CN107814797A - The recovery preparation method of racemization pyrrole quinoline amine - Google Patents
The recovery preparation method of racemization pyrrole quinoline amine Download PDFInfo
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- CN107814797A CN107814797A CN201610819578.9A CN201610819578A CN107814797A CN 107814797 A CN107814797 A CN 107814797A CN 201610819578 A CN201610819578 A CN 201610819578A CN 107814797 A CN107814797 A CN 107814797A
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- pyrrole quinoline
- racemization
- quinoline amine
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- 0 C(*1)[C@](c2ccccc2)N*11C=CC=C1 Chemical compound C(*1)[C@](c2ccccc2)N*11C=CC=C1 0.000 description 10
- BHHGXPLMPWCGHP-UHFFFAOYSA-N NCCc1ccccc1 Chemical compound NCCc1ccccc1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- XWXZBLWPMMPLJS-UHFFFAOYSA-N O=C(Cc1ccccc1)NCC(c1ccccc1CC1)N1C(CCl)=O Chemical compound O=C(Cc1ccccc1)NCC(c1ccccc1CC1)N1C(CCl)=O XWXZBLWPMMPLJS-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N O=C(c1ccccc1)Cl Chemical compound O=C(c1ccccc1)Cl PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- NAFKORXBGRILHW-UHFFFAOYSA-N O=C(c1ccccc1)NCC1NCCc2c1cccc2 Chemical compound O=C(c1ccccc1)NCC1NCCc2c1cccc2 NAFKORXBGRILHW-UHFFFAOYSA-N 0.000 description 1
- OQXIETWSFRQXPP-UHFFFAOYSA-N OC(c1c2cccc1)N(CCC(Cl)=O)C2=O Chemical compound OC(c1c2cccc1)N(CCC(Cl)=O)C2=O OQXIETWSFRQXPP-UHFFFAOYSA-N 0.000 description 1
- NPEAUIYDEKCCHA-UHFFFAOYSA-N OC1(C(CN(C(c2c3cccc2)=O)C3=O)C1)NCCc1ccccc1 Chemical compound OC1(C(CN(C(c2c3cccc2)=O)C3=O)C1)NCCc1ccccc1 NPEAUIYDEKCCHA-UHFFFAOYSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N c1ccccc1 Chemical compound c1ccccc1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B55/00—Racemisation; Complete or partial inversion
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of recovery preparation method of racemization pyrrole quinoline amine 1, it is dissolved in using waste material S pyrrole quinoline amine intermediate 1 as initiation material in solvent, in the presence of the hydrogen of catalyst and certain pressure, react at moderate temperatures, the pyrrole quinoline amine intermediate 1 of raceme is prepared.The present invention by by unwanted configuration pyrrole quinoline amine S 1 in high yield efficiently, simple operation, fully recycle obtained raceme compound 1, levo-praziquantel is prepared by Split Method being utilized again, so as to turn waste into wealth, the manufacturing cost of levo-praziquantel is greatly saved.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, and in particular to the pharmaceutical intermediate of pest-resistant medicine-levo-praziquantel-racemization pyrrole quinoline
The recovery preparation method of amine.
Background technology
Praziquantel (Praziquantel) is a kind of broad spectrum activity medicine for parasitic disease, suitable for Japanese schistosomiasis, angstrom
And snail fever, Manson's schistosomiasis, paragonimiasis (paragonimiasis), clonorchiasis, echinococcosis, cysticercosis, Meng Shi
Sparganosis, fasciolopsiasis, the treatment for forming parasitosis etc., the treatment of the Japanese schistosomiasis that is particularly suitable for use in and clonorchiasis.
After Germany takes the lead in listing with trade name " Cesol ", the verminotic choice drug for the treatment of is quickly become within 1980.
Raceme praziquantel dosage is big, and adverse reaction is obvious.Document report, levo-praziquantel (R-3) are the effective of desinsection
Composition, curative effect is better than raceme, and dextrorotation praziquantel (S-3) is then nearly unavailable, and has certain toxic side effect.Levo-praziquantel
Have the advantages that dosage is small, curative effect is higher and adverse reaction is lighter.
At present, the problem of synthesis of the scientific circles to levo-praziquantel has made intensive studies, be primarily present is that cost occupies height
, can not industrialized production under not.Therefore, exploitation levo-praziquantel has important economic and social benefit.
