CN110407808B - Novel crystal form of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole and preparation method thereof - Google Patents
Novel crystal form of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole and preparation method thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 62
- ZTIWYTIUWACGKI-KRWDZBQOSA-N 1h-imidazol-2-yl-[(1s)-1-phenyl-3,4-dihydro-1h-isoquinolin-2-yl]methanone Chemical compound C1([C@H]2C3=CC=CC=C3CCN2C(=O)C=2NC=CN=2)=CC=CC=C1 ZTIWYTIUWACGKI-KRWDZBQOSA-N 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims description 25
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 18
- 230000005855 radiation Effects 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 44
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 38
- PRTRSEDVLBBFJZ-HNNXBMFYSA-N (1s)-1-phenyl-1,2,3,4-tetrahydroisoquinoline Chemical compound C1([C@H]2C3=CC=CC=C3CCN2)=CC=CC=C1 PRTRSEDVLBBFJZ-HNNXBMFYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 21
- 239000012074 organic phase Substances 0.000 claims description 21
- 239000008213 purified water Substances 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 229910002483 Cu Ka Inorganic materials 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 13
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 230000009286 beneficial effect Effects 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 5
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 26
- 150000001875 compounds Chemical class 0.000 description 22
- 238000005303 weighing Methods 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 10
- FBOUYBDGKBSUES-KEKNWZKVSA-N 1-azabicyclo[2.2.2]octan-3-yl (1s)-1-phenyl-3,4-dihydro-1h-isoquinoline-2-carboxylate Chemical compound C1([C@H]2C3=CC=CC=C3CCN2C(OC2C3CCN(CC3)C2)=O)=CC=CC=C1 FBOUYBDGKBSUES-KEKNWZKVSA-N 0.000 description 9
- -1 1H-imidazole-2-carbonyl Chemical group 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- 229960001368 solifenacin succinate Drugs 0.000 description 9
- 238000007605 air drying Methods 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 206010020853 Hypertonic bladder Diseases 0.000 description 7
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 7
- 208000020629 overactive bladder Diseases 0.000 description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229960003855 solifenacin Drugs 0.000 description 3
- FBOUYBDGKBSUES-VXKWHMMOSA-N solifenacin Chemical class C1([C@H]2C3=CC=CC=C3CCN2C(O[C@@H]2C3CCN(CC3)C2)=O)=CC=CC=C1 FBOUYBDGKBSUES-VXKWHMMOSA-N 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- IUTDICPUOGGCKH-UHFFFAOYSA-N isoquinoline-1-carbonyl chloride Chemical compound C1=CC=C2C(C(=O)Cl)=NC=CC2=C1 IUTDICPUOGGCKH-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- IVLICPVPXWEGCA-UHFFFAOYSA-N 3-quinuclidinol Chemical compound C1C[C@@H]2C(O)C[N@]1CC2 IVLICPVPXWEGCA-UHFFFAOYSA-N 0.000 description 1
- 206010069632 Bladder dysfunction Diseases 0.000 description 1
- 102000017925 CHRM3 Human genes 0.000 description 1
- 101150060249 CHRM3 gene Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 208000000921 Urge Urinary Incontinence Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 238000003403 chloroformylation reaction Methods 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 206010046494 urge incontinence Diseases 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 230000003202 urodynamic effect Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole crystal form A, which is characterized in that characteristic diffraction peaks are present at 7.6, 8.7, 10.9, 11.9, 19.3, 20.6, 21.5 and 22.8 in an X-ray powder diffraction pattern expressed by Cu-Kalpha radiation and 2 theta +/-0.2 DEG diffraction angle. The (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole crystal form A disclosed by the invention has good stability and convenient use, and is beneficial to removing impurities and storing intermediates in the production process.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a new crystal form of a solifenacin intermediate (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole and a preparation method thereof.
