CN107382958A - A kind of method for crystallising of duloxetine. intermediate - Google Patents
A kind of method for crystallising of duloxetine. intermediate Download PDFInfo
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- CN107382958A CN107382958A CN201710542585.3A CN201710542585A CN107382958A CN 107382958 A CN107382958 A CN 107382958A CN 201710542585 A CN201710542585 A CN 201710542585A CN 107382958 A CN107382958 A CN 107382958A
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- dimethyl
- naphthoxys
- oxalates
- thiophenepropanamine
- thiophenepropyiamines
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- KBUVXRDFMQNIPD-UHFFFAOYSA-N CC1=CCCS1 Chemical compound CC1=CCCS1 KBUVXRDFMQNIPD-UHFFFAOYSA-N 0.000 description 1
- TVZQDMRKJSXJPZ-UHFFFAOYSA-O [OH2+]C1c(cccc2)c2C=CC1 Chemical compound [OH2+]C1c(cccc2)c2C=CC1 TVZQDMRKJSXJPZ-UHFFFAOYSA-O 0.000 description 1
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- 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
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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- 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
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
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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
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Abstract
The invention discloses a kind of duloxetine. intermediate (+) (S) N, the method for crystallising of N dimethyl γ (1 naphthoxy) 2 thiophenepropanamine oxalates, this method is included (+) (S) N, N dimethyl γ (1 naphthoxy) 2 thiophenepropyIamines and oxalic acid crystallize in the system that ethyl acetate, toluene or above-mentioned solvent mix with water；The invention also discloses the novel crystal forms that above-mentioned method for crystallising obtains.The granularity that method for crystallising of the present invention obtains is big, easily filtering and product purity height.
Description
Technical field
The present invention relates to a kind of preparation method of duloxetine. intermediate.
Background technology
Duloxetine hydrochloride is approved for treating major depressive disorder, Diabetic Peripheral dysmenorrhoea, fiber in August, 2004
Myalgia and chronic muscular and skeletal pain, chemical entitled (+)-(S)-N- methyl-γ-(1- naphthoxys) -2- thiophenepropyIamine hydrochlorides,
Chemical structural formula is as shown in Formula II：
(+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropyIamines (abbreviation Duloxetine thiophene ether) oxalic acid
Salt is the key intermediate of synthetic hydrochloric acid Duloxetine, and structural formula is shown in formula I：
US5362886 reports Duloxetine thiophene ether oxalates after free, then a methyl is sloughed from N, with hydrochloric acid
Duloxetine hydrochloride is obtained after into salt.The purity of Duloxetine thiophene ether oxalates directly affects follow-up duloxetine hydrochloride finished product
Purity.
WO2004/56795 reports use ethyl acetate as Duloxetine thiophene ether oxalates into salt solvent, due to this
Intermediate crystallizations state difference prepared by method, easily wraps up isomer impurities, and residue of mother is more, so isolated is different
Structure body impurity content is high, the isomers particularly shown in formula III.Further drawback is Duloxetine thiophene ether prepared by the method
Oxalate crystal deposition is thinner, easily blocks filter cloth during filtering, causes filtration difficulty, have a strong impact on production.
WO201079404 reports use solvent of the mixed liquor of ethyl acetate and methanol as crystallization, repeat the above method
Though isomer impurities can be removed effectively, its crystalline particle is thinner, is not easy to filter, and influences to produce.And Duloxetine thiophene ether
In the synthesis technique of intermediate, the solvent that typically uses is the non-polar solvens such as toluene, and above-mentioned patent in oxalates into salt mistake
Novel solvent is refer in journey, solvent recovery is applied mechanically and causes difficulty, so as to add production cost.
The content of the invention
It is an object of the invention to provide (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates are new
Purification process, methods described includes：
(a) (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropyIamines and oxalic acid are tied in dicyandiamide solution
Crystalline substance, obtains (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates, and the dicyandiamide solution is acetic acid second
The mixture of ester or ethyl acetate and water, wherein described oxalic acid is (+)-(S)-N, N- dimethyl-γ-(1- using mole
Naphthoxy) -2- thiophenepropyIamines 1.5 equivalents more than；Or (b) by (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenes
Fen propylamine and oxalic acid crystallize in dicyandiamide solution obtains (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropyIamines grass
Hydrochlorate, the dicyandiamide solution are toluene or the mixture of toluene and water.
Wherein when the mixture or toluene and the mixture of water for using ethyl acetate and water are as dicyandiamide solution, the body of water
Product content range is 0.2%~10%.