According to the literature, the synthesis of levo-praziquantel is broadly divided into two class methods：
(1) its unique chiral centre of chiral asymmetric syntheses, the method use expensive chiral catalyst or chiral auxiliary,
Total recovery is low, and cost is higher, can not industrialized production.
For example, document Tetrahedron：Asymmetry, 17 (2006), the left-handed pyrrole of synthesis that p1415-1419 is reported
The method of quinoline ketone mainly used Noyori chiral catalysts to build chiral centre, specifically, using Bischler-
Napieralski reaction structure 3,4- dihydro-isoquinoline rings, then using Noyori catalyst catalytic asymmetric reduction imines, build
Vertical chiral centre.The step key uses the chiral catalyst of costliness, and reaction yield is only 52%, and optical purity is only 62%
ee.And the route total recovery is relatively low, cost of material is high, it is difficult to large-scale production, the specific following route one of synthesized reference.
Document Journal of Chemical Research；nb.3；(2004)；P186-187 report method be：First
Chiral auxiliary (R)-p-tolysulfinyl is introduced, then structure tetrahydroisoquinoline ring is reacted by Pictet-Spengler, so as to
Induce chiral centre.The step key use relatively expensive chiral auxiliary reagent (1S, 2R, 5S)-(+)-menthyl (R)-
To toluenesulfinate, and reaction need to be carried out at -78 DEG C, and yield is only 63%.Therefore, the route total recovery is relatively low, about
20%, cost of material is high, severe reaction conditions, it is difficult to large-scale production.
Document Tetrahedron,；70(2014)；P3864-3870 report method be：It is using cheap phenylalanine
Raw material, chiral centre is induced by ring-closure reaction.Wherein, final step decarboxylic reaction is cumbersome, and reaction condition is more severe
Carve, product impurity is more, needs column chromatography to purify, and total recovery is only 20%.
To sum up apparently, the crucial chiral centre of levo-praziquantel is built by chiral asymmetric syntheses, otherwise it is to close
Expensive chiral catalyst or chiral auxiliary are used into method, or being chiral induction asymmetric syntheses structure, route is tediously long,
Reaction condition is harsh, and purification of intermediate trouble, total recovery is low, and total cost of production is higher, can not realize industrial mass production.
(2) chiral resolution, i.e., key intermediate (such as pyrrole quinoline amine 1) is torn open with tartrate derivative L-(-)-DBTA
Point, the R-1 of the chiral centre required for acquisition preparation levo-praziquantel.Cyclohexyl formylated is carried out with regard to R-1 secondary amine amino again
Levo-praziquantel (R-3) is obtained, sees following route two.
Synthesis to racemization pyrrole quinoline amine 1, existing many reports, these documents relate to racemization pyrrole more in previous document
The fully synthetic technique of quinoline ketone.
Such as：German patent DE 2504250, the route that DE 2508947 is reported：Using isoquinolin as initiation material, warp
Racemization pyrrole quinoline amine is made in Reissert reactions, catalytic hydrogenation, acylation, cyclization, hydrolysis five steps reaction；See following route three.The party
Method technical maturity, raw material are easy to get, cost is relatively low.This method was once praziquantel industrial process widely used both at home and abroad.
In addition, document Journal of Heterocyclc Chemistry vol23 (1986) p189-190 is then reported
：Using cheap N- benzyliminodiacetic acids and β-phenyl ethylamine as raw material, through cyclization, again reduction, cyclization, the de- step of benzyl four of hydrogenation
Racemization pyrrole quinoline amine is made in reaction；See following route four.The method raw material is easy to get, and reaction condition is gentle, and step is not grown, environment friend
It is good, it is easy to large-scale production.
The route that document Tetrahedron vol.54nb.26 (1998) 7395 are reported：With β-phenyl ethylamine, chloracetyl chloride,
Aminoacetaldehyde dimethyl acetal etc. is raw material, and racemization pyrrole quinoline amine is made through acylation, substitution, cyclization three-step reaction；See following route five.
This method raw material is cheap and easy to get, and technique is simple, environment-friendly, and synthesis step is few, and total recovery is high, and cost is low, is easy to industrial metaplasia
Production.
Prepared by levo-praziquantel with regard to above-mentioned Split Method, 50% unwanted configuration pyrrole quinoline amine S- in raceme can be lost
1 key intermediate, so as to cause cost to be substantially increased.