Background
Overactive Bladder (OAB), abbreviated as Overactive Bladder, is a syndrome characterized by symptoms of urgency, often accompanied by symptoms of urination, with or without urge incontinence, urodynamics manifested as detrusor overactivity, and also other forms of urethra-Bladder dysfunction. OAB has no clear etiology and does not include symptoms caused by acute urinary tract infections or other forms of local lesions of the bladder and urethra. Overactive bladder brings inconvenience to the life of patients, greatly affects the quality of life of patients, and even daily life and work.
Solifenacin Succinate (Solifenacin Succinate) is a selective M3 receptor antagonist developed and marketed by astela (astella) pharmaceutical company, japan, for the treatment of overactive bladder (OAB), first marketed simultaneously in the netherlands, germany, uk, france and danish in 8 months of 2004, and upon 11 months of 2004, for approval by the FDA in the united states, and has the structural formula shown below:
various methods for preparing solifenacin succinate are disclosed in the existing documents, for example, patent documents EP0801067, WO2005105795, WO2007147374, WO2009142522 and WO2011086003 report methods for preparing solifenacin succinate by chloroformylation of isoquinoline, but chloroformylisoquinoline intermediates are unstable, the yield is low when chloroformylisoquinoline is prepared, impurities are many and difficult to remove, phosgene with high toxicity is required, and industrial mass production is not facilitated.
Patent documents WO2012001481, WO2009139002, WO2009011844, WO2007076116 and WO2008011462 report methods for preparing solifenacin succinate by using an ethoxyformylated isoquinoline as an intermediate, but the ethyl chloroformate adopted in the route has high toxicity, and long-time high-temperature reflux is required for transesterification of the ethoxyformylated isoquinoline and quinuclidine alcohol, so that the energy consumption is high and the yield is low.
The general structural formula of solifenacin intermediate (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole is disclosed in patent document EP0801067, but the preparation method and related properties thereof are not disclosed. Patent document US2010029944 specifically discloses a reaction of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole as an intermediate with 3-quinuclidinol to generate solifenacin, wherein the reaction route is as follows:
however, the (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole prepared in the patent document US2010029944 is not in a solid form but in an oily form, and the intermediate in the form is not beneficial to removal of impurities, separation and storage of the intermediate, and is also not beneficial to stability of the product, so that the scale production and purity of the product are seriously affected. Therefore, how to obtain the solid form substance of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole has important significance for the preparation of solifenacin succinate.
Disclosure of Invention
Aiming at the defects and blanks in the prior art, the inventor of the invention provides the (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole in a crystal form and a preparation method of the crystal, and the obtained (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole in the crystal form A has good stability and convenient use, is beneficial to removing impurities and storing intermediates in the production process, and greatly improves various defects of an oily intermediate adopted in the new production process of solifenacin succinate.
The invention firstly provides a novel crystal form A of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole, which is characterized in that characteristic diffraction peaks are at 7.6, 8.7, 10.9, 11.9, 19.3, 20.6, 21.5 and 22.8 in an X-ray powder diffraction pattern expressed by Cu-Ka radiation and 2 theta +/-0.2 DEG diffraction angle.
Specifically, the crystal form A of the (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole has characteristic diffraction peaks at 7.6, 8.7, 10.9, 11.9, 12.9, 13.5, 14.1, 17.4, 19.3, 20.6, 21.5, 22.8, 24.5 and 28.5 in an X-ray powder diffraction pattern expressed by Cu-Kalpha radiation and a 2 theta +/-0.2 DEG diffraction angle.
More specifically, the crystal form A of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole has characteristic diffraction peaks at 7.6, 8.7, 10.9, 11.9, 12.9, 13.5, 14.1, 15.1, 16.1, 16.5, 17.1, 17.4, 18.7, 19.3, 20.6, 21.5, 22.3, 24.0, 22.8, 24.5 and 28.5 in an X-ray powder diffraction pattern expressed by Cu-Ka radiation and 2 theta +/-0.2 DEG diffraction angle.
