CN106278947B

CN106278947B - Crystal form of phenol derivative and preparation method thereof

Info

Publication number: CN106278947B
Application number: CN201510255867.6A
Authority: CN
Inventors: 杨家亮; 张校伟; 刘兆军; 陈国龙
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Tibet Haisike Pharmaceutical Co ltd
Priority date: 2015-05-19
Filing date: 2015-05-19
Publication date: 2020-03-06
Anticipated expiration: 2035-05-19
Also published as: CN106278947A

Abstract

The invention provides a crystal form of a phenol derivative and a preparation method thereof, and particularly provides a crystal form of a phenol derivative(I) The crystal forms and the preparation methods of the compound and the isomer thereof and the application of the compound and the isomer thereof in the field of medicine. The structure is as follows.

Description

Crystal form of phenol derivative and preparation method thereof

Technical Field

The invention relates to a crystal form of a compound shown as a formula (I) and an isomer thereof, a preparation method thereof and application thereof in the field of medicines.

Background

Propofol activates multiple GABA_AThe receptor subtype, a clinically mature intravenous anesthetic, is widely used for induction and maintenance of general anesthesia. Clinical dose-related propofol can directly activate GABA in mammalian neurons_AThe receptor-chloride channel complex increases chloride conductance, decreases excitability of the neural network, and in turn causes general anesthesia (ManamiHara et al (1993) Anesthesiology,79, 781-788). The remarkable pharmacokinetic and pharmacodynamic properties of propofol are fast onset, short maintenance time and fast reversibility. After intravenous administration, propofol rapidly enters high perfusion areas such as heart, lung and liver from blood, and high lipid solubility enables propofol to easily cross blood brain barrier and enter brain to play a general anesthetic effect. 2- [ (1R) -1-cyclopropylethyl]-6-isopropyl-phenol is a propofol analogue, a highly lipid soluble substance, administered directly into the bloodstream, which causes a rapid onset of anaesthesia.

[2- [ (1R) -1-cyclopropylethyl ] -6-isopropylphenyl ] N- [ (1R) -phenylethyl ] carbamate, a compound of formula (I), is an intermediate in the preparation of 2- [ (1R) -1-cyclopropylethyl ] -6-isopropylphenol and, on examination of its solid form, we have found a solid form which has a pronounced powder X-ray diffraction pattern.

Disclosure of Invention

The invention relates to a compound of formula (I) and a crystal form I of an isomer compound of formula (II).

The invention relates to a compound of formula (IV) and a crystal form II of an isomer compound of formula (III).

The invention relates to a method for preparing a compound of formula (I) and isomeric crystal forms of formula (II), (III) and (IV).

The invention provides a compound of formula (I) and an isomer compound of formula (II) thereof, which have the same crystal form, namely a crystal form I, wherein a powder X-ray diffraction pattern of the compound has characteristic diffraction peaks at d values of 19.3 +/-0.2, 9.5 +/-0.2, 4.8 +/-0.2 and 3.7 +/-0.2; preferably, characteristic diffraction peaks are correspondingly arranged at d values of 19.3 +/-0.2, 9.5 +/-0.2, 8.7 +/-0.2, 4.8 +/-0.2, 4.5 +/-0.2, 4.1 +/-0.2 and 3.7 +/-0.2; preferably having the characteristics represented by the powder X-ray diffraction pattern shown in figure 1.

Further, characteristic XRD peaks of form I of the compound of formula (I) according to the present invention, expressed in ° 2 θ and d values:

serial number	°2θ	d value
			01	4.616	19.128
02	9.394	9.407
			03	10.165	8.695
04	11.840	7.469
			05	15.608	5.673
06	16.459	5.381
			07	17.091	5.184
08	18.413	4.814
			09	19.796	4.481
10	21.887	4.057
			11	23.880	3.723

Further, characteristic XRD peaks of form I of the compound of formula (II) according to the present invention, expressed in ° 2 θ and d values:

serial number	°2θ	d value
			01	4.535	19.467
02	9.257	9.545
			03	10.087	8.762
04	16.994	5.213
			05	17.430	5.084

06	18.394	4.819
			07	19.736	4.495
08	21.810	4.072
			09	23.781	3.738
10	24.017	3.702
			11	24.235	3.669
12	25.339	3.512
			13	25.773	3.454

The invention provides a compound of a formula (IV) and an isomer compound of the formula (III), which have the same crystal form, namely a crystal form II, wherein a powder X-ray diffraction pattern of the compound has characteristic diffraction peaks at d values of 10.3 +/-0.2, 9.4 +/-0.2, 7.7 +/-0.2, 6.2 +/-0.2 and 4.6 +/-0.2, and preferably has characteristic diffraction peaks at d values of 10.3 +/-0.2, 9.4 +/-0.2, 8.4 +/-0.2, 7.7 +/-0.2, 6.2 +/-0.2, 5.8 +/-0.2, 5.0 +/-0.2, 4.6 +/-0.2 and 3.9 +/-0.2; preferably having the characteristics represented by the powder X-ray diffraction pattern shown in FIG. 2;

further, characteristic XRD peaks of form II of the compound of formula (IV) according to the present invention, expressed in ° 2 θ and d values:

serial number	°2θ	d value
			01	8.566	10.314
02	9.375	9.426
			03	10.578	8.356
04	11.505	7.685
			05	14.368	6.160
06	15.176	5.833
			07	17.269	5.131

08	17.645	5.022
			09	18.908	4.690
10	19.242	4.609
			11	20.803	4.266
12	21.099	4.207
			13	22.952	3.872
14	23.268	3.820
			15	24.236	3.669

Further, characteristic XRD peaks of form II of the compound of formula (III) according to the present invention, expressed in ° 2 θ and d values:

serial number	°2θ	d value
			01	8.545	10.339
02	9.354	9.447
			03	10.556	8.374
04	11.447	7.724
			05	14.329	6.176
06	15.138	5.848
			07	17.229	5.142
08	17.624	5.028
			09	18.869	4.699
10	19.202	4.618
			11	20.802	4.267
12	21.078	4.211
			13	22.913	3.878
14	23.229	3.826
			15	24.178	3.678

In a particular embodiment, the present invention provides a compound of formula (I) prepared having a crystalline form I content (mass content) of generally greater than 70%, preferably greater than 80%, and even most preferably greater than 90%.