In addition, with regard to the racemization of tetrahydro isoquinoline derivative, part document is also reported that oxidationreduction reacts in two steps and disappeared
The method of rotation, i.e., first with oxidant such as sodium hypochlorite, sym-closene or metal catalytic oxidation etc. by tetrahydroisoquinoline
Secondary amine aoxidizes, and tetrahydroisoquinoline is changed into dihydro-isoquinoline, then restores.So cumbersome, yield is relatively low, particularly
Oxidation reaction, generation impurity are more.
Such as：Document Organic Process Research＆Development vol.11 nb.3 (2007) 642 are reported
Road iridium catalyst [IrCl2Cp*]2, and for the racemization of tetrahydro isoquinoline derivative.This method is carried out under open environment, warp
A dihydro-isoquinoline intermediate state is gone through, still, used catalyst is expensive, and can not avoid the aromatization of tetrahydro isoquinoline derivative
Metaplasia causes yield relatively low into isoquinolin.
Scheme 1.Dehydtogenation and racemisation of (1S) -6,7-dimethoxy-l-
Methyl-1,2,3,4-tetrahydroisoquinoline using [IrCl2Cp*]2catalyst 1a
The present invention aims at：By the pyrrole quinoline amine twice laid again of the S configurations of discarding, by its racemization, and will obtain
The pyrrole quinoline amine of racemization is used for Split Method synthesis levo-praziquantel；So as to improve the yield of target product, reduce to greatest extent
The production cost of levo-praziquantel.
The content of the invention
A kind of the present invention is intended to provide racemization method of the pyrrole quinoline amine of S configurations by discarding twice laid again.
The present inventor seminar has carried out many-sided in-depth study for this：First, organic chemistry is used to pyrrole quinoline amine S-1
Conventional racemization method in theory, for example racemization in the presence of acid, alkali or heating, but we attempt for several times after all without
Method obtains the product of racemization, and violent condition result in pyrrole quinoline amine S-1 and decompose destruction generation other impurities.Reality many times
Verify it is bright, conventional racemization method can not be applied to S configuration pyrrole quinoline amine racemization technique.
By in-depth study, the present inventor audaciously innovates, and successfully develops the recovery preparation side of racemization pyrrole quinoline amine
Method.
The present invention is made using the method for splitting pyrrole quinoline amine -1 to prepare the S- pyrrole quinolines amine -1 that levo-praziquantel (R-3) is abandoned
For initiation material, racemization pyrrole quinoline amine -1 is prepared in the presence of the hydrogen of catalyst and certain pressure.And the pyrrole quinoline of raceme
Amine -1 is used for Split Method synthesis levo-praziquantel, splits synthesis of chiral praziquantel so as to establish a kind of effective circulation, makes to be not required to
The configuration pyrrole quinoline amine S-1 wanted is fully recycled, and can reduce the production cost of levo-praziquantel to greatest extent.
Therefore, more specifically, on the one hand, the invention provides the pyrrole quinoline amine intermediate -1 that a kind of absorption method prepares raceme
Method, i.e., be dissolved in using waste material S- pyrrole quinoline amine intermediate -1 as initiation material in solvent, in catalyst and certain pressure
Hydrogen in the presence of, react at moderate temperatures, the pyrrole quinoline amine intermediate -1 of raceme be prepared.
Compound 1 is the pyrrole quinoline amine of raceme, and the non-required configuration pyrrole that S-1 then abandons for fractionation synthesis levo-praziquantel
Quinoline amine intermediate.
It is described by among waste material S- pyrrole quinoline amine in the absorption method of the present invention prepares the method for racemization pyrrole quinoline amine -1
Body -1 is dissolved in solvent as initiation material, in the presence of the hydrogen of catalyst and certain pressure, is reacted at moderate temperatures,
The pyrrole quinoline amine intermediate -1 of raceme is prepared.
Wherein, the catalyst is selected from the common metal catalyst such as Raney-Ni, Ru/C, Pt/C, Pd/C.The catalyst
It is preferred that Pt/C, Raney-Ni, Pd/C.The catalyst most preferably Pd/C.