The invention also provides a preparation method of the (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole crystal form A, which comprises the following steps:
(1) dissolving (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline and N, N' -carbonyldiimidazole in an organic solvent, and stirring at room temperature for reaction for 1-3 h;
(2) after the reaction is finished, washing with purified water, and collecting an organic phase; and (3) taking an organic phase, slowly dropwise adding a poor solvent, stirring and crystallizing for 1-4H, and drying to obtain the 2- (1H-imidazole-2-ylcarbonyl) - (1S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline crystal form A.
The preparation method of the crystal form A of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole comprises the step of (1) wherein the molar ratio of the (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline to the N, N' -carbonyl diimidazole is 1:1-1:1.5, preferably 1:1.05-1: 1.3.
The preparation method of the crystal form A of the (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole, wherein the organic solvent in the step (1) is selected from one of dichloromethane and toluene, preferably toluene; the volume of the organic solvent is 2 to 8 times (mL/g), preferably 3 to 6 times (mL/g) the weight of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline.
The preparation method of the crystal form A of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole, wherein the volume of the purified water in the step (2) is 2-4 times (mL/g), preferably 2.5 times (mL/g) of the weight of the (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline.
The preparation method of the crystal form a of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole, wherein in the step (2), the poor solvent is selected from one of cyclohexane, n-hexane, n-heptane, diethyl ether, petroleum ether or methyl tert-butyl ether, preferably from one of cyclohexane, n-hexane and n-heptane, and more preferably from n-heptane; the volume of the poor solvent is 2-50 times (mL/g), preferably 10-20 times (mL/g) of the weight of the (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline.
In the above preparation method of the crystalline form a of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonylimidazole, the organic phase collected in step (2) may be further optionally washed with a saturated NaCl solution having a volume 2 to 4 times (mL/g), preferably 2.5 times (mL/g), the weight of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline.
In the preparation method of the crystal form A of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole, the crystallization reaction temperature in the step (2) can be any temperature between-10 ℃ and 30 ℃, and is preferably 0-20 ℃.
In view of the above-described preferred conditions, the present inventors provide a specific process for the preparation of crystalline form a of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole which comprises the steps of:
(1) dissolving (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline and N, N' -carbonyldiimidazole in toluene, and stirring at room temperature for reaction for 2 hours;
(2) after the reaction is finished, washing with purified water and saturated NaCl solution, and collecting an organic phase; and taking an organic phase, slowly dropwise adding a poor solvent n-heptane, stirring and crystallizing for 2H, and drying to obtain the 2- (1H-imidazole-2-ylcarbonyl) - (1S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline crystal form A.
In conclusion, the crystal form A of the (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline and the N, N' -carbonyldiimidazole provided by the invention has good stability in the process of preparing solifenacin succinate. Compared with the oily intermediate of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole prepared in the patent document US2010029944, the crystal form A of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline and N, N' -carbonyl diimidazole does not need to be subjected to reduced pressure concentration, so that the industrial operability is improved, and the energy consumption and the production cost are reduced. The (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline and the N, N' -carbonyldiimidazole have good stability of the crystal form A, are beneficial to removing impurities in the production process, storing intermediates and facilitating the next step of feeding, and greatly improve various defects of the existing solifenacin succinate production process adopting oily intermediates. In the preparation aspect, the reaction conditions of the (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline and the N, N' -carbonyldiimidazole are mild, the preparation and the purification are easy, the operation is more convenient and simpler, and the method is more suitable for industrial mass production.
Drawings
Figure 1 is an X-ray powder diffraction pattern of the compound of form a of example 1.
Detailed Description
The invention is further illustrated below with reference to examples, but the invention is by no means limited to these examples.