In a specific embodiment, the present invention provides a compound of formula (II) prepared having a crystalline form I content (mass content) of generally greater than 70%, preferably greater than 80%, and more preferably greater than 90%.

In a specific embodiment, the present invention provides a compound of formula (IV) prepared having a crystalline form II content (mass content) of generally greater than 70%, preferably greater than 80%, and more preferably greater than 90%.

In a specific embodiment, the present invention provides a compound of formula (III) prepared having a crystalline form II content (mass content) generally greater than 70%, preferably greater than 80%, and more preferably greater than 90%.

The invention provides a method for preparing a compound of formula (I) and isomeric crystal forms of formula (II), (III) and (IV), comprising the following steps:

1. crystal slurry crystallization method: mixing the compound of the formula (I) or the isomer thereof with a single solvent or a combined solvent, performing ultrasonic treatment at room temperature to obtain a suspension, and then performing crystal slurry on the suspension obtained by ultrasonic treatment at room temperature for 3 days. And (4) taking the turbid liquid after crystal mush, filtering under reduced pressure, and drying to obtain the target crystal form.

2. And (3) a volatilization crystallization method: mixing the compound of formula (I) or an isomer thereof with a single solvent, performing ultrasonic treatment at room temperature to obtain a clear solution or a nearly clear solution, naturally volatilizing at room temperature after being opened, and drying to obtain the target crystal form.

3. Cooling crystallization method: mixing the compound of formula (I) or an isomer thereof with a combined solvent, performing ultrasonic treatment at room temperature to obtain a suspension, heating and stirring the suspension until the suspension is clear or close to the clear, placing the suspension at room temperature for stirring, performing reduced pressure filtration after crystallization, and drying to obtain the target crystal form.

4. Anti-solvent crystallization method: adding a good solvent into the compound of the formula (I) or the isomer thereof, performing ultrasonic treatment at room temperature to obtain a clear solution or a nearly clear solution, then adding an anti-solvent in a corresponding proportion into the sample clear solution in a forward adding manner, stirring, performing reduced pressure filtration after crystallization, and drying to obtain the target crystal form.

In a preferred embodiment of the present invention, a process for preparing a compound of formula (I) and its isomeric forms (II), (III), (IV), which process comprises: mixing the compound of formula (I) or its isomer with solvent, performing ultrasound at room temperature to obtain suspension, crystallizing the suspension at room temperature for 3 days, collecting the crystallized suspension, filtering under reduced pressure, and drying; the solvent is selected from the combination of water and one or more of ethanol, isopropanol, acetone or 1, 4-dioxane;

preferably, the solvent is selected from the group consisting of water and one of ethanol, isopropanol, acetone or 1, 4-dioxane, and the ratio of the two solvents is 5: 1-0: 1;

it is further preferred that the ratio of the two solvents is 1: 1;

in a preferred embodiment of the present invention, a process for preparing a compound of formula (I) and its isomeric forms (II), (III), (IV), which process comprises: mixing the compound of formula (I) or its isomer with solvent, ultrasonic treating at room temperature to obtain clear solution or near clear solution, naturally volatilizing at room temperature, and drying; the solvent is selected from one or more of ethanol, acetone, 1, 4-dioxane, isopropyl ether, n-hexane or n-heptane;

preferably, the solvent is a combination of two solvents, and the ratio of the two solvents is 5: 1-0: 1;

it is further preferred that the ratio of the two solvents is 0: 1.

in a preferred embodiment of the present invention, a process for preparing a compound of formula (I) and its isomeric forms (II), (III), (IV), which process comprises: mixing the compound of formula (I) or its isomer with solvent, ultrasonic treating at room temperature to obtain suspension, heating and stirring the suspension until it is clear or nearly clear, stirring at room temperature, crystallizing, filtering under reduced pressure, and drying; the solvent is selected from one or more of water, n-heptane, n-hexane, isopropyl ether, ethanol, 1, 4-dioxane, acetone or acetonitrile;

wherein, when the two solvents are combined, the two solvents can be selected from any two of water, n-heptane, n-hexane, isopropyl ether, ethanol, 1, 4-dioxane, acetone or acetonitrile;

in some preferred embodiments of the present invention, the solvent is water, and a combination of any one selected from the group consisting of n-heptane, n-hexane, isopropyl ether, ethanol, 1, 4-dioxane, acetone, and acetonitrile;

it is further preferred that the ratio of the two solvents is 3: 1-1: 2.

in a preferred embodiment of the present invention, a process for preparing a compound of formula (I) and its isomeric forms (II), (III), (IV), which process comprises: adding a good solvent into the compound of the formula (I) or an isomer thereof, performing ultrasonic treatment at room temperature to obtain a clear solution or a nearly clear solution, adding an anti-solvent in a corresponding proportion into the clear solution of the sample in a forward adding manner, stirring, performing reduced pressure filtration after crystallization, and drying; the good solvent is selected from one or more of ethanol, isopropanol, acetone, 1, 4-dioxane, acetonitrile and isopropyl ether, and the anti-solvent is selected from one or more of water and n-heptane;

wherein when the anti-solvent is water, the good solvent can be one or more selected from ethanol, isopropanol, acetone, 1, 4-dioxane, acetonitrile and isopropyl ether;

wherein when the anti-solvent is n-heptane, the good solvent can be selected from one or more of ethanol, isopropanol, acetone, 1, 4-dioxane, acetonitrile, and isopropyl ether;

preferably, the good solvent is selected from ethanol, isopropanol, acetone, 1, 4-dioxane, acetonitrile and isopropyl ether, the anti-solvent is selected from water or n-heptane, and the ratio of the anti-solvent to the good solvent is 5: 1-0: 1;

further preferably, the ratio of the antisolvent to the good solvent is 4: 1-1: 1.

drawings

Figure 1 is an XRD pattern of form I of compound of formula (I).

