CN117486798A - Crystal form of ramipam intermediate hydrochloride and preparation method thereof - Google Patents

Crystal form of ramipam intermediate hydrochloride and preparation method thereof Download PDF

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CN117486798A
CN117486798A CN202311768466.1A CN202311768466A CN117486798A CN 117486798 A CN117486798 A CN 117486798A CN 202311768466 A CN202311768466 A CN 202311768466A CN 117486798 A CN117486798 A CN 117486798A
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hydrochloride
degrees
ramelteon
ethanol
crystal form
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廖文向
顾理群
周西朋
龚彦春
刘云龙
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Hubei Tianshu Pharmaceutical Co ltd
Nanjing Weikaier Biomedical Technology Co ltd
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Hubei Tianshu Pharmaceutical Co ltd
Nanjing Weikaier Biomedical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • 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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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a crystal form of a ramipam intermediate hydrochloride and a preparation method thereof. The crystal form A of the Ruimegem intermediate hydrochloride has the advantages of high purity, difficult moisture absorption, high chemical stability and the like, and can be kept stable and not degraded in the long-term storage process of the product. The preparation method of the crystal form A has the advantages of simple process, short time consumption, suitability for technological production and the like.

Description

Crystal form of ramipam intermediate hydrochloride and preparation method thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a crystal form of a ramipam intermediate hydrochloride and a preparation method thereof.
Background
Migraine is a neurological disorder with a wide range of effects. In recent years, according to epidemiological statistics of migraine, the incidence of migraine in the world is 8.4% -28%, and female incidence is higher than male incidence, so that the migraine becomes a global third pandemic. There are 3600 ten thousand patients in the united states alone; the incidence rate of the Japanese migraine is 8.4-12%, and the visit rate is 36-38%. The Ruimepam is a calcitonin related gene peptide (CGRP) receptor antagonist and has good market prospect.
Patent WO2012050764A1 reports the synthetic route of ramelteon, which is as follows:
the method relates to the preparation of a Ruimegempam intermediate hydrochloride (I), and according to the description of the patent specification, the method takes (6S, 9R) -6- (2, 3-difluorophenyl) -9- ((triisopropylsilyl) oxy) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridine-5-ketone as a raw material, and firstly prepares a free base of the intermediate (I), wherein the free base is oily; dissolving the oily free alkali in isopropanol, adding hydrochloric acid to form salt, and preparing the Ruimegempam intermediate hydrochloride (I). The applicant finds that the retipam intermediate hydrochloride (I) prepared by the method is an amorphous substance, and the amorphous substance has higher hygroscopicity and poor chemical stability. Since this intermediate hydrochloride (I) is liable to undergo side reactions such as cyclization after moisture absorption and deliquescence, the intermediate hydrochloride (I) is degraded, further resulting in poor chemical stability. In addition, the amorphous material is not easy to facilitate the feeding in the next reaction after deliquescence, and the material is easy to adhere in the bag, thereby adversely affecting the convenience of production.
In addition, the chiral sites of the intermediate hydrochloride (I) of the Ruimegempam are more, and the isomers generated in the preparation process are more, and particularly diastereoisomers such as (5R, 6S, 9R) -6- (2, 3-difluorophenyl) -9- ((triisopropylsilyl) oxy) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridine-5-amine and the like can be generated. In the preparation method reported in the prior patent, more impurities exist in the product, so that the impurities of the obtained rui-metazipam are more in subsequent synthesis of the rui-metazipam, and the purification difficulty of the subsequent step is increased.
Disclosure of Invention
The invention aims to solve the technical problems of easy moisture absorption, poor chemical stability, low purity and unfavorable production and feeding of a Ruimegem intermediate hydrochloride (I) in the prior art.
In order to solve the technical problems, the invention provides a crystal form A of a Ruimepam intermediate hydrochloride (I):
the Ruimepam intermediate hydrochloride (I) is a hydrate; the X-ray powder diffraction pattern has diffraction peaks at the following 2 theta angles of 5.0+/-0.2 degrees, 10.0+/-0.2 degrees, 13.7+/-0.2 degrees and 19.9+/-0.2 degrees.
Further, the ramelteon intermediate hydrochloride (I) is dihydrate.
Further, the X-ray powder diffraction pattern has diffraction peaks at the following 2 theta angles of 5.0 + -0.2 DEG, 10.0 + -0.2 DEG, 13.7 + -0.2 DEG, 18.0 + -0.2 DEG, 19.9 + -0.2 DEG, 22.2 + -0.2 deg.