Comparative example 2- (1H-imidazol-2-ylcarbonyl) - (1S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline oil preparation
Comparative example 1
Weighing (S) -1-phenyl-1, 2,3, 4-four hydrogen isoquinoline 8.0g (38.2mmol), N' -carbonyl two imidazole 6.8g (41.9mmol) into the reaction bottle, adding dichloromethane 50 ml. The stirring is started, and the reaction is stirred for 2h at room temperature. After the reaction, 50mL of purified water was added and the mixture was separated to obtain an organic phase. The resulting organic phase was washed with purified water (2X 25mL), anhydrous Na2SO4Drying, vacuum concentration to dryness, 2- (1H-imidazole-2-carbonyl) - (1S) -1-phenyl-1, 2,3, 4-four hydrogen isoquinoline oily matter 12.3g, yield 106.2%, purity 99.32%. (see US2010029944 example 3)
Comparative example 2
Weighing (S) -1-phenyl-1, 2,3, 4-four hydrogen isoquinoline 8.0g (38.2mmol), N' -carbonyl two imidazole 6.8g (41.9mmol) into the reaction bottle, adding tetrahydrofuran 50 ml. The stirring is started, and the reaction is stirred for 2h at room temperature. After the reaction, 50mL of purified water was added and the mixture was separated to obtain an organic phase. The resulting organic phase was washed with purified water (2X 25mL), anhydrous Na2SO4Drying, vacuum concentration to dryness, 2- (1H-imidazole-2-carbonyl) - (1S) -1-phenyl-1, 2,3, 4-four hydrogen isoquinoline oily matter 12.3g, yield 106.2%, purity 98.91%. (see US2010029944 example 4)
EXAMPLE 2 preparation of (1H-imidazol-2-ylcarbonyl) - (1S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline form A
Example 1
Weighing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline 5.0g (23.89mmol) and N, N' -carbonyldiimidazole 3.87g (23.89mmol), adding into a reaction flask, adding dichloromethane 10ml, and stirring; the reaction was stirred at room temperature for 1 h. After the reaction, the reaction mixture was washed once with 10ml each of purified water and a saturated aqueous NaCl solution, and the liquids were separated. 10ml of cyclohexane is added dropwise into the organic phase, and the mixture is stirred at about 30 ℃ for crystallization for 1 hour. Filtering, blowing and drying at 50 ℃ to constant weight to obtain 2- (1H-imidazole-2-ylcarbonyl) - (1S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline crystal form A6.49g, yield 89.73% and purity 99.89%.
The crystalline compound is analyzed by X-ray powder diffraction, the X-ray diffraction pattern of the crystalline compound is shown in figure 1, the crystalline compound is called as a crystal form A, the data are shown in the following table 1, other weaker peaks given in the figure 1 are omitted in the table 1, and the error of the 2 theta diffraction angle is +/-0.2 degrees.
Table 1X-ray powder diffraction data for the compound of example 1 form a
Example 2
Weighing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline 5.0g (23.89mmol) and N, N' -carbonyldiimidazole 4.07g (25.08mmol), adding into a reaction flask, adding dichloromethane 15ml, and stirring; the reaction was stirred at room temperature for 2 h. After the reaction, the reaction mixture was washed once with 12.5ml each of purified water and a saturated aqueous NaCl solution, and the solution was separated. And (3) taking an organic phase, dropwise adding 25ml of n-hexane, and stirring at about 25 ℃ for crystallization for 2 hours. Suction filtration, 50 degrees C forced air drying to constant weight, 2- (1H-imidazole-2-carbonyl) - (1S) -1-phenyl-1, 2,3, 4-four hydrogen isoquinoline crystal form A6.73g, yield 92.93%, purity 99.91%.
Analyzing the crystal form compound through X-ray powder diffraction, wherein the crystal form compound is a crystal form A.
Example 3
Weighing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline 5.0g (23.89mmol) and N, N' -carbonyldiimidazole 4.26g (26.27mmol), adding into a reaction flask, adding toluene 20ml, and stirring; the reaction was stirred at room temperature for 3 h. After the reaction, the reaction mixture was washed once with 15ml each of purified water and a saturated aqueous NaCl solution, and the solutions were separated. Taking the organic phase, dropwise adding 50ml of n-heptane, and stirring at about 20 ℃ for crystallization for 3 h. Suction filtration, 50 degrees C air drying to constant weight, 2- (1H-imidazole-2-carbonyl) - (1S) -1-phenyl-1, 2,3, 4-four hydrogen isoquinoline crystal form A6.89g, yield 95.23%, purity 99.94%.