Wherein, the solvent is selected from following：Ether solvent is selected from 1,2- dimethoxy-ethanes, methyl tertiary butyl ether(MTBE), 2- first
Base tetrahydrofuran, cyclopentyl methyl ether；Aromatic hydrocarbon solvent be selected from benzene, toluene, ethylbenzene, dimethylbenzene, trimethylbenzene, to isopropyl methyl
Benzene, nitrobenzene, chlorobenzene, dichloro-benzenes；Hydro carbons or halogenated hydrocarbon solvent are selected from normal heptane, normal octane, decahydronaphthalene, dichloroethanes；
Esters solvent is selected from ethyl acetate, isopropyl acetate, isobutyl acetate；Ketones solvent is selected from 2- butanone, the different base ketone of methyl；Alcohols
Solvent is selected from methanol, ethanol, isopropanol, the tert-butyl alcohol, n-butanol, isobutanol；Other solvents are selected from dimethyl sulfoxide, N, N- dimethyl
Formamide.The solvent is more preferably toluene, dimethylbenzene, ethanol, isopropanol.
Wherein, 80-200 DEG C of described reaction temperature, preferably 120-150 DEG C.
Wherein, described Hydrogen Vapor Pressure 1-50atm, preferably 5-30atm.
In above-mentioned optimal case, it is preferable that methods described using toluene as solvent, from Pd/C as catalyst,
Reaction temperature is 130-150 DEG C, Hydrogen Vapor Pressure 10-25atm.
Above preferred embodiment can be with independent assortment, so as to obtain the various preferred embodiments of the present invention.
The invention has the advantages that by unwanted configuration pyrrole quinoline amine S-1 in high yield efficiently, simple operation, fully return
Receive using obtained raceme compound 1, levo-praziquantel is prepared by Split Method being utilized again.So as to become give up into
Treasured, greatly save the manufacturing cost of levo-praziquantel.Relative to document Organic Process Research＆
Development vol.11 nb.3(2007)642；Initiation material pyrrole quinoline amine S-1 of the present invention, structure is very special,
Secondary amino group on tetrahydroisoquinoline ring is protected by acyl group, is prohibited amino herein and is participated in oxidation reaction, so as to block dihydro
The generating process of isoquinolin intermediate state and isoquinolin, therefore above-mentioned conventional oxide-reduction method can not be applied to carry out racemization.
Brief description of the drawings
Fig. 1 shows the chiral HPLC figures for the racemization pyrrole quinoline amine -1 (reference substance) that purchase obtains.
Fig. 2 is shownThe pyrrole quinoline amine S-1 raw materials of S configurationsChiral HPLC figure.
Fig. 3 shows that the chiral HPLC figures of the product of racemization pyrrole quinoline amine 1 are prepared in embodiment 5.
Embodiment
The present invention is further illustrated by the examples that follow, following examples are only used for the more specific description present invention preferably
Embodiment, be not used in and technical scheme be defined.The scheme of the invention described above is that the present invention can be achieved
The technical scheme of purpose.Following examples use temperature and reagent, can be substituted with above-mentioned relevant temperature and reagent with reality
The purpose of the existing present invention.
In following preparation embodiments, for nuclear magnetic resonance by Varian Inova type nmr determinations, TMS is internal standard,
Chemical shift unit is ppm.
For the pyrrole quinoline amine 1 of racemization, S configuration pyrrole quinoline amine S-1, R configuration pyrrole quinoline amine R-1 structure contents are detected by following
Chiral HPLC Method.
Using chiral HPLC method：
Chromatographic column：250mm × 4.6mm,IC-3,3 μm；
UV-detector wavelength：210nm；
Flow velocity：0.4mL/min；
Column temperature：30℃；
Mobile phase：N-hexane (diethylamine for containing 0.1%):Isopropanol=30:70.
The HPLC collection of illustrative plates for buying the racemization pyrrole quinoline amine -1 (reference substance) obtained is as shown in Figure 1, wherein abscissa is that the time is (single
Position min), ordinate is mAU peak heights：
Drawn from Fig. 1, S-1 retention time 34.51min, content 50.65%；R-1 retention time 30.31min, content
49.35%.
After what the embodiment of the present invention used prepares levo-praziquantel by Split Method, among the pyrrole quinoline amine of discarded S configurations
Body S-1；It is initiation material of the present invention.
The HPLC collection of illustrative plates of the pyrrole quinoline amine S-1 raw materials of S configurations is as shown in Figure 2：Wherein abscissa is the time (unit min), is indulged
Coordinate is mAU peak heights：
Drawn from Fig. 2, S-1 retention time 34.61min, content 99.66%；R-1 retention time 31.13min, content
0.34%.