The crystal form A of the ramigempam intermediate hydrochloride (I) has the data shown in the table 1, wherein the X-ray powder diffraction expressed in 2 theta:
TABLE 1
The X-ray powder diffraction pattern of the crystal form A of the ramigempam intermediate hydrochloride (I) is shown in figure 1.
The crystal form A of the ramigempam intermediate hydrochloride (I) has DSC endothermic peaks at 140+/-10 ℃ as shown in figure 2. The TG graph shows that the weight loss is 6.3-6.8% at 20-110 ℃, as shown in figure 3; TG pattern analysis shows that the weight loss of the crystal form A is about 6.7% from about 29 ℃ to about 100 ℃.
The invention relates to a crystal form A of a Ruimegempam intermediate hydrochloride (I), and the infrared spectrum of the Ruimegempam intermediate hydrochloride is 2946+/-2 cm -1 、2868±2cm -1 、1625±2cm -1 、1489±2cm -1 、1390±2cm -1 、1270±2cm -1 、1134±2cm -1 、883±2cm -1 、789±2cm -1 、690±2cm -1 An absorption peak is arranged at the position; the infrared spectrum is shown in fig. 4.
In another aspect, the invention provides a method for preparing crystal form a of a ramigempam intermediate hydrochloride (I):
mixing the free alkali (II) of the intermediate of the remigermpam with ethanol and isopropyl acetate, adding an ethanol solution of hydrochloric acid to form salt, filtering, and drying a filter cake to obtain a crystal form A of the hydrochloride (I) of the intermediate of the remigermpam;
the Ruimeigum intermediate hydrochloride (I) is a hydrate; the X-ray powder diffraction pattern has diffraction peaks at the following 2 theta angles of 5.0+/-0.2 degrees, 10.0+/-0.2 degrees, 13.7+/-0.2 degrees and 19.9+/-0.2 degrees.
Further, the ramelteon intermediate hydrochloride (I) is dihydrate.
Further, the X-ray powder diffraction pattern has diffraction peaks at the following 2 theta angles of 5.0+/-0.2 degrees, 10.0+/-0.2 degrees, 13.7+/-0.2 degrees, 18.0+/-0.2 degrees, 19.9+/-0.2 degrees and 22.2+/-0.2 degrees; the X-ray powder diffraction pattern is basically shown in figure 1.
The crystal form A of the Ruimepam intermediate hydrochloride (I) has DSC endothermic peaks at 140+/-10 ℃, as shown in figure 2. The TG graph shows that the weight loss is 6.3-6.8% at 20-110 ℃, as shown in FIG. 3. TG pattern analysis shows that the weight loss of the crystal form A is about 6.7% from about 29 ℃ to about 100 ℃.
The infrared spectrum of the crystal form A of the Ruimepam intermediate hydrochloride (I) is 2946+/-2 cm -1 、2868±2cm -1 、1625±2cm -1 、1489±2cm -1 、1390±2cm -1 、1270±2cm -1 、1134±2cm -1 、883±2cm -1 、789±2cm -1 、690±2cm -1 An absorption peak is arranged at the position; the infrared spectrum is shown in fig. 4.
The weight ratio of the free alkali (II) of the Ruimei gem intermediate to the ethanol is 1:2-10; the weight ratio of the ethanol to the isopropyl acetate is 1:1-10; the weight ratio of the free base (II) of the Ruimepam intermediate to the hydrochloric acid in the ethanol solution of the hydrochloric acid is 1.0:0.14-0.30.
Further, the weight ratio of the free base (II) of the Ruimei gemma intermediate to the ethanol is 1:2-3; the weight ratio of the ethanol to the isopropyl acetate is 1:1-6; the weight ratio of the free base (II) of the Ruimepam intermediate to the hydrochloric acid in the ethanol solution of the hydrochloric acid is 1.0:0.14-0.22.
Furthermore, the filter cake is preferably dried under reduced pressure, provided that the vacuum degree is not less than 0.09mPa and the drying temperature is 0-20 ℃.
The free base (II) of the ruimetadiazepam intermediate can be a crude product or a refined product, preferably the purity is more than or equal to 95 percent, and the specific preparation method can be referred to documents such as WO201205076A1 and the like.
The beneficial effects are that: the crystal form A of the Ruimei pam intermediate hydrochloride (I) has the advantages of high purity, difficult moisture absorption, high chemical stability and the like, and can be kept stable and not degraded in the long-term placement process of the product. The preparation method of the crystal form A of the rui Mei Ji pam intermediate hydrochloride (I) has the advantages of simple process, short time consumption, suitability for technological production and the like.