Analyzing the crystal form compound through X-ray powder diffraction, wherein the crystal form compound is a crystal form A.
Example 4
Weighing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline 5.0g (23.89mmol) and N, N' -carbonyldiimidazole 4.65g (28.67mmol), adding into a reaction flask, adding toluene 25ml, and stirring; the reaction was stirred at room temperature for 2 h. After the reaction, the reaction mixture was washed once with 20ml each of purified water and a saturated aqueous NaCl solution, and the solutions were separated. And (3) taking an organic phase, dropwise adding 75ml of cyclohexane, and stirring at about 15 ℃ for crystallization for 4 hours. Suction filtration, 50 ℃ forced air drying to constant weight, 2- (1H-imidazole-2-carbonyl) - (1S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline crystal form A6.80g, yield 93.92%, purity 99.95%.
Analyzing the crystal form compound through X-ray powder diffraction, wherein the crystal form compound is a crystal form A.
Example 5
Weighing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline 5.0g (23.89mmol) and N, N' -carbonyldiimidazole 5.04g (31.06mmol) and adding into a reaction bottle, adding dichloromethane 30ml, starting stirring; the reaction was stirred at room temperature for 2 h. After the reaction, the reaction mixture was washed once with purified water and 12.5ml of a saturated aqueous NaCl solution, and the solutions were separated. Taking the organic phase, dropwise adding 100ml of diethyl ether, and stirring at about 10 ℃ for crystallization for 2 h. Suction filtration, 50 ℃ forced air drying to constant weight, get 2- (1H-imidazole-2-carbonyl) - (1S) -1-phenyl-1, 2,3, 4-four hydrogen isoquinoline crystal form A6.72g, yield 92.76%, purity 99.93%.
Analyzing the crystal form compound through X-ray powder diffraction, wherein the crystal form compound is a crystal form A.
Example 6
Weighing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline 5.0g (23.89mmol) and N, N' -carbonyldiimidazole 5.42g (33.45mmol), adding into a reaction flask, adding toluene 35ml, and stirring; the reaction was stirred at room temperature for 2 h. After the reaction, the reaction mixture was washed once with purified water and 15ml of a saturated aqueous NaCl solution, and the solutions were separated. And (3) taking the organic phase, dropwise adding 125ml of methyl tert-butyl ether, and stirring at about 5 ℃ for crystallization for 2 h. Suction filtration, 50 ℃ forced air drying to constant weight, 2- (1H-imidazole-2-carbonyl) - (1S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline crystal form A6.65g, yield 91.89%, purity 99.92%.
Analyzing the crystal form compound through X-ray powder diffraction, wherein the crystal form compound is a crystal form A.
Example 7
Weighing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline 4.0g (23.89mmol) and N, N' -carbonyldiimidazole 5.81g (35.83mmol), adding into a reaction flask, adding dichloromethane 40ml, stirring; the reaction was stirred at room temperature for 2 h. After the reaction, the reaction mixture was washed once with purified water and 15ml of a saturated aqueous NaCl solution, and the solutions were separated. And (3) taking an organic phase, dropwise adding 150ml of petroleum ether, and stirring at about 0 ℃ for crystallization for 2 hours. Suction filtration, 50 degrees C forced air drying to constant weight, 2- (1H-imidazole-2-carbonyl) - (1S) -1-phenyl-1, 2,3, 4-four hydrogen isoquinoline crystal form A6.61g, yield 91.24%, purity 99.93%.
Analyzing the crystal form compound through X-ray powder diffraction, wherein the crystal form compound is a crystal form A.
Example 8
Weighing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline 5.0g (23.89mmol) and N, N' -carbonyldiimidazole 4.65g (28.67mmol), adding into a reaction flask, adding dichloromethane 15ml, stirring, and reacting at room temperature for 2 h. After the reaction, the reaction mixture was washed once with purified water and 12.5ml of a saturated aqueous NaCl solution, and the solutions were separated. And (3) taking the organic phase, dropwise adding 250ml of n-heptane, and stirring at about 20 ℃ for crystallization for 2 h. Suction filtration, 50 degrees C forced air drying to constant weight, 2- (1H-imidazole-2-carbonyl) - (1S) -1-phenyl-1, 2,3, 4-four hydrogen isoquinoline crystal form A6.51g, yield 89.97%, purity 99.92%.