Figure 2 is an XRD pattern of compound of formula (IV) form II.

Figure 3 is an XRD pattern of form I of compound of formula (II).

Figure 4 is an XRD pattern of compound of formula (III) form II.

Figure 5 is a Differential Scanning Calorimetry (DSC) curve of form I of compound of formula (I).

Figure 6 is a thermogravimetric analysis (TGA) curve of form I of compound of formula (I).

Figure 7 is a Differential Scanning Calorimetry (DSC) curve of compound form II of formula (IV).

Figure 8 is a thermogravimetric analysis (TGA) curve of crystalline form II of the compound of formula (IV).

Detailed Description

The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10^-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

The apparatus used for the X-ray powder diffractometer was a Bruker D8Advance diffractometer, using a Cu-Ka radiation source, unless otherwise specified, the sample was not ground prior to detection.

Differential thermal analysis scanner (DSC) data were obtained from TA Instruments Q200DSC, samples were dried N at 40mL/min at a ramp rate of 10 ℃/min₂The sample was warmed from 0 ℃ to 200 ℃ under the protection of (1).

Thermogravimetric analyzer (TGA) data were taken from TA Instruments Q500TGA, and the sample was heated to 300 ℃ at a ramp rate of 10 ℃/min.

Fourier Infrared (FT-IR) data was taken from Bruker Tensor 27.

MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6 mm).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical, Shaoshan far chemical technology, and Bailingwei technology.

The nitrogen atmosphere means that the reaction flask is connected with a nitrogen balloon with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is room temperature, unless otherwise specified.

The room temperature is the most suitable reaction temperature and is 20-30 ℃.

Example 1: 2- [ (1R) -1-Cyclopropylethyl ] -6-isopropyl-phenol (Compound 1)

2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol

The first step is as follows: 1- [ (E) -but-2-enyloxy ] -2-isopropyl-benzene (1B)

1-[(E)-but-2-enoxy]-2-isopropyl-benzene

2-isopropylphenol 1A (3000g, 22.0mol) and N, N-dimethylformamide (9.0L) were charged into a 10L reactor, and the temperature was lowered to 10 ℃ in an ice-water bath. Solid sodium hydroxide (969g, 24.2mol) was added in portions, the temperature was kept between 10 ℃ and 15 ℃, and after the addition, a solution of 1-chloro-2-butene (2595g, 28.7mol) in N, N-dimethylformamide (6.0L) was added dropwise. After the dropwise addition, the temperature is kept between 10 and 15 ℃ for reaction for 5 hours. The reaction mixture was poured into ice water, extracted with n-hexane, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product 1- [ (E) -but-2-enyloxy ] -2-isopropyl-benzene 1B (3985g, 95.08% yield) as a bright yellow liquid.

¹H NMR(400MHz,CDCl₃)δ7.20(dd,1H),7.16～7.07(m,1H),6.90(t,1H),6.82(dd,1H),5.89～5.67(m,2H),4.50～4.39(m,2H),3.35(m,1H),1.79～1.69(m,3H),1.21(dd,6H)。

The second step is that: (R, S) -2-isopropyl-6- (1-methylallyl) phenol (1C)

(R,S)-2-isopropyl-6-(1-methylallyl)phenol

1- [ (E) -but-2-enyloxy ] -2-isopropyl-benzene 1B (3985g, 20.5mol) and potassium carbonate (28.3g, 0.205mol) were charged into a 5L reactor, and the mixture was heated to 200 ℃ under nitrogen protection to react for 7 hours. The reaction mixture was cooled to room temperature, dissolved in a mixed solvent of ethylene glycol and methanol (v: v ═ 1:1), and extracted with n-hexane for 3 times, and the lower layer was separated. Adding saturated sodium chloride solution into the lower layer, extracting with n-hexane, combining n-hexane layers, washing with saturated sodium chloride solution, and drying with anhydrous sodium sulfate. The mixture was filtered, concentrated, and the residue was subjected to column chromatography (eluent: n-hexane: ethyl acetate (v: v) ═ 100:1 to 20:1), and then distilled under reduced pressure to give the title product (R, S) -2-isopropyl-6- (1-methylallyl) phenol 1C (1340g, yield 33.63%, HPLC: 98.22%) as a colorless oil.

¹H NMR(400MHz,CDCl₃)δ7.10(d,1H),6.98(d,1H),6.88(t,1H),6.07(m,1H),5.20(m,3H),3.69～3.56(m,1H),3.24(m,1H),1.40(d,3H),1.23(dd,6H)。

The third step: (R, S) -2- (1-Cyclopropylethyl) -6-isopropyl-phenol (1D)

(R,S)-2-(1-cyclopropylethyl)-6-isopropyl-phenol

Under the protection of nitrogen flow, 1.0M triethyl aluminum n-hexane solution (64.00L, 64.00mol) is added into a 100L glass reaction kettle, and the temperature is cooled to-5 ℃ to 5 ℃. (R, S) -2-isopropyl-6- (1-methylallyl) -phenol 1C (4.06kg, 21.34mol) solution in dichloromethane (13.56kg) was added dropwise with stirring, after 3 hours; diiodomethane (20.00kg, 74.67mol) was added dropwise over about 40 minutes; after the addition, the reaction is kept for 48 hours at the temperature of between 30 and 35 ℃. The reaction mixture was quenched dropwise into a 10.0% aqueous solution of sodium hydroxide while stirring. Standing and layering the quenching liquid, and separating an organic layer; extracting the water layer with n-hexane once, separating out alkaline water layer, and combining organic layers; the organic layer was washed with deionized water and a sodium chloride solution in this order, and then dried over anhydrous sodium sulfate. After concentration by filtration, the title product (R, S) -2- (1-cyclopropylethyl) -6-isopropyl-phenol 1D was obtained as a pale yellow oil by distillation under the reduced pressure (3.52kg, yield 80.73%, HPLC: 96.59%).

