacterial strain used, both from clinical separation strain.
By above-mentioned test it is found that crystalline compounds provided by the invention have certain antibacterial activity.
Test example 2, the stability of crystal form of the present invention and hygroscopicity are investigated
1, stability
Crystalline compounds of the invention are put into stability test case and carry out accelerated test, experimental condition are as follows: temperature, 40
℃±2℃；Humidity, RH75% ± 5%, time are 3 months.As a result: being measured using TLC and HPLC, find crystalline substance of the invention
Significant change does not occur for body compound, illustrates that stability of crystal form of the present invention is good.
2, hygroscopicity
Using 2010 editions second annex XIX J drug draws moist test guidelines of Pharmacopoeia of People's Republic of China, survey
It is as follows to determine result:
3 hygroscopicity of table is investigated
| Used time (day) | 0 | 5 | 10 | 15 |
| Compound draws wet weight gain | 1.8% | 1.9% | 1.9% | 1.9% |
Upper table the result shows that, this crystal of the invention is placed 15 days in wet condition, draws unobvious, the explanation of wet weight gain
Crystal form of the present invention effectively can avoid compound moisture absorption from deliquescing.
The specific embodiment of the application above described embodiment only expresses, the description thereof is more specific and detailed, but simultaneously
The limitation to the application protection scope therefore cannot be interpreted as.It should be pointed out that for those of ordinary skill in the art
For, under the premise of not departing from technical scheme design, various modifications and improvements can be made, these belong to this
The protection scope of application.
Claims (6)
1. a kind of compound, which is characterized in that shown in structural formula such as formula (1):
2. the preparation method of compound according to claim 1, which is characterized in that take (5R, 6R, 7R) -6-benzyl-6-
Chloro-7- (4-chlorophenyl) -2-phenyl-6,7-dihydro-5H-pyrano [2,3-d] thiazol-5-ol,
Using acetonitrile as solvent, 1,8- diazabicylo, 11 carbon -7- alkene is added as catalyst, reacts at room temperature to obtain the final product.
3. a kind of preparation method of compound according to claim 2, which is characterized in that 1,8- diazabicylo 11
The molar ratio of carbon -7- alkene and acetonitrile is 5 ︰ 95.
4. the crystal of compound according to claim 1, which is characterized in that the crystal form of the crystal is orthorhombic system, space
Group is P212121, cell parameter is9.1647 (3),13.1993 (4),17.5575 (4), α/°: 90, β/°:
90, γ/°: 90, unit cell volume is 2123.90 (11), and the fusing point of crystal form is 143-147 DEG C.
5. the preparation method of the crystal of compound according to claim 4, which is characterized in that the compound of modus ponens (1),
Room temperature volatilization crystallizes in petroleum ether-ethyl acetate system to obtain the final product, wherein in petroleum ether-ethyl acetate system, petroleum ether content is
80-90%v/v.
6. the application of compound according to claim 1 or crystal as claimed in claim 4 in antibacterial.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711388943.6A CN108047199B (en) | 2017-12-21 | 2017-12-21 | A kind of thiazole spirocyclopropane skeleton object and its crystal and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711388943.6A CN108047199B (en) | 2017-12-21 | 2017-12-21 | A kind of thiazole spirocyclopropane skeleton object and its crystal and preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108047199A CN108047199A (en) | 2018-05-18 |
| CN108047199B true CN108047199B (en) | 2019-09-03 |
Family
ID=62130697
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711388943.6A Active CN108047199B (en) | 2017-12-21 | 2017-12-21 | A kind of thiazole spirocyclopropane skeleton object and its crystal and preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108047199B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497182A (en) * | 2013-10-25 | 2014-01-08 | 南开大学 | 3,4-dichloro isothiazole derivative containing 4,5-dihydro thiazole alkyd resin and preparation method and application thereof |
| CN105658059A (en) * | 2013-10-22 | 2016-06-08 | 美国陶氏益农公司 | Pesticidal compositions and related methods |
-
2017
- 2017-12-21 CN CN201711388943.6A patent/CN108047199B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105658059A (en) * | 2013-10-22 | 2016-06-08 | 美国陶氏益农公司 | Pesticidal compositions and related methods |
| CN103497182A (en) * | 2013-10-25 | 2014-01-08 | 南开大学 | 3,4-dichloro isothiazole derivative containing 4,5-dihydro thiazole alkyd resin and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108047199A (en) | 2018-05-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106361706B (en) | Cefuroxime sodium for injection powder injection formulation | |
| CN107903260B (en) | A kind of indoles and dihydropyridine ketone compound and its crystal form and preparation method | |
| CN108047199B (en) | A kind of thiazole spirocyclopropane skeleton object and its crystal and preparation method | |
| CN110003131B (en) | Crystal form of tri-substituted thiazole compound and preparation method thereof | |
| CN107880059B (en) | A kind of thiazole and dihydro quaternary carbon pyrans skeleton object and its crystal and preparation method | |
| KR20020008155A (en) | Novel Ribose-Substituted Aromatic Amides, Method for the Production and Use Thereof as Medicaments | |
| CN104530082B (en) | Cefathiamidine compound | |
| CN108033897B (en) | Naphthalic hydrazide compound and preparation method thereof | |
| EP2081926B1 (en) | Preparation and purification of mupirocin calcium | |
| CN107973803B (en) | Seven-membered lactonofuran derivative and preparation method and application thereof | |
| CN108047237B (en) | A kind of oxinane [2,3-b] indoles skeleton object and its crystal and preparation method and purposes | |
| CN107954964B (en) | One kind 3,4,6 3 substitution-α-pyrone derivative and its preparation method and application | |
| CN110002996B (en) | Diphenyl ether compound and preparation method and application thereof | |
| CN109956896B (en) | Spiro [ cyclopropane-1, 3-indoline ] framework, crystal thereof, preparation method and application thereof | |
| CN107954860B (en) | Succinic acid derivative and preparation method and application thereof | |
| CN103880788B (en) | A kind of crystal formation of furans lactonic ring analog derivative | |
| EP0075449A1 (en) | Penicillin derivatives | |
| CN112480146B (en) | Cefuroxime acid mixed solvate, crystal form and preparation method | |
| CN115124544B (en) | Spiro [ tetrahydrofuran-3, 3' -indoline ] framework and crystal form thereof, and preparation method and application thereof | |
| CN116836164A (en) | 2-indoline imine spiro-pyrrolidone compound and crystal form, preparation method and application thereof | |
| CN107954965B (en) | A kind of gamma-pyrone derivative and its preparation method and application | |
| CN103601663B (en) | Tryptamine derivative compound and preparation method and application thereof | |
| CN117820283A (en) | Spherical pore sponge-derived peroxy ring compound, and preparation method and application thereof | |
| CN116462675A (en) | Berberine derivative and preparation method and application thereof | |
| CN116969874A (en) | 2-p-methylphenyl-3-trifluoroethyl indole compound and crystal form, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210415 Address after: 610100 waidong Shiling Town, Longquanyi District, Chengdu City, Sichuan Province Patentee after: CHENGDU University Address before: No.168, Huaguan Road, Longtan headquarters economic city, Chenghua District, Chengdu, Sichuan 610052 Patentee before: SICHUAN INDUSTRIAL INSTITUTE OF ANTIBIOTICS, CHINA NATIONAL PHARMACEUTICAL Group Corp. |
|
| TR01 | Transfer of patent right |