Analyzing the crystal form compound through X-ray powder diffraction, wherein the crystal form compound is a crystal form A.
Example 9
Weighing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline 5.0g (23.89mmol) and N, N' -carbonyldiimidazole 4.26g (26.27mmol), adding into a reaction flask, adding toluene 25ml, and stirring; the reaction was stirred at room temperature for 2 h. After the reaction, the reaction mixture was washed once with purified water and 15ml of a saturated aqueous NaCl solution, and the solutions were separated. And (3) taking an organic phase, dropwise adding 75ml of cyclohexane, and stirring at about 20 ℃ for crystallization for 2 hours. Suction filtration, 50 degrees C forced air drying to constant weight, 2- (1H-imidazole-2-carbonyl) - (1S) -1-phenyl-1, 2,3, 4-four hydrogen isoquinoline crystal form A6.89g, yield 95.13%, purity 99.96%.
Analyzing the crystal form compound through X-ray powder diffraction, wherein the crystal form compound is a crystal form A.
Example 10 stability test
A proper amount of the 2- (1H-imidazol-2-ylcarbonyl) - (1S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline crystal form A sample obtained in the invention example 9 and the oily 2- (1H-imidazol-2-ylcarbonyl) - (1S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline sample obtained in the reference example 1 and the reference example 2 were placed in a glass plate and left at 40 ℃ and 75% humidity for 1 month, and the appearance, purity and crystal form were evaluated as indices. The results are shown in Table 1 below.
Table 1 stability test results
The experimental results show that compared with the 2- (1H-imidazole-2-ylcarbonyl) - (1S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline oily substance, the 2- (1H-imidazole-2-ylcarbonyl) - (1S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline oily substance crystal form A has high purity and good stability, and is more beneficial to long-term storage.
EXAMPLE 11 reproducibility of different batches of form A crystals
Three different batches of crystalline form a compound of 2- (1H-imidazol-2-ylcarbonyl) - (1S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline were prepared according to the procedure of example 9 and analyzed by X-ray powder diffraction, which showed X-ray diffraction patterns of the three batches, all shown in fig. 1, having the same physical properties as the sample of example 9.
Claims (10)
1. A (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole crystal form A is characterized by having characteristic diffraction peaks at 7.6, 8.7, 10.9, 11.9, 19.3, 20.6, 21.5 and 22.8 in an X-ray powder diffraction pattern expressed by Cu-Ka radiation and 2 theta +/-0.2 DEG diffraction angles.
2. Crystalline form a of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonylimidazole according to claim 1 characterized by characteristic diffraction peaks at 7.6, 8.7, 10.9, 11.9, 12.9, 13.5, 14.1, 17.4, 19.3, 20.6, 21.5, 22.8, 24.5, 28.5 in the X-ray powder diffraction pattern expressed in Cu-ka radiation at 2 Θ ± 0.2 ° diffraction angles.
3. Crystalline form a of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonylimidazole according to claim 1 characterized by characteristic diffraction peaks at 7.6, 8.7, 10.9, 11.9, 12.9, 13.5, 14.1, 15.1, 16.1, 16.5, 17.1, 17.4, 18.7, 19.3, 20.6, 21.5, 22.3, 24.0, 22.8, 24.5, 28.5 in the X-ray powder diffraction pattern expressed in Cu-ka radiation at 2 Θ ± 0.2 ° diffraction angles.
4. A process for the preparation of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole crystalline form a according to any one of claims 1 to 3 comprising the steps of:
(1) dissolving (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline and N, N' -carbonyldiimidazole in an organic solvent, and stirring at room temperature for reaction for 1-3 h;
(2) after the reaction is finished, washing with purified water, and collecting an organic phase; and (3) taking an organic phase, slowly dropwise adding a poor solvent, stirring and crystallizing for 1-4H, and drying to obtain the 2- (1H-imidazole-2-ylcarbonyl) - (1S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline crystal form A.