Method (a) mesoxalic acid is preferably (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- using molar equivalent
1.5~2 equivalents of thiophenepropyIamine.
Method (b) mesoxalic acid is preferably (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- using molar equivalent
1~3 equivalent of thiophenepropyIamine.
The specific operating method of crystallization may be selected from：By (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophene
The ethyl acetate or toluene solution of propylamine are added dropwise in the oxalic acid solution of ethyl acetate, toluene or water dissolving；Or oxalic acid solid is straight
Meet or be added portionwise (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropyIamines to ethyl acetate or toluene dissolving
In；Or ethyl acetate or toluene dissolving are added dropwise to after water and ethyl acetate mixtures or water and toluene mixture liquid dissolving oxalic acid
In (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropyIamines.
(+) obtained according to the above method-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates can
The method further provided according to prior art is translated into Duloxetine or its acid salt.
Present invention also offers two kinds of novel crystal forms：
(+) obtained according to method (a)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates'
Novel crystal forms, crystal formation H1 is named as in the description of the present invention, it has X-ray powder diffraction collection as shown in Figure 2,
Its X-ray powder diffraction peak value is with the θ angles of Prague 2, interplanar distance d and relative intensity (with relative to the percentage of most strong ray
Represent) it is characterized as below：
(+) obtained according to method (b)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates'
Novel crystal forms, crystal formation H2 is named as in the description of the present invention, it has X-ray powder diffraction collection as shown in Figure 3,
Its X-ray powder diffraction peak value is with the θ angles of Prague 2, interplanar distance d and relative intensity (with relative to the percentage of most strong ray
Represent) it is characterized as below：
The present invention has advantages below relative to the method for crystallising of prior art：
It is high to obtain (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates purity, granularity is big,
High income, easily filtering.Simultaneously using the reaction dissolvent for preparing Duloxetine thiophene ether as recrystallisation solvent, reduce new solubilizer and use,
It is easy to operate, reduce production cost.
Brief description of the drawings
Fig. 1：Implement the X-ray powder diffraction figure of 1 crystal formation prepared according to contrast.
Fig. 2：The crystal formation H1 prepared according to Examples 1 and 2 X-ray powder diffraction figure.
Fig. 3：The crystal formation H2 prepared according to embodiment 3 and 4 X-ray powder diffraction figure.
Fig. 4：The picture (100 times of amplification) for implementing to show under the electron microscope of 1 crystal formation prepared according to contrast.
Fig. 5：The picture (100 times of amplification) shown under crystal formation H1 electron microscope.
Fig. 6：The picture (40 times of amplification) shown under crystal formation H2 electron microscope.
Embodiment
The universal testing method of the present invention：
X-ray powder diffraction (XRD) instrument：
Dutch PANalytical X ' pert Pro types：Radiation source：Copper targetScan at ambient temperature：Voltage：
45kv, electric current：40mA, originate 2 θ：2000 °, scanning range：3.0000~50.0000 °, step-length：0.017 °, time of measuring：
50.2 seconds/step；
Electron microscope (FSEM)：German OLYMPUS, CX-31.
Determine the HPLC analysis methods of purity and external standard content：
Chromatographic column：XTERRA RP18 250*4.6mm, 5 μm；
Mobile phase A：2mL triethylamines are dissolved in 500mL water, and pH 7.0 is adjusted with concentrated phosphoric acid
Mobile phase B：Acetonitrile Flow rate：1.0mL/min column temperature：30 DEG C of Detection wavelengths：230nm.
Gradient table：
| Time min | Mobile phase A (%V/V) | Mobile phase B (%V/V) |
| 0-5 | 90 | 10 |
| 5-10 | 90-45 | 10-55 |
| 10-26 | 45 | 55 |
| 26-31 | 45-90 | 55-10 |
| 31-40 | 90 | 10 |
Determine the HPLC analysis methods of Enantiomeric excess：
Chromatographic column：CHIRALCEL OD-H 250*4.6mm, 5 μm；
Mobile phase：N-hexane：Isopropanol：Diethylamine=85:15:0.2(V/V/V)；Flow velocity：0.5mL/min column temperatures：25℃
Run time：30 minutes；Detection wavelength：230nm.
Reference implementation example 1
The preparation of (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropyIamines
18.5g (+)-(S)-N, N- dimethyl-γ-hydroxyl -2- thiophenepropyIamines are added in 500mL four-hole boiling flasks
(0.1mol) and 100mL DMSO, after stirring and dissolving, add 8g sodium hydrides (60% content), after stirring 10 minutes, be heated to 60
DEG C, stir 1 hour；17.5g 1- fluoronaphthalenes (0.12mol) are added at 60 DEG C, and keep this temperature to stir 24 hours, reaction knot
200mL water is added after beam, and is extracted twice with 100mL ethyl acetate, combined ethyl acetate layer, is washed twice with 200mL X 2,
Obtain ethyl acetate solution (purity 95.2%, the isomery of (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropyIamines
Body content 4.8%, external standard conversion content 29.0g, yield 93.5%).