¹H NMR(400MHz,CDCl₃)δ7.11(d,1H),7.06(d,1H),6.89(t,1H),4.92(s,1H),3.15(m,1H),2.57～2.39(m,1H),1.35～1.19(m,9H),1.04(m,1H),0.55(m,1H),0.51～0.38(m,1H),0.29～0.09(m,2H)。

The fourth step: [2- [ (1R,1S) - (1-cyclopropylethyl) ] -6-isopropyl-phenyl ] N- [ (1R) -1-phenylethyl ] carbamate (1E)

[2-[(1R,1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate

Into a 50L glass reactor were charged n-heptane (25.00kg), (R, S) -2- (1-cyclopropylethyl) -6-isopropyl-phenol 1D (5.00kg, 24.47mol), (R) - (+) -1-phenylethyl isocyanate (4.69kg, 31.87mol) and triethylamine (1.24kg, 12.26mol) in this order, and the reaction was carried out at 28 to 33 ℃ for 48 hours. And after the reaction is finished, filtering the reaction liquid, and performing suction filtration until the reaction liquid is dry to obtain a wet product. Dissolving the wet product with ethyl acetate, stirring for 2 hours, adding n-hexane, and continuing stirring for 1 hour. The mixture was filtered through celite, and the filtrate was collected. The filtrate was concentrated under reduced pressure and dried in vacuo to give the title product [2- [ (1R,1S) - (1-cyclopropylethyl) ] -6-isopropyl-phenyl ] N- [ (1R) -1-phenylethyl ] carbamate 1E (2.68kg) as an off-white solid.

The fifth step: [2- [ (1R) -1-cyclopropylethyl ] -6-isopropylphenyl ] N- [ (1R) -phenylethyl ] carbamate (1F)

[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate

[2- [ (1R,1S) - (1-cyclopropylethyl) ] -6-isopropyl-phenyl ] N- [ (1R) -1-phenylethyl ] carbamate 1E (2.68kg) was recrystallized from N-heptane 3 times, filtered and the filter cake was dried to give the title product [2- [ (1R) -1-cyclopropylethyl ] -6-isopropylphenyl ] N- [ (1R) -phenylethyl ] carbamate 1F as an off-white solid (2.00kg, overall yield of the fourth and fifth steps 46.52%, HPLC: 97.31%, chiral-HPLC: 99.90%).

¹H NMR(400MHz,CDCl₃)δ7.45～7.01(m,8H),5.27(d,1H),4.91(m,1H),3.15～2.86(m,1H),2.08(s,1H),1.55(d,3H),1.33～0.86(m,10H),0.49(s,1H),0.31(s,1H),0.15～-0.04(m,2H)。

And a sixth step: 2- [ (1R) -1-Cyclopropylethyl ] -6-isopropyl-phenol (Compound 1)

2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol

A50L glass reactor was purged with nitrogen gas, 1, 4-dioxane (10.17kg) and [2- [ (1R) -1-cyclopropylethyl ] -6-isopropylphenyl ] N- [ (1R) -phenylethyl ] carbamate 1F (1.99kg) were charged, 6.0% aqueous sodium hydroxide solution (10.17kg) was added dropwise, and after completion of the addition, the temperature was raised to 65 ℃ to 75 ℃ for reaction for 2 hours. Adding n-hexane into the cooled reaction solution, stirring, spreading diatomite, filtering, and collecting filtrate. Transferring the filtrate into a 100L glass kettle, adding deionized water, stirring, standing for layering, separating out a water layer, extracting once with n-hexane, and combining organic layers; the organic layer was washed with 3.6% aqueous hydrochloric acid, deionized water, 10.0% aqueous sodium hydrogencarbonate and aqueous sodium chloride in this order, and then dried over anhydrous sodium sulfate. After concentration by filtration, the title product, 2- [ (1R) -1-cyclopropylethyl ] -6-isopropyl-phenol compound 1, was obtained as a pale yellow oil by distillation under the reduced pressure (1.00kg, yield 86.45%, HPLC: 99.93%, chiral-HPLC: 99.91%).

¹H NMR(400MHz,CDCl₃)δ7.11(d,2H),7.06(d,2H),6.89(t,1H),4.91(s,1H),3.15(m,1H),2.49(m,1H),1.35～1.19(m,9H),1.10～0.98(m,1H),0.55(m,1H),0.50～0.41(m,1H),0.19(m,2H)。

Example 2: 2- [ (1S) -1-Cyclopropylethyl ] -6-isopropyl-phenol (Compound 2)

2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenol

The first step is as follows: [2- [ (1R,1S) - (1-Cyclopropylethyl) ] -6-isopropyl-phenyl ] N- [ (1S) -1-phenylethyl ] carbamate (2A)

[2-[(1R,1S)-cyclopropylethyl)]-6-isopropyl-phenyl]N-[(1S)-1-phenylethyl]carbamate

To a reaction flask were added (R, S) -2- (1-cyclopropylethyl) -6-isopropylphenol 1D (42.00g, 205.57mmol) and tetrahydrofuran (200mL), triethylamine (58.00g, 573.18mmol) was added dropwise, after stirring to homogeneity, (S) - (-) -1-phenylethyl isocyanate (45.00g, 308.36mmol) was added, heating was carried out to 63 ℃ and stirring was carried out for 6 hours, the solid was concentrated under reduced pressure, dissolved in ethyl acetate, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to give the title product [2- [ (1R,1S) - (1-cyclopropylethyl) ] -6-isopropyl-phenyl ] N- [ (1S) -1-phenylethyl ] carbamate 2A (80.00g) as a white solid.