5. The process for the preparation of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonylimidazole crystalline form A according to claim 4 wherein in step (1), the molar ratio of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline to N, N' -carbonyldiimidazole is 1:1-1: 1.5; the organic solvent is selected from one of dichloromethane or toluene; the volume of the organic solvent is 2-8 times of the weight of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline.
6. The process for the preparation of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonylimidazole crystalline form A according to claim 5 wherein in step (1) the molar ratio of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline to N, N' -carbonyldiimidazole is 1:1.05-1: 1.3; the organic solvent is toluene; the volume of the organic solvent is 3-6 times of the weight of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline.
7. The process for the preparation of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonylimidazole crystalline form A according to claim 4 wherein in step (2) the volume of purified water is 2-4 times the weight of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline; the poor solvent is selected from one of cyclohexane, normal hexane, normal heptane, diethyl ether, petroleum ether or methyl tert-butyl ether; the volume of the poor solvent is 2 to 50 times of the weight of the (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline; the crystallization reaction temperature can be any temperature between-10 ℃ and 30 ℃.
8. The process for the preparation of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonylimidazole crystalline form a according to claim 7 wherein, in step (2), the volume of purified water is 2.5 times the weight of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline; the poor solvent is selected from one of cyclohexane, normal hexane and normal heptane; the volume of the poor solvent is 10 to 20 times of the weight of the (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline; the crystallization reaction temperature is 0-20 ℃.
9. The process according to claim 7 for the preparation of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole in crystalline form A, characterized in that in step (2) the poor solvent is n-heptane.
10. The process for the preparation of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonylimidazole crystalline form A according to claim 4 wherein the organic phase collected in step (2) is further optionally washed with a saturated NaCl solution having a volume 2-4 times the weight of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080114028A1 (en) * | 2006-07-24 | 2008-05-15 | Tamas Koltai | Process for preparing polymorphic forms of solifenacin succinate |
| CN101601673A (en) * | 2004-03-25 | 2009-12-16 | 安斯泰来制药株式会社 | The compositions that is used for solifenacin or its salt of solid preparation |
| US20100029944A1 (en) * | 2006-11-22 | 2010-02-04 | Corporacion Medichem, S.L. | Process for the Synthesis of Solifenacin |
| CN101711248A (en) * | 2007-03-30 | 2010-05-19 | 医药化学公司 | An improved process for the synthesis of solifenacin |
| CN103664780A (en) * | 2013-12-04 | 2014-03-26 | 齐鲁制药有限公司 | (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-phenyl formate novel crystal form and preparation method thereof |
| CN104817555A (en) * | 2015-05-21 | 2015-08-05 | 南京华威医药科技开发有限公司 | M crystal form of solifenacin succinate and preparation method of M crystal form |
-
2018
- 2018-04-27 CN CN201810391233.7A patent/CN110407808B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101601673A (en) * | 2004-03-25 | 2009-12-16 | 安斯泰来制药株式会社 | The compositions that is used for solifenacin or its salt of solid preparation |
| US20080114028A1 (en) * | 2006-07-24 | 2008-05-15 | Tamas Koltai | Process for preparing polymorphic forms of solifenacin succinate |
| US20100029944A1 (en) * | 2006-11-22 | 2010-02-04 | Corporacion Medichem, S.L. | Process for the Synthesis of Solifenacin |
| CN101711248A (en) * | 2007-03-30 | 2010-05-19 | 医药化学公司 | An improved process for the synthesis of solifenacin |
| CN103664780A (en) * | 2013-12-04 | 2014-03-26 | 齐鲁制药有限公司 | (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-phenyl formate novel crystal form and preparation method thereof |
| CN104817555A (en) * | 2015-05-21 | 2015-08-05 | 南京华威医药科技开发有限公司 | M crystal form of solifenacin succinate and preparation method of M crystal form |
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