Drawings
Figure 1, X-ray powder diffraction pattern of crystalline form a of the intermediate hydrochloride salt of remigempam (I).
Figure 2, DSC diagram of crystalline form a of the intermediate hydrochloride (I) of ramelteon.
Fig. 3, TG diagram of crystalline form a of the ramelteon intermediate hydrochloride (I).
Fig. 4, infrared spectra of crystalline form a of the ramelteon intermediate hydrochloride (I).
Fig. 5, liquid chromatogram of crystalline form a of the ramelteon intermediate hydrochloride (I).
Figure 6, X-ray powder diffraction pattern of an amorphous form of the intermediate hydrochloride (I) of ramelteon.
Fig. 7, liquid chromatograms of amorphous form of the intermediate hydrochloride (I) of ramelteon.
Detailed Description
EXAMPLE 1 preparation of Raimepam intermediate free base (II)
Preparation of the ramelteon intermediate free base (II) reference is made to the process disclosed in example 1 of patent WO2012050764 A1: (6S, 9R) -6- (2, 3-difluorophenyl) -9- ((triisopropylsilyl) oxy) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ]]Pyridin-5-one (III, 5.00 g, 11.22 mmol), 1, 4-dioxane (50 mL) and titanium tetra (isopropyl alcohol) (8.33 mL, 28.11 mmol) were added to a 100 mL hastelloy autoclave. The reactor was purged three times with nitrogen and three times with ammonia. After the purge cycle was completed, the reactor was pressurized to 100 psi with ammonia. The reaction mixture was heated to 50 ℃ and stirred at a rate to ensure thorough mixing. The reaction mixture was reacted with ammonia gas at 100 psi and 50 ℃ for 20 h. The mixture was then cooled to 20 ℃, then 5% Pd/alumina (1.0 g, 20 wt%) was charged to the autoclave reactor. The reactor was purged three times with nitrogen and three more times with hydrogen. After the purge cycle was completed, the reactor was pressurized to 100 psi with hydrogen and the mixture was heated to 50 ℃ and stirred at a rate to ensure thorough mixing. The reaction mixture was stirred at 100 psi H 2 23 h are heated at 50 ℃. The mixture was then cooled to 20 ℃, then filtered, and then transferred to a 100 mL three-necked flask. To the mixture was added dropwise water (0.55, mL), stirred for 30 min and filtered, the filter cake was washed with 1, 4-dioxane (30, mL), the filtrates were combined and concentrated to give the ramezone intermediate free base (II) as an oil.
EXAMPLE 2 preparation of the amorphous form of the Raimepam intermediate hydrochloride (I)
Preparation of the amorphous form of the intermediate hydrochloride salt of remigem (I) reference is made to the process disclosed in example 1 of patent WO2012050764 A1: dissolving the free base (II) 5 g of the Ruimegempam intermediate in isopropanol, adding a hydrogen chloride (5N) isopropanol solution 9 mL under stirring, then adding isopropyl acetate 60 mL, heating to 45 ℃, keeping for 10 min, cooling to 22 ℃ through 3 h, filtering, and drying a filter cake to obtain the amorphous substance 3 g of the hydrochloride (I) of the Ruimegempam intermediate, wherein the yield is 51.5 percent and the purity is as follows: 98.88%.
EXAMPLE 3 preparation of Raimepam intermediate hydrochloride (I) form A
Batch 1: adding the free alkali (II) 146.2 g of the Ruimei gem intermediate, ethanol 438.6 g and isopropyl acetate 2631 g into a four-mouth bottle, replacing nitrogen for three times, stirring and dissolving, controlling the temperature to minus 10+/-10 ℃, dropwise adding an ethanol hydrochloride solution (30.7 g in terms of hydrogen chloride), and after the dropwise adding, keeping the temperature and stirring for 1 hour at minus 5 ℃ to minus 10 ℃ to separate out a large amount of white solids. Centrifuging, and rinsing with isopropyl acetate; adding isopropyl acetate 731 g and n-heptane 731 g into the filter cake, pulping and purifying, suction filtering, and drying the filter cake under reduced pressure (vacuum degree: 0.095 mPa, drying temperature: 20-25 ℃) to obtain a Ruimepam intermediate hydrochloride (I) 123 g, yield: 67.63%, purity: 99.59%. Sample X-ray powder diffraction has diffraction peaks at 5.0 °, 10.0 °, 13.8 °, 18.0 °, 19.9 °, 22.2 °.