According to racemization method of the present invention, the pyrrole quinoline amine S-1 of S configurations is changed into the typical case of the product of racemization pyrrole quinoline amine 1 HPLC collection of illustrative plates is as shown in Figure 3：Wherein abscissa is the time (unit min), and ordinate is mAU peak heights：
Wherein：S-1 retention time 33.84min, content 50.18%；R-1 retention time 29.68min, content 49.82%.
Fig. 3 is that the product of racemization pyrrole quinoline amine 1, the chiral HPLC collection of illustrative plates tested, to confirm product is prepared by embodiment 5
Racemization degree.
The product of racemization pyrrole quinoline amine 1 is prepared in embodiment 1-12, tests, shows through above-mentioned chiral HPLC collection of illustrative plates, product
The racemization degree for the product that racemization degree is prepared with embodiment 5 is also consistent；Therefore, chirality is not listed one by one herein
HPLC tests collection of illustrative plates.
Racemization praziquantel product -1 being prepared in embodiment 1-12, test the HPLC purity of raceme.Test
Method is as follows：
Raceme purity is tested by general achirality post, and analysis method is as follows：
Chromatographic column：150mm × 4.6mm, XBridge C18,3.5 μm；
UV-detector wavelength：210nm；
Flow velocity：1.0mL/min；
Column temperature：35℃；
Mobile phase is the mixed solvent of the trifluoroacetic acid aqueous solution of acetonitrile/0.1%
Using gradient elution mode, see the table below in detail：
| Time (min) | Acetonitrile (%) | 0.1% trifluoroacetic acid aqueous solution (%) |
| 0 | 5 | 95 |
| 3 | 5 | 95 |
| 8 | 20 | 80 |
| 20 | 70 | 30 |
| 24 | 70 | 30 |
| 24.1 | 5 | 95 |
| 30 | 5 | 95 |
Note：The configuration of 0.1% trifluoroacetic acid aqueous solution：1mL trifluoroacetic acids are added to 1L water.
Embodiment 1
5g S- pyrrole quinoline amine (S-1), 0.5g palladium carbons and the mixing of 50ml toluene, 5atm H2Lower 130 DEG C of heating responses 48h is cold
But, filter, remove solvent under reduced pressure and obtain target product, be white solid 5.0g, yield 99%, HPLC purity 95%.mp 116.7-
117.4℃.1H NMR(400MHz,CDCl3):δ=7.26-7.11 (m, 4H), 4.88 (ddd, J=12.5,5.1,2.6Hz,
1H), 4.80 (dd, J=10.0,4.6Hz, 1H), 3.74 (ddd, J=13.0,4.7,1.2Hz, 1H), 3.61 (dd, J=57.1,
17.4Hz,2H),3.04–2.71(m,4H).13C NMR(100MHz,CDCl3):δ=167.30,134.98,134.25,
129.40,127.04,126.64,124.71,56.89,50.08,49.85,38.82,28.84.MS(ESI)m/z:203.1([M
+1]+),241.1([M+K]+).HRMS(ESI):m/z calcd for C12H14N2O[M+H]+:203.1179,found
203.1180.
Embodiment 2
5g S- pyrrole quinoline amine (S-1), 0.25g palladium carbons and the mixing of 50ml toluene, 5atm H2Lower 130 DEG C of heating responses 48h is cold
But, filter, remove solvent under reduced pressure and obtain target product, be white solid 5.0g, yield 99%, HPLC purity 95%.
Embodiment 3
5g S- pyrrole quinoline amine (S-1), 0.5g palladium carbons and the mixing of 50ml toluene, 10atm H2Lower 130 DEG C of heating responses 48h is cold
But, filter, remove solvent under reduced pressure and obtain target product, be white solid 5.0g, yield 99%, HPLC purity 95%.
Embodiment 4
5g S- pyrrole quinoline amine (S-1), 0.5g palladium carbons and the mixing of 50ml toluene, 20atm H2Lower 130 DEG C of heating responses 48h is cold
But, filter, remove solvent under reduced pressure and obtain target product, be white solid 5.0g, yield 99%, HPLC purity 95%.
Embodiment 5
5g S- pyrrole quinoline amine (S-1), 0.5g palladium carbons and the mixing of 50ml toluene, 30atm H2Lower 130 DEG C of heating responses 48h is cold
But, filter, remove solvent under reduced pressure and obtain target product, be white solid 5.0g, yield 99%, HPLC purity 95%.