MS m/z(ESI):352.5[M+1]⁺。

¹HNMR(400MHz,CDCl₃)：δ7.38～7.11(m,8H),5.27～5.08(m,1H),4.94～4.87(m,1H),3.00～2.97(m,1H),2.08(s,1H),1.55(d,3H),1.23～1.13(m,9H)，0.95(s,1H),0.49(s,1H),0.31(s,1H),0.05(s,1H)。

The second step is that: [2- [ (1S) -1-cyclopropylethyl ] -6-isopropylphenyl ] N- [ (1S) -phenylethyl ] carbamate (2B)

[2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]N-[(1S)-1-phenylethyl]carbamate

The [2- [ (1R,1S) - (1-cyclopropylethyl) ] -6-isopropyl-phenyl ] N- [ (1S) -1-phenylethyl ] carbamate 2A (80.00g) obtained in the previous step was recrystallized 4 times from N-hexane, filtered and the filter cake was dried to give the title product [2- [ (1S) -1-cyclopropylethyl ] -6-isopropylphenyl ] N- [ (1S) -1-phenylethyl ] carbamate 2B (39g, yield: 54.93%, HPLC: 97.62%, chiral-HPLC: 99.84%) as a white powder.

The compound 1D contains 1 chiral center, and only two isomers, namely the compound 1 and the compound 2, can be obtained after resolution. The compound 2B contains two chiral centers, wherein 1 chiral center is introduced by (S) - (-) -1-phenethyl isocyanate, and the chiral carbon atom connected with the cyclopropane group is consistent with the chirality of the compound 2.

The third step: 2- [ (1S) -1-Cyclopropylethyl ] -6-isopropyl-phenol (Compound 2)

2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenol

[2- [ (1S) -1-cyclopropylethyl ] -6-isopropylphenyl ] N- [ (1S) -1-phenylethyl ] carbamate 2B (39.00g, 110.96mmol) was dissolved in tetrahydrofuran (390mL), 1.0M aqueous sodium hydroxide (190mL, 190mmol) was added, the mixture was heated to 70 ℃ under nitrogen protection to react for 4 hours, the mixture was allowed to stand and separate into layers, the organic layer was collected, the aqueous layer was adjusted to pH 7 with 1M hydrochloric acid, extracted with ethyl acetate, the organic layers were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 100:1) to give the title product 2- [ (1S) -1-cyclopropylethyl ] -6-isopropyl-phenol compound 2(17.2g, yield: 75.80%, HPLC: 97.67%, chiral-HPLC: 99.86%). The compound 1D contains a chiral center, and can only obtain two isomers, namely a compound 1 and a compound 2 after resolution.

MS m/z(ESI):203.1[M-1]^-。

¹HNMR(400MHz,CDCl₃):δ7.14(dd,1H),7.08(dd,1H),6.93(t,1H),4.93(s,1H),3.22～3.15(m，1H),2.55～2.48(m,1H),1.32(d，6H),1.28(d,3H),1.10～1.04(m,1H),0.60～0.58(m,1H),0.49～0.46(m,1H),0.25～0.18(m,2H)。

Example 3: [2- [ (1S) - (1-Cyclopropylethyl) ] -6-isopropyl-phenyl ] N- [ (1R) -1-phenylethyl ] carbamate (Compound 3)

[2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate

2- [ (1S) -1-Cyclopropylethyl ] -6-isopropyl-phenol (Compound 2) (5.00g,24.47mmol) and tetrahydrofuran (50mL) were added to a reaction flask, triethylamine (4.95g,48.95mmol) was added dropwise, after stirring well, (1R) -1-phenethylisocyanate (5.40g,36.71mmol) was added, heating was carried out to 63 ℃ and stirring overnight, concentration under reduced pressure was carried out, dissolution was carried out with ethyl acetate (10mL), suction filtration was carried out under reduced pressure, and the filtrate was concentrated under reduced pressure to give [2- [ (1S) -1-cyclopropylethyl ] -6-isopropylphenyl ] N- [ (1R) -1-phenethyl ] carbamate (Compound 3) (9.00g, HPLC: 98.4%, chiralHPLC: 97.3%) as a white solid.

MS m/z(ESI):352.5[M+1]。

1HNMR(400MHz,CDCl3):δ7.36～7.13(m,8H),5.26(d,1H),4.94～4.87(m,1H),3.01～2.98(m,1H),2.04～2.09(m,1H),1.55(d,3H),1.20～1.15(m,9H),0.96～0.93(m,1H),0.45～0.43(m,1H),0.37～0.30(m,1H),0.18～0.09(m,2H)。

Example 4: [2- [ (1R) - (1-Cyclopropylethyl) ] -6-isopropyl-phenyl ] N- [ (1S) -1-phenylethyl ] carbamate (Compound 4)

[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]N-[(1S)-1-phenylethyl]carbamate

2- [ (1R) -1-Cyclopropylethyl ] -6-isopropyl-phenol (Compound 1) (5.00g,24.47mmol) and tetrahydrofuran (50mL) were added to a reaction flask, triethylamine (4.95g,48.95mmol) was added dropwise, after stirring well, (1S) -1-phenethylisocyanate (5.40g,36.71mmol) was added, heating was carried out to 63 ℃ and stirring overnight, concentration under reduced pressure was carried out, dissolution was carried out with ethyl acetate (10mL), suction filtration was carried out under reduced pressure, and the filtrate was concentrated under reduced pressure to give [2- [ (1R) -1-cyclopropylethyl ] -6-isopropylphenyl ] N- [ (1S) -1-phenethyl ] carbamate (Compound 4) (9.50g, HPLC: 99.4%, chiralHPLC: 99.5%) as a white solid.