Batch 2: adding the free alkali (II) 146.2 g of the Ruimei gem intermediate, ethanol 438.6 g and isopropyl acetate 2631 g into a four-mouth bottle, replacing nitrogen for three times, stirring and dissolving, controlling the temperature to minus 10+/-10 ℃, adding an ethanol solution of hydrochloric acid (32 g based on hydrogen chloride), and after dripping, keeping the temperature and stirring for 1 hour at minus 5 ℃ to minus 10 ℃ to separate out a large amount of white solids. Suction filtration, and filter cake decompression drying (vacuum degree: 0.090 mPa, drying temperature: 40-45 ℃) to obtain the Ruimegempam intermediate hydrochloride (I) 125 g, yield: 68.73%, purity: 99.69%. Sample X-ray powder diffraction has diffraction peaks at 5.0 °, 10.0 °, 13.7 °, 18.0 °, 19.9 °, 22.2 °.
Batch 3: the four-mouth bottle is added with 150 g of the free alkali (II) of the Ruimei gem intermediate, 300 g of ethanol and 300 g of isopropyl acetate, stirred and dissolved, and added with ethanol solution of hydrochloric acid (21 g calculated by hydrogen chloride) to separate out a large amount of white solid. Suction filtration, and filter cake decompression drying (vacuum degree: 0.095 mPa, drying temperature: 20-25 ℃) to obtain the Ruimegempam intermediate hydrochloride (I) 112 g, yield: 60.02%, purity: 99.57%. Sample X-ray powder diffraction has diffraction peaks at 5.1 °, 10.0 °, 13.8 °, 18.1 °, 19.9 °, 22.2 °.
Batch 4: the four-mouth bottle is added with 150 g parts of the free alkali (II) of the Ruimei gem intermediate, 1500 g parts of ethanol and 5000 g parts of isopropyl acetate, stirred and dissolved, and added with ethanol solution of hydrochloric acid (45 g parts of hydrogen chloride) to separate out a large amount of white solid. Suction filtration, and filter cake decompression drying (vacuum degree: 0.095 mPa, drying temperature: 45-50 ℃) to obtain the Ruimegempam intermediate hydrochloride (I) 86 g, yield: 46.09%, purity: 99.77%. Sample X-ray powder diffraction has diffraction peaks at 4.9 °, 9.9 °, 13.6 °, 17.9 °, 19.8 °, 22.1 °.
Batch 5: the four-mouth bottle is added with 150 g parts of the free alkali (II) of the intermediate of the Ruimei gem, 300 g parts of ethanol and 3000 parts of isopropyl acetate g parts of ethanol, stirred and dissolved, and added with ethanol solution of hydrochloric acid (22 parts of g parts of ethanol are calculated by hydrogen chloride), so as to separate out a large amount of white solid. Suction filtration, filter cake wet product, boiling and drying, thus obtaining the Ruimegem intermediate hydrochloride (I) 95 g, yield: 50.91%, purity: 99.71%. Sample X-ray powder diffraction has diffraction peaks at 5.0 °, 9.9 °, 13.6 °, 18.0 °, 19.9 °, 22.2 °.
Example 4 preparation of other salt forms of the Raimepam intermediate
Phosphate: to the reaction flask was added the ramelteon intermediate free base (II) 3.03. 3.03 g and absolute ethanol 30. 30 mL. After heating to dissolve, phosphoric acid 220.3 and mg are added. Cooling to room temperature and stirring for 17-18 h. Cooling to room temperature and stirring for 2-3 h. Suction filtering, and drying the filter cake at 35-45 ℃ under reduced pressure for 2-4 h to obtain the acemetapam intermediate phosphate 2.2 g.
Tartrate: to the reaction flask was added the ramegempam intermediate free base (II) 3.05 g and ethyl acetate 30 mL. After heating and dissolving, L-tartaric acid 343.3 mg is added. Cooling to room temperature and stirring for 2-3 h. Suction filtering, and drying the filter cake at 35-45 ℃ under reduced pressure for 15-18 h to obtain the rimmetapam intermediate tartrate 2.5-g.
Oxalic acid salt: to the reaction flask was added the ramegempam intermediate free base (II) 3.22 g and ethyl acetate 30 mL. After heating and dissolving, oxalic acid 334.1. 334.1 mg is added. Cooling to room temperature and stirring for 17-18 h. N-heptane 3 mL is added, cooled to-5 to-10 ℃ and stirred for 10 h. Suction filtering, and drying the filter cake at 35-45 ℃ under reduced pressure for 10-14 and h to obtain the zimetapam intermediate oxalate salt 2.6-g.