Reference implementation example 2
The preparation of (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropyIamines
18.5g (+)-(S)-N, N- dimethyl-γ-hydroxyl -2- thiophenepropyIamines are added in 500mL four-hole boiling flasks
(0.1mol) and 100mL DMSO, after stirring and dissolving, add 8g sodium hydrides (60% content), after stirring 10 minutes, be heated to 60
DEG C, stir 1 hour；17.5g 1- fluoronaphthalenes (0.12mol) are added at 60 DEG C, and keep this temperature to stir 24 hours, reaction knot
200mL water is added after beam, and is extracted twice with the toluene of 100mL X 2, combining methylbenzene layer, is washed twice, obtained with 200mL X 2
Toluene solution (purity 95.4%, the content of isomer of (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropyIamines
4.7%, external standard content 29.2g, yield 93.9%).
Reference implementation example 3
The preparation of (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropyIamines
18.5g (+)-(S)-N, N- dimethyl-γ-hydroxyl -2- thiophenepropyIamines are added in 500mL four-hole boiling flasks
(0.1mol), 13.4g potassium tert-butoxides and 100mL toluene, after stirring and dissolving, 17.5g 1- fluoronaphthalenes (0.1mol) are added, are warming up to
Backflow, return stirring 8 hours, after reaction terminates, 60 DEG C are cooled to, add 200mL water, after stirring layering, separate water layer, water layer
With 50mL toluene extract, combining methylbenzene, with 200mL washing once, obtain (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys)-
The toluene solution (purity 90.6%, content of isomer 5.8%, external standard content 27.5g, yield 88.4%) of 2- thiophenepropyIamines.
Comparative example 1
The preparation of (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates
11.7g oxalic acid dihydrates (1.0 equivalent), and 50mL ethyl acetate are added in 500mL three-necked flasks, stirs 30 points
Clock, under room temperature condition, be added dropwise into the ethyl acetate solution of oxalic acid (+)-(S)-N, N- dimethyl prepared by reference implementation example 1-
The ethyl acetate solution of γ-(1- naphthoxys) -2- thiophenepropyIamines, is stirred at room temperature 4 hours after being added dropwise to complete, filtering, and uses 30mL
Ethyl acetate is eluted, and 34.4g (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates are obtained after drying
(purity 98.2%, content of isomer 3.2%, yield 86.0%), X-ray powder diffraction figure such as Fig. 1, show under microscope
Picture is as shown in Figure 4.
Embodiment 1
The preparation of (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates
Oxalic acid dihydrate is added in 500mL three-necked flasks, 50mL ethyl acetate, is stirred 30 minutes, it is past under room temperature condition
(+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- prepared by reference implementation example 1 is added dropwise in the ethyl acetate solution of oxalic acid
The ethyl acetate solution of thiophenepropyIamine, it is stirred at room temperature 4 hours, filters after being added dropwise to complete, and is eluted with 30mL ethyl acetate, drying
After obtain (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates, X-ray powder diffraction figure is as schemed
2, the picture of (100 times of amplification) display is as shown in Figure 5 under microscope.
Using different equivalent oxalic acid, as a result as shown in table 1：
Table 1
| Consumption of oxalic acid (equivalent) | Yield % | Purity % | Content of isomer % |
| 1.5 | 92.2 | 99.2 | 0.65 |
| 1.6 | 93.4 | 99.4 | 0.60 |
| 1.8 | 93.6 | 99.3 | 0.64 |
| 2.0 | 93.5 | 99.4 | 0.67 |
Embodiment 2
The preparation of (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates
17.6g oxalic acid dihydrates (1.5 equivalent), 50mL ethyl acetate and a certain amount of are added in 500mL three-necked flasks
Water, stir 30 minutes, under room temperature condition, be added dropwise into the ethyl acetate solution of oxalic acid (+)-(S) of the preparation of reference implementation example 1-
The ethyl acetate solution of N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropyIamines, are stirred at room temperature 4 hours, mistake after being added dropwise to complete
Filter, and eluted with 30mL ethyl acetate, (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropyIamines are obtained after drying
Oxalates, X-ray powder diffraction figure such as Fig. 2, the picture of (100 times of amplification) display is as shown in Figure 5 under microscope.