MS m/z(ESI):352.5[M+1]。

Example 5: x-ray single crystal diffraction test of [2- [ (1R) -1-cyclopropylethyl ] -6-isopropylphenyl ] N- [ (1R) -phenylethyl ] carbamate (1F)

Colorless plate-like single crystals having a size of 0.30mm × 0.20mm × 0.20mm were selected from the off-white solids prepared in the fifth step of example 1 and adhered to a glass filament, and the crystals for diffraction experiments were triclinic, space group was P1, unit cell parameters: 5.3665(3) and 10.3493(11) respectively,

α 97.598(9) ° β 96.660(7) ° γ 90.165(6) ° unit cell volume

Asymmetric unit number Z2. diffraction intensity data were collected at 293.15K on an Xcalibur four-circle single crystal diffractometer using Mo K α radiation (λ 0.7107, tube pressure: 50kv, tube flow: 40ma), the distance D between the crystal and the CCD detector was 45mm, and the scanning mode was 2 θ (6.32 °)<θ<52.744 deg.) and a total of 8385 diffraction points were collected (-6. ltoreq. h.ltoreq.6, -12. ltoreq. k.ltoreq.12, -21. ltoreq. l.ltoreq.23), wherein 5645 diffraction points were [ Rint. 0.0372 and Rsigma. 0.0588)]. The acquisition and reduction of the diffraction intensity data of the crystal use the matching software of a diffractometer: CrysAlisPro, crystal structure analysis used Olex2 and SHELXS-13 (direct method), and the coordinates of all atoms and anisotropy parameters were refined using SHELXL-13 (partial least squares). The residual factor R of the finally obtained crystal structure₁＝0.0850,wR₂＝0.2088[I>＝2σ(I)]，R₁＝0.1115,wR₂＝0.2405[all data]And S is 1.064, the refinement parameters are 480, and the constraint condition is 3.

The absolute configuration of the 16-position carbon atom of the compound 1F is introduced from the known (R) - (+) -1-phenylethyl isocyanate, so that the absolute configuration of the 16-position carbon atom of the compound 1F is the known R configuration, which is shown by an X-ray single crystal diffraction pattern (fig. 1): the absolute configuration of C-7 is identical to that of 16-C, and is therefore also the R configuration. The absolute configuration of the compound 1F confirms that the absolute configuration of the C-7 of the compound 1 is the R configuration.

Example 1:

the crystal slurry crystallization method is used for preparing the compound shown in the formula (I) and the isomers (II), (III) and (IV) crystal forms thereof.

Taking about 50mg of a research sample, placing the research sample into a 10mL glass vial, adding 5.0mL of a single solvent or a mixed solvent formed by a solvent A and a solvent B in different proportions into the glass vial in which the sample is placed, then placing the glass vial in which the sample and the solvent are placed at room temperature, carrying out ultrasonic treatment for 10min to ensure that a suspension is obtained, and then carrying out crystal slurry on the suspension obtained by ultrasonic treatment at room temperature for 3 days. And (4) filtering the turbid liquid after taking the crystal slurry under reduced pressure, and drying the crystal and then sampling XRD, DSC and TGA for characterization. The results are shown in tables 1-8.

TABLE 1 results for the preparation of crystalline forms of the compound of formula (I)

Numbering

Temperature of

Solvent A

Solvent B

A:B

Results of research and development

XRD results

1

At room temperature

Water (W)

Ethanol

1:1

Has crystals

Crystal form I

2

At room temperature

Water (W)

Isopropanol (I-propanol)

1:1

Has crystals

Crystal form I

3

At room temperature

Water (W)

Acetone (II)

1:1

Has crystals

Crystal form I

4

At room temperature

Water (W)

1, 4-dioxane

1:1

Has crystals

Crystal form I

The research result of the crystal form of the compound shown in the formula (I) shows that all crystals are the same crystal form I, and other new crystal forms are not found. As seen in the DSC curve of fig. 5, form I has good thermal stability, and the DSC curve shows that the onset of the endothermic heat flow of form I is at about 112.6 ℃ (enthalpy 102.2J/g). The DSC and TGA profile (figure 6) data illustrate the absence of mixed crystals, solvents, and water of crystallization in form I.

TABLE 2 characteristic powder X-ray diffraction (XRD) peaks (FIG. 1) of form I of Compound of formula (I)

Serial number	°2θ	d value
			01	4.616	19.128
02	9.394	9.407
			03	10.165	8.695
04	11.840	7.469
			05	15.608	5.673
06	16.459	5.381

07	17.091	5.184
			08	18.413	4.814
09	19.796	4.481
			10	21.887	4.057
11	23.880	3.723

TABLE 3 results of obtaining crystalline forms of the compound of formula (IV)

Numbering

Temperature of

Solvent A

Solvent B

A:B

Results of research and development

XRD results

1

At room temperature

Water (W)

Ethanol

1:1

Has crystals

Crystal form II

2

At room temperature

Water (W)

Isopropanol (I-propanol)

1:1

Has crystals

Crystal form II

The research result of the crystal form of the compound shown in the formula (IV) shows that all crystals are the same crystal form II, and other new crystal forms are not found. As seen in the DSC curve of fig. 7, form II has good thermal stability, and the DSC curve shows that the onset of endothermic heat flow for form II is at about 76.2 ℃ (enthalpy 56.8J/g). The DSC and TGA profile (figure 8) data show no mixed crystals, solvents and water of crystallization in form II.

TABLE 4 characteristic powder X-ray diffraction (XRD) peaks (FIG. 2) of form II of compound of formula (IV)

Serial number	°2θ	d value
			01	8.566	10.314
02	9.375	9.426
			03	10.578	8.356
04	11.505	7.685
			05	14.368	6.160
06	15.176	5.833
			07	17.269	5.131
08	17.645	5.022
			09	18.908	4.690
10	19.242	4.609
			11	20.803	4.266
12	21.099	4.207
			13	22.952	3.872

14	23.268	3.820
			15	24.236	3.669

TABLE 5 results of obtaining crystalline forms of the compound of formula (II)

Numbering

Temperature of

Solvent A

Solvent B

A:B

Results of research and development

XRD results

1

At room temperature

Water (W)

Ethanol

1:1

Has crystals

Crystal form I

2

At room temperature

Water (W)

Isopropanol (I-propanol)

1:1

Has crystals

Crystal form I

3

At room temperature

Water (W)

Acetone (II)

1:1

Has crystals

Crystal form I

4

At room temperature

Water (W)

1, 4-dioxane

1:1

Has crystals

Crystal form I

The research result of the crystal form of the compound shown in the formula (II) shows that all crystals are the same crystal form I, other new crystal forms are not found, and DSC and TGA data show that no mixed crystal, solvent and crystal water phenomenon exists in the crystal form I.