Maleic acid salt: to the reaction flask was added the ramegempam intermediate free base (II) 3.10 g and acetone 30 mL. After the temperature is raised and the solution is cleared, maleic acid 265.7 mg is added. Cooling to room temperature and stirring for 17-18 h. N-heptane 3 mL is added, seed crystal is added, the temperature is reduced to 4+/-5 ℃ and the stirring is carried out for 4 to 5 h. Suction filtering, and drying the filter cake at 35-45 ℃ under reduced pressure for 2-4 h to obtain the ramification maleate intermediate 2.3-g.
Sulfate: to the reaction flask was added the ramegempam intermediate free base (II) 3.10 g and acetone 30 mL. After heating to dissolve, 245.6mg of sulfuric acid was added. Cooling to room temperature and stirring for 17-18 h. N-heptane 3 mL is added, seed crystal is added, the temperature is reduced to 4+/-5 ℃ and the stirring is carried out for 4 to 5 h. Suction filtering, and drying the filter cake at 35-45 ℃ under reduced pressure for 2-4 h to obtain the acemetapam intermediate sulfate 2.3 g.
Example 5 stability test of Crystal form
Stability studies were performed on batches 1 to 5 of the crystal form a of the intermediate hydrochloride of ramelteon prepared in example 3, and the crystal form was detected by X-ray powder diffraction at room temperature for 6 months under the following measurement conditions: the X-ray powder diffractometer D8ADVANCE, current intensity 10 mA, voltage 30 kV, step size 0.012 DEG, cu target, diffraction angle 2 theta measurement error of + -0.2 deg. The test data are shown in Table 2.
TABLE 2
Conclusion of experiment: the crystal form A of the ramiazepam intermediate hydrochloride prepared by the invention has good stability, and is placed in a sealed way for 6 months at normal temperature, and the crystal form is not changed.
Example 6 comparative experiments on hygroscopicity and stability
Batches 1-5 of the pam intermediate hydrochloride form a prepared in example 3 and each of the salt forms prepared in example 4 were tested for purity and moisture stability. The method for measuring the moisture comprises the following steps: karl fischer method, solvent DMSO, aldehyde ketone specific titration solution. The purity is detected by high performance liquid chromatography, and the chromatographic conditions are as follows:
chromatographic column: agilent Infinity Lab Poroshell 120 EC-C18 4.6X100 mm 4um or equivalent chromatographic column
Flow rate: 1.0 mL/min
Wavelength: 260 nm (nm)
Column temperature: 35 DEG C
Sample injection amount: 10. mu L
Mobile phase a was acetonitrile: methanol=7:3 (V/V) (precision measurement 700 mL acetonitrile, 300 mL methanol, mixing well, ultrasound for use)
Mobile phase B was 30 mMol/L ammonium acetate (precisely 2.31. 2.31 g ammonium acetate was weighed into a beaker containing 1000 mL ultrapure water, and dissolved by sonication for further use)
Elution mode: gradient elution was performed according to the following ratio
The results of the moisture detection are shown in Table 3, and the results of the purity detection are shown in Table 4.
TABLE 3 Table 3
TABLE 4 Table 4
Conclusion of experiment: the crystal form A of the zimetapam intermediate hydrochloride prepared by the invention has no hygroscopicity, and has excellent stability compared with hydrochloride amorphous substances and other salt forms.
Example 7 preparation of Rametagempam comparative experiments
The preparation of the zimetapam by using the batches 1 to 5 of the zimetapam intermediate hydrochloride crystal form A prepared in the embodiment 3 and the salt forms prepared in the embodiment 4 of the invention as raw materials according to the methods disclosed in the embodiments 2 and 3 of the specification of the patent WO2012050764A1 shows the purity detection results of the batches of the zimetapam product.
TABLE 5
Conclusion of experiment: compared with hydrochloride amorphous substances and other salt forms, the crystal form A of the retipam intermediate hydrochloride provided by the invention is used as a raw material to prepare the final product retipam, and has the advantages of higher purity, lower impurity and obvious advantages.

Claims (10)

1. A crystalline form a of the intermediate hydrochloride salt of remigempam (I), characterized in that:
，
the Ruimepam intermediate hydrochloride (I) is a hydrate; the X-ray powder diffraction pattern has diffraction peaks at the following 2 theta angles of 5.0+/-0.2 degrees, 10.0+/-0.2 degrees, 13.7+/-0.2 degrees and 19.9+/-0.2 degrees.