Using different ethyl acetate and the percent by volume of water content, as a result as shown in table 2：
Table 2
| Ethyl acetate/water (V/V) | Yield % | Purity % | Content of isomer % |
| (99.8:0.2) | 92.4 | 99.2 | 0.55 |
| (99.5:0.5) | 92.8 | 99.1 | 0.55 |
| (95.0:5.0) | 90.8 | 99.3 | 0.54 |
| (90.0:10.0) | 89.2 | 99.4 | 0.53 |
Embodiment 3
The preparation of (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates
11.8g oxalic acid dihydrates (1.0 equivalent), and 130mL water are added in 500mL three-necked flasks, is stirred 30 minutes, room
Under the conditions of temperature, (+)-(S)-N, N- dimethyl-γ-(1- naphthalene oxygen prepared by reference implementation example 2 is added dropwise into the aqueous solution of oxalic acid
Base) -2- thiophenepropyIamines toluene solution, be stirred at room temperature after being added dropwise to complete 4 hours, filter, and with 30mL toluene elution, after drying
Obtain 36.2g (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates (purity 99.2%, isomers
Content 0.55%, yield 96.3%) X-ray powder diffraction figure such as Fig. 3, picture such as Fig. 6 of (40 times of amplification) display under microscope
It is shown.
Embodiment 4
The preparation of (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates
11.1g oxalic acid dihydrates (1.0 equivalent), and 130mL water are added in 500mL three-necked flasks, is stirred 30 minutes, room
Under the conditions of temperature, (+)-(S)-N, N- dimethyl-γ-(1- naphthalene oxygen prepared by reference implementation example 3 is added dropwise into the aqueous solution of oxalic acid
Base) -2- thiophenepropyIamines toluene solution, be stirred at room temperature after being added dropwise to complete 4 hours, filter, and with 30mL toluene elution, after drying
Obtain 33.6g (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates (purity 98.6%, isomers
Content 1.0%, yield 94.9%), X-ray powder diffraction figure such as Fig. 3, picture such as Fig. 6 of (40 times of amplification) display under microscope
It is shown.
It is above-mentioned that only the preferred embodiments of the present invention are elaborated, it is any right the invention is not restricted to above-described embodiment
The conversion and modification of the present invention all belongs to protection scope of the present invention.
Claims (7)
1. a kind of method for crystallising of (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates, including：
(a) (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropyIamines and oxalic acid are crystallized in dicyandiamide solution, obtained
To (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates, the dicyandiamide solution be ethyl acetate or
The mixture of ethyl acetate and water, wherein described oxalic acid is (+)-(S)-N, N- dimethyl-γ-(1- naphthalene oxygen using mole
Base) -2- thiophenepropyIamines 1.5 equivalents more than；Or
(b) (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropyIamines and oxalic acid are crystallized in dicyandiamide solution
To (+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates, the dicyandiamide solution is toluene or toluene
With the mixture of water.
2. method according to claim 1, when the mixture conduct of the mixture selected from ethyl acetate and water or toluene and water
During dicyandiamide solution, the volume content scope of water is 0.2%~10%.
3. method according to claim 1, the mole of method (a) mesoxalic acid is (+)-(S)-N, N- dimethyl-γ-(1-
Naphthoxy) -2- thiophenepropyIamines 1.5~2 equivalents.
4. method according to claim 1, the mole of method (b) mesoxalic acid is (+)-(S)-N, N- dimethyl-γ-(1-
Naphthoxy) -2- thiophenepropyIamines 1~3 equivalent.
5. a kind of prepare Duloxetine or the method for its acid salt, including right wanted (+)-(S) obtained by any one of 1-4-
N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates are further converted to Duloxetine or its acid salt.
The crystal formation of (6.+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates, have as shown in Figure 2
X-ray powder diffraction collection, its X-ray powder diffraction peak value is with the θ angles of Prague 2, interplanar distance d and relative intensity (with phase
Represented for the percentage of most strong ray) it is characterized as below：
The crystal formation of (7.+)-(S)-N, N- dimethyl-γ-(1- naphthoxys) -2- thiophenepropanamine oxalates, have as shown in Figure 3
X-ray powder diffraction collection, its X-ray powder diffraction peak value is with the θ angles of Prague 2, interplanar distance d and relative intensity (with phase
Represented for the percentage of most strong ray) it is characterized as below：
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| 高丽梅等: "盐酸度洛西汀的合成", 《CHINESE JOURNAL OF NEW DRUGS》 * |
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