TABLE 6 characteristic powder X-ray diffraction (XRD) peaks (FIG. 3) of form I of Compound of formula (II)

Serial number	°2θ	d value
			01	4.535	19.467
02	9.257	9.545
			03	10.087	8.762
04	16.994	5.213
			05	17.430	5.084
06	18.394	4.819
			07	19.736	4.495
08	21.810	4.072
			09	23.781	3.738
10	24.017	3.702
			11	24.235	3.669
12	25.339	3.512
			13	25.773	3.454

TABLE 7 results for the compound of formula (III) in crystal form

Numbering

Temperature of

Solvent A

Solvent B

A:B

Results of research and development

XRD results

1

At room temperature

Water (W)

Ethanol

1:1

Has crystals

Crystal form II

2

At room temperature

Water (W)

Isopropanol (I-propanol)

1:1

Has crystals

Crystal form II

The research result of the crystal form of the compound shown in the formula (III) shows that all crystals are the same crystal form II, other new crystal forms are not found, and DSC and TGA data show that no mixed crystal, solvent and crystal water phenomenon exists in the crystal form II.

TABLE 8 characteristic powder X-ray diffraction (XRD) peaks (FIG. 4) of form II of compound of formula (III)

Example 2:

the compound of formula (I) and the crystal forms of isomers (II), (III) and (IV) thereof are prepared by a volatilization crystallization method.

Placing about 25mg of a research sample into a 10mL or 25mL glass vial, adding 0.25-20.0 mL of a single solvent into the glass vial in which the sample is placed, then placing the glass vial in which the sample and the solvent are placed at room temperature, carrying out ultrasonic treatment for 30min to obtain a solution clear liquid or a near solution clear liquid (if a layered suspension is formed after ultrasonic treatment, taking a solution clear layer), and directly placing the solution clear liquid open to the atmosphere to naturally volatilize at room temperature. The obtained crystals were dried and then characterized by XRD, DSC and TGA by sampling. The results are shown in tables 9 to 12.

TABLE 9 results for the compound of formula (I) in crystal form

Numbering	Temperature of	Solvent B	Results of research and development	XRD results
					1	At room temperature	Ethanol	Has crystals	Crystal form I
2	At room temperature	Acetone (II)	Has crystals	Crystal form I
					3	At room temperature	1, 4-dioxane	Has crystals	Crystal form I
4	At room temperature	Isopropyl ether	Has crystals	Crystal form I
					5	At room temperature	N-hexane	Has crystals	Crystal form I
6	At room temperature	N-heptane	Has crystals	Crystal form I

The research result of the crystal form of the compound shown in the formula (I) shows that all crystals are the same crystal form I, and DSC and TGA data show that no mixed crystal, solvent or crystal water exists in the crystal form I.

TABLE 10 results for the compound of formula (IV) in crystal form

Numbering	Temperature of	Solvent B	Results of research and development	XRD results
					1	At room temperature	Ethanol	Has crystals	Crystal form II
2	At room temperature	Acetone (II)	Has crystals	Crystal form II
					3	At room temperature	1, 4-dioxane	Has crystals	Crystal form II
4	At room temperature	Isopropyl ether	Has crystals	Crystal form II
					5	At room temperature	N-hexane	Has crystals	Crystal form II
6	At room temperature	N-heptane	Has crystals	Crystal form II

The research result of the crystal form of the compound shown in the formula (IV) shows that all crystals are the same crystal form II, and DSC and TGA data show that no mixed crystal, solvent and crystal water phenomenon exists in the crystal form II.

TABLE 11 results for the compound of formula (II) in crystal form

The research result of the crystal form of the compound shown in the formula (II) shows that all crystals are the same crystal form I, and DSC and TGA data show that no mixed crystal, solvent and crystal water phenomenon exists in the crystal form I.

TABLE 12 results for the compound of formula (III) obtained in crystalline form

The research result of the crystal form of the compound shown in the formula (III) shows that all crystals are the same crystal form II, and DSC and TGA data show that no mixed crystal, solvent and crystal water phenomenon exists in the crystal form II.

Example 3:

the compound of formula (I) and the crystal forms of isomers (II), (III) and (IV) thereof are prepared by a cooling crystallization method.

Placing about 50mg of a research sample into a 10mL or 25mL glass vial, adding a mixed solvent formed by 2.0-10.0 mL of solvent A and solvent B in different proportions into the glass vial in which the sample is placed, then placing the glass vial in which the sample and the solvent are placed at room temperature for 30min to obtain a suspension, directly placing the glass vial containing the suspension into a water bath heated to 60 ℃, stirring until the suspension is clear or nearly clear, and placing the glass vial at room temperature for stirring. After crystallization, the mixture is filtered under reduced pressure, and after drying, the mixture is characterized by sampling XRD, DSC and TGA. The results are shown in tables 13 to 16.

TABLE 13 results for the compound of formula (I) in crystal form

Numbering	Solvent A	Solvent B	A:B	Results of research and development	XRD results
						1	/	N-heptane	/	Has crystals	Crystal form I
2	/	N-hexane	/	Has crystals	Crystal form I
						3	/	Isopropyl ether	/	Has crystals	Crystal form I
4	Water (W)	Ethanol	1:2	Has crystals	Crystal form I
						5	Water (W)	1, 4-dioxane	3:1	Has crystals	Crystal form I
6	Water (W)	Acetone (II)	1:1	Has crystals	Crystal form I
						7	Water (W)	Acetonitrile	3:2	Has crystals	Crystal form I

TABLE 14 results for the compound of formula (IV) in crystal form

Numbering	Solvent A	Solvent B	A:B	Results of research and development	XRD results
						1	/	N-heptane	/	Has crystals	Crystal form II
4	Water (W)	Ethanol	1:2	Has crystals	Crystal form II

TABLE 15 results for the compound of formula (II) in crystal form

TABLE 16 results for the compound of formula (III) in crystal form

Numbering	Solvent A	Solvent B	A:B	Results of research and development	XRD results
						1	/	N-heptane	/	Has crystals	Crystal form II
2	/	N-hexane	/	Has crystals	Crystal form II
						4	Water (W)	Ethanol	1:2	Has crystals	Crystal form II
5	Water (W)	1, 4-dioxane	3:1	Has crystals	Crystal form II

Example 4:

the compound of formula (I) and isomers (II) and (III) crystal forms thereof are prepared by an anti-solvent crystallization method.