Embodiment 6
5g S- pyrrole quinoline amine (S-1), 0.5g palladium carbons and the mixing of 50ml toluene, 20atm H2Lower 140 DEG C of heating responses 48h is cold
But, filter, remove solvent under reduced pressure and obtain target product, be white solid 5.0g, yield 99%, HPLC purity 92%.
Embodiment 7
5g S- pyrrole quinoline amine (S-1), 0.5g palladium carbons and the mixing of 50ml toluene, 20atm H2Lower 150 DEG C of heating responses 48h is cold
But, filter, remove solvent under reduced pressure and obtain target product, be white solid 5.0g, yield 99%, HPLC purity 91%.
Embodiment 8
5g S- pyrrole quinoline amine (S-1), 0.5g palladium carbons and the mixing of 50ml dimethylbenzene, 20atm H2Lower 140 DEG C of heating response 48h,
Cooling, filtering, removes solvent under reduced pressure and obtains target product, is white solid 5.0g, yield 99%, HPLC purity 92%.
Embodiment 9
5g S- pyrrole quinoline amine (S-1), 0.5g palladium carbons and the mixing of 50ml isopropanols, 30atm H2Lower 140 DEG C of heating response 48h,
Cooling, filtering, removes solvent under reduced pressure and obtains target product, is white solid 5.0g, yield 99%, HPLC purity 92%.
Embodiment 10
5g S- pyrrole quinoline amine (S-1), 0.5g palladium carbons and the mixing of 50ml ethanol, 30atm H2Lower 130 DEG C of heating responses 48h is cold
But, filter, remove solvent under reduced pressure and obtain target product, be white solid 5.0g, yield 99%, HPLC purity 95%.
Embodiment 11
5g S- pyrrole quinoline amine (S-1), 0.5g platinum carbons and the mixing of 50ml toluene, 20atm H2Lower 130 DEG C of heating responses 48h is cold
But, filter, remove solvent under reduced pressure and obtain target product, be white solid 5.0g, yield 99%, HPLC purity 92%.
Embodiment 12
5g S- pyrrole quinoline amine (S-1), 2.5 Raney's nickels and the mixing of 50ml toluene, 20atm H2Lower 130 DEG C of heating response 48h,
Cooling, filtering, removes solvent under reduced pressure and obtains target product, is white solid 5.0g, yield 99%, HPLC purity 85%.
Comparative example 13-17
Using racemization method conventional in organic chemistry theory and experiment, such as disappear in the presence of acid, alkali or heating
Rotation, attempt to carry out racemization processing to pyrrole quinoline amine S-1；But we can not obtain the product of racemization after attempting for several times,
And violent condition result in pyrrole quinoline amine S-1 and decompose destruction generation other impurities.Many times it is demonstrated experimentally that conventional racemization side
Method can not be applied to the racemization technique of S configuration pyrrole quinoline amine.
Embodiment 13
2.0g S- pyrrole quinoline amine (S-1,99%ee), 0.83g KOH, 30ml DMSO, nitrogen are sequentially added in 100ml reaction bulbs
The lower 60 DEG C of heating response 24h of gas shielded, cooling, sample chiral HPLC analyses and show that the optical purity of S- pyrrole quinoline amine is still 99%
Ee, therefore, this method do not have racemization effect.
Embodiment 14
2.0g S- pyrrole quinoline amine (S-1,99%ee), 1.0g NaOCH are sequentially added in 100ml reaction bulbs3, 30ml methanol,
Nitrogen protects lower 60 DEG C of heating response 24h, cooling, samples chiral HPLC analyses and shows that the optical purity of S- pyrrole quinoline amine is still
99%ee, therefore, this method do not have racemization effect.
Embodiment 15
2.0g S- pyrrole quinoline amine (S-1,99%ee), 1.33g potassium tert-butoxides, the tertiary fourths of 30ml are sequentially added in 100ml reaction bulbs
Alcohol, nitrogen protect lower 60 DEG C of heating response 12h, cooling, and most of raw material S- pyrrole quinolines amine degradation generates other impurities.