2. Form a of the ramelteon intermediate hydrochloride (I) according to claim 1, characterized in that: the retipam intermediate hydrochloride (I) is dihydrate.
3. Form a of the ramelteon intermediate hydrochloride (I) according to claim 2, characterized in that: the X-ray powder diffraction pattern has diffraction peaks at the following 2 theta angles of 5.0+/-0.2 degrees, 10.0+/-0.2 degrees, 13.7+/-0.2 degrees, 18.0+/-0.2 degrees, 19.9+/-0.2 degrees and 22.2+/-0.2 degrees.
4. A crystalline form a of the ramelteon intermediate hydrochloride (I) according to claim 3, characterized in that: the X-ray powder diffraction pattern is shown in figure 1.
5. A crystalline form a of the ramelteon intermediate hydrochloride (I) according to any one of claims 1 to 3, characterized in that: the crystal form A has DSC endothermic peaks at 140+/-10 ℃; TG shows that it loses weight 6.3-6.8% at 20-110 ℃.
6. A ramelteon intermediate according to any of claims 1 to 3Form a of hydrochloride (I) characterized in that: the infrared spectrum is 2946+/-2 cm -1 、2868±2cm -1 、1625±2cm -1 、1489±2cm -1 、1390±2cm -1 、1270±2cm -1 、1134±2cm -1 、883±2cm -1 、789±2cm -1 、690±2cm -1 There is an absorption peak.
7. Form a of the ramelteon intermediate hydrochloride (I) according to claim 6, characterized in that: the infrared spectrum is shown in fig. 4.
8. A preparation method of a crystal form A of a Ruimepam intermediate hydrochloride (I), which is characterized by comprising the following steps:
，
mixing the free alkali (II) of the intermediate of the remigermpam with ethanol and isopropyl acetate, adding an ethanol solution of hydrochloric acid to form salt, filtering, and drying a filter cake to obtain a crystal form A of the hydrochloride (I) of the intermediate of the remigermpam;
the Ruimeigum intermediate hydrochloride (I) is a hydrate; the X-ray powder diffraction pattern has diffraction peaks at the following 2 theta angles of 5.0+/-0.2 degrees, 10.0+/-0.2 degrees, 13.7+/-0.2 degrees and 19.9+/-0.2 degrees.
9. The process for the preparation of crystalline form a of the intermediate hydrochloride salt of ramelteon (I) according to claim 8, characterized in that: the weight ratio of the free alkali (II) of the Ruimei gem intermediate to the ethanol is 1:2-10; the weight ratio of the ethanol to the isopropyl acetate is 1:1-10; the weight ratio of the free base (II) of the Ruimepam intermediate to the hydrochloric acid in the ethanol solution of the hydrochloric acid is 1.0:0.14-0.30.
10. Process for the preparation of form a of the intermediate hydrochloride salt of ramelteon (I) according to claim 9, characterized in that: the weight ratio of the free alkali (II) of the Ruimei gem intermediate to the ethanol is 1:2-3; the weight ratio of the ethanol to the isopropyl acetate is 1:1-6; the weight ratio of the free base (II) of the Ruimepam intermediate to the hydrochloric acid in the ethanol solution of the hydrochloric acid is 1.0:0.14-0.22.
CN202311768466.1A 2023-12-21 2023-12-21 Crystal form of ramipam intermediate hydrochloride and preparation method thereof Pending CN117486798A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012050764A1 (en) * 2010-10-12 2012-04-19 Bristol-Myers Squibb Company Process for the preparation of cycloheptapyridine cgrp receptor antagonists
CN102656159A (en) * 2009-10-14 2012-09-05 百时美施贵宝公司 Cgrp receptor antagonists
CN116768938A (en) * 2023-05-17 2023-09-19 南京艾德凯腾生物医药有限责任公司 Preparation method of iron catalyst and Ruimei gem intermediate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102656159A (en) * 2009-10-14 2012-09-05 百时美施贵宝公司 Cgrp receptor antagonists
WO2012050764A1 (en) * 2010-10-12 2012-04-19 Bristol-Myers Squibb Company Process for the preparation of cycloheptapyridine cgrp receptor antagonists
CN116768938A (en) * 2023-05-17 2023-09-19 南京艾德凯腾生物医药有限责任公司 Preparation method of iron catalyst and Ruimei gem intermediate

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