Taking about 50mg of a research sample, placing the research sample in a 5mL or 10mL glass vial, adding 1.0mL of good solvent into the glass vial in which the sample is placed, then placing the glass vial in which the sample and the good solvent are placed at room temperature, carrying out ultrasonic treatment for 30min to obtain a solution or a solution close to the solution, then adding an anti-solvent in a corresponding proportion into the sample solution in a positive adding mode, stirring, filtering under reduced pressure after stirring until crystallization exists, and carrying out sampling XRD, DSC and TGA characterization after drying. The results are shown in Table 17-19.

TABLE 17 results for the compound of formula (I) in crystal form

Numbering	Anti-solvent	Good solvent	Antisolvent good solvent	Results of research and development	XRD results
						1	Water (W)	Ethanol	4:1	Has crystals	Crystal form I
2	Water (W)	Isopropanol (I-propanol)	2:1	Has crystals	Crystal form I
						3	Water (W)	Acetone (II)	4:1	Has crystals	Crystal form I
4	Water (W)	1, 4-dioxane	4:1	Has crystals	Crystal form I
						5	Water (W)	Acetonitrile	4:1	Has crystals	Crystal form I
6	N-heptane	Isopropyl ether	1:1	Has crystals	Crystal form I

TABLE 18 results for the compound of formula (II) in crystal form

TABLE 19 results for the compound of formula (III) in crystal form

Numbering	Anti-solvent	Good solvent	Antisolvent good solvent	Results of research and development	XRD results
						1	Water (W)	Ethanol	4:1	Has crystals	Crystal form II

2	Water (W)	Isopropanol (I-propanol)	2:1	Has crystals	Crystal form II
						3	Water (W)	Acetone (II)	4:1	Has crystals	Crystal form II

Claims

1. A crystalline form of a compound of formula (II), form I, characterized by a powder X-ray diffraction pattern corresponding to characteristic diffraction peaks at d values of 19.3 ± 0.2, 9.5 ± 0.2, 4.8 ± 0.2 and 3.7 ± 0.2;

2. the crystalline form according to claim 1, characterized by a powder X-ray diffraction pattern corresponding to characteristic diffraction peaks at d-values of 19.3 ± 0.2, 9.5 ± 0.2, 8.7 ± 0.2, 4.8 ± 0.2, 4.5 ± 0.2, 4.1 ± 0.2 and 3.7 ± 0.2.

3. The compound of the formula (IV) and the isomer thereof, namely the compound of the formula (III), have the same crystal form, namely a crystal form II, and are characterized in that the powder X-ray diffraction pattern thereof correspondingly has characteristic diffraction peaks at d values of 10.3 +/-0.2, 9.4 +/-0.2, 7.7 +/-0.2, 6.2 +/-0.2 and 4.6 +/-0.2;

4. the crystalline form according to claim 3, characterized by a powder X-ray diffraction pattern corresponding to characteristic diffraction peaks at d-values of 10.3 ± 0.2, 9.4 ± 0.2, 8.4 ± 0.2, 7.7 ± 0.2, 6.2 ± 0.2, 5.8 ± 0.2, 5.0 ± 0.2, 4.6 ± 0.2 and 3.9 ± 0.2.

5. A process for preparing the crystalline form I of the compound of formula (II) as shown in claim 1 or2, or the crystalline form II of the compounds of formulae (III) and (IV) as shown in claim 3 or 4, which process comprises: mixing the compound of formula (II), (III) or (IV) with solvent, performing ultrasonic treatment at room temperature to obtain suspension, crystallizing the suspension at room temperature for 3 days, collecting the crystallized suspension, filtering under reduced pressure, and drying; the solvent is selected from the group consisting of water and one or more of ethanol, isopropanol, acetone or 1, 4-dioxane.

6. A process for preparing the crystalline form I of the compound of formula (II) as shown in claim 1 or2, or the crystalline form II of the compounds of formulae (III) and (IV) as shown in claim 3 or 4, which process comprises: mixing the compound of formula (II), (III) or (IV) with a solvent, performing ultrasonic treatment at room temperature to obtain a clear solution, naturally volatilizing at room temperature after being opened, and drying; the solvent is selected from one or more of ethanol, acetone, 1, 4-dioxane, isopropyl ether, n-hexane or n-heptane.

7. A process for preparing the crystalline form I of the compound of formula (II) as shown in claim 1 or2, or the crystalline form II of the compounds of formulae (III) and (IV) as shown in claim 3 or 4, which process comprises: mixing the compound of formula (II), (III) or (IV) with solvent, performing ultrasonic treatment at room temperature to obtain suspension, heating and stirring the suspension until the suspension is clear, placing the suspension at room temperature and stirring, crystallizing, filtering under reduced pressure, and drying; the solvent is selected from one or more of water, n-heptane, n-hexane, isopropyl ether, ethanol, 1, 4-dioxane, acetone or acetonitrile.

8. A process for preparing the crystalline form I of the compound of formula (II) as shown in claim 1 or2, or the crystalline form II of the compounds of formulae (III) and (IV) as shown in claim 3 or 4, which process comprises: adding a good solvent into the compound of the formula (II), (III) or (IV), performing ultrasonic treatment at room temperature to obtain a clear solution, adding an anti-solvent, stirring until crystals exist, performing reduced pressure filtration, and drying; the good solvent is selected from ethanol, isopropanol, acetone, 1, 4-dioxane, acetonitrile and isopropyl ether, and the anti-solvent is selected from water or n-heptane.