Embodiment 16
Sequentially add 2.0g S- pyrrole quinoline amine (S-1,99%ee) in 100ml reaction bulbs, the dense HCl of 2.5ml, 50ml water, 70 DEG C
Heating response 24h, cooling, sample chiral HPLC analyses and show that the optical purity of S- pyrrole quinoline amine is still 99%ee, and have part
Feed degradation generates impurity, and therefore, this method does not have racemization effect.
Embodiment 17
2.0g S- pyrrole quinoline amine (S-1,99%ee), the dense H of 2.2g are sequentially added in 100ml reaction bulbs2SO4, 50ml water, 70 DEG C
Heating response 24h, cooling, sample chiral HPLC analyses and show that the optical purity of S- pyrrole quinoline amine is still 99%ee, and have part
Feed degradation generates impurity, and therefore, this method does not have racemization effect.
Claims (8)
- A kind of 1. recovery preparation method of racemization pyrrole quinoline amine -1, i.e., using waste material S- pyrrole quinoline amine intermediates -1 as initiation material It is dissolved in solvent, in the presence of the hydrogen of catalyst and certain pressure, reacts at moderate temperatures, raceme is prepared Pyrrole quinoline amine intermediate -1.
- 2. the recovery preparation method of racemization pyrrole quinoline amine -1 as claimed in claim 1, it is characterised in that：It is described to urge in methods described Agent is selected from the common metal catalyst such as Raney-Ni, Ru/C, Pt/C, Pd/C.
- 3. the recovery preparation method of racemization pyrrole quinoline amine -1 as claimed in claim 2, it is characterised in that：It is described to urge in methods described Agent is selected from Pt/C, Raney-Ni, Pd/C.
- 4. the recovery preparation method of racemization pyrrole quinoline amine -1 as claimed in claim 1, it is characterised in that：It is described molten in methods described Agent, which is selected from, includes the ether solvents such as 1,2- dimethoxy-ethanes, methyl tertiary butyl ether(MTBE), 2- methyltetrahydrofurans, cyclopentyl methyl ether； It is molten including arenes such as benzene, toluene, ethylbenzene, dimethylbenzene, trimethylbenzene, p -Methylisopropylbenzene, nitrobenzene, chlorobenzene, dichloro-benzenes Agent；Including the hydro carbons such as normal heptane, normal octane, decahydronaphthalene, dichloroethanes or halogenated hydrocarbon solvent；Including ethyl acetate, acetic acid The esters solvents such as isopropyl ester, isobutyl acetate；Including ketones solvents such as 2- butanone, the different base ketone of methyl；Including methanol, ethanol, different The alcohols solvents such as propyl alcohol, the tert-butyl alcohol, n-butanol, isobutanol；The aprotonic polars such as dimethyl sulfoxide, N,N-dimethylformamide are molten Agent.
- 5. the recovery preparation method of racemization pyrrole quinoline amine -1 as claimed in claim 4, it is characterised in that：It is described molten in methods described Agent is selected from toluene, dimethylbenzene, ethanol, isopropanol.
- 6. the recovery preparation method of racemization pyrrole quinoline amine -1 as claimed in claim 1, it is characterised in that：In methods described, the hydrogen Atmospheric pressure 1-50atm, preferably 5-30atm.
- 7. the recovery preparation method of racemization pyrrole quinoline amine -1 as claimed in claim 1, it is characterised in that：The reaction temperature of methods described 80-200 DEG C, preferably 120-150 DEG C.
- 8. the recovery preparation method of racemization pyrrole quinoline amine -1 as claimed in claim 1, it is characterised in that：Methods described is made using toluene For solvent, from Pd/C as catalyst, reaction temperature is 130-150 DEG C, Hydrogen Vapor Pressure 10-25atm.
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| CN112375005A (en) * | 2019-08-16 | 2021-02-19 | 国药集团工业有限公司 | Racemization method of ketamine, its derivative or its salt |
| CN114057640A (en) * | 2020-08-05 | 2022-02-18 | 凯特立斯（深圳）科技有限公司 | Asymmetric synthesis method of optically pure (R)/(S) -hydroxychloroquine side chain |
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| CN112375005A (en) * | 2019-08-16 | 2021-02-19 | 国药集团工业有限公司 | Racemization method of ketamine, its derivative or its salt |
| CN114057640A (en) * | 2020-08-05 | 2022-02-18 | 凯特立斯（深圳）科技有限公司 | Asymmetric synthesis method of optically pure (R)/(S) -hydroxychloroquine side chain |
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