CN104844540A - New crystal form of (2S)-2-aomni group-4-methyl-1-[(2R)-2-methyl epoxy ethyl]-1-pentanone trifluoroacetic acid salt and preparation method thereof - Google Patents

Abstract

The invention relates to a new crystal form of (2S)-2-aomni group-4-methyl-1-[(2R)-2-methyl epoxy ethyl]-1-pentanone trifluoroacetic acid salt and a preparation method thereof. The compound is a key intermediate of the medicine Carfilzomib for treating multiple myeloma. The method is simple and convenient to operate and efficient, and favorable for industrialized production, and a high-purity product is easier to obtain.

Description

New crystal of a kind of (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate and preparation method thereof

Technical field

The present invention relates to a kind of preparation method of compound, particularly relate to new crystal of key intermediate (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate of a kind of medicine Ka Feizuo meter (Carfilzomib) for multiple myeloma and preparation method thereof.

Background technology:

Ka Feizuo meter (Carfilzomib) is that drugmaker of U.S. Onyx Pharmaceuticals Inc applies for proteinase inhibitor, and trade(brand)name Kyprolis, is used for the treatment of multiple myeloma.This medicine is injection liquid, obtains U.S. FDA approval listing, the treatment of multiple myeloma patients failed after treating for adopting other drug in July, 2012.And (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate I is a key intermediate of preparation Ka Feizuo meter.(WO 2005105827)

Yuan Yan producer Proteolix Inc. discloses crystal formation and the preparation method of (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate in patent WO2009045497.Its X-ray powder diffraction figure is 8.84 in 2theta value; 15.18; 15.32; 16.20; 16.82; 17.66; 18.26; 19.10; 21.20; 22.58; 23.06; 23.52; 25.32; 26.58; 28.60; 30.08; 30.48; 30.84; 32.20; 36.14; 37.12 place has characteristic peak.The preparation method of (the 2S)-2-amino-4-methyl isophthalic acid disclosed in this patent-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate is the dichloromethane solution of the compound trifluoroacetic acid of 10 times of molar weights being added Boc protection, directly concentrates and obtain corresponding trifluoroacetate after reaction response.The method has two obvious shortcomings: 1) directly the concentrated trifluoroacetic acid purity salt obtained is low, needs further crystallization purifying, can not be directly used in next step synthesis; 2) methylene dichloride is under the reaction conditions of solvent, and the less stable of product, easily produces by product, and total recovery is lower.

For improving the shortcoming existing for original bibliographical information, the present inventor is through the screening of multiple reaction conditions and crystallization condition and optimization, obtain the condition that simultaneously can obtain higher yields and purity, simultaneously in process of experimental, find that (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate also exists other new crystal, be different from existing disclosed crystal formation, the application of (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate is provided more choices.

Summary of the invention:

The technical problem to be solved in the present invention is to provide new crystal of a kind of key intermediate for the preparation of Ka Feizuo meter (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate and preparation method thereof.The method is easy and simple to handle, efficient, be beneficial to suitability for industrialized production, the highly purified product simultaneously more easily obtained, the stability of new crystal is better than the crystal formation had been reported, not easily degrade, and highly purified quality control important in inhibiting in Ka Feizuo meter production of raw medicine.

The invention provides the new crystal of (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate, called after crystal form B, crystal C in the present invention.

An object of the present invention is to provide the crystal form B of (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate, it is characterized in that, its X-ray powder diffraction figure is 8.44 ± 0.2 ° in 2theta value; 8.82 ± 0.2 °; 14.92 ± 0.2 °; 15.30 ± 0.2 °; 16.24 ± 0.2 °; 16.79 ± 0.2 °; 17.32 ± 0.2 °; 17.67 ± 0.2 °; 18.34 ± 0.2 °; 19.13 ± 0.2 °; 21.32 ± 0.2 °; 22.61 ± 0.2 °; 23.10 ± 0.2 °; 23.34 ± 0.2 °; 23.54 ± 0.2 °; 24.74 ± 0.2 °; 25.35 ± 0.2 °; 26.05 ± 0.2 °; 26.64 ± 0.2 °; 28.65 ± 0.2 °; 30.14 ± 0.2 °; 30.49 ± 0.2 °; 32.27 ± 0.2 °; 36.27 ± 0.2 ° of places have characteristic peak.

Further, the crystal form B of (2S) provided by the invention-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate, is further characterized in that, its X-ray powder diffraction and Fig. 1 basically identical.

Further, the crystal form B of (2S) provided by the invention-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate, it is characterized in that, start to occur endotherm(ic)peak near being heated to 129.5 DEG C, start to occur exothermic peak near being heated to 140.7 DEG C, its dsc analysis chart is basic consistent with Fig. 2.

Further, the crystal form B of (2S) provided by the invention-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate, it is characterized in that, when being heated to 300 DEG C, have the weightlessness of about 87.3%, its thermogravimetric analysis figure is basic consistent with Fig. 3.

Second object of the present invention is to provide the preparation method of crystal form B, comprises following process:

A) under zero degree, be dissolved in by Compound II per in acetonitrile solvent, drip the trifluoroacetic acid of 10 times of molar weights, after TLC observes Compound II per spot disappear, reaction completes;

B) by reaction soln with spin concentration instrument concentrating under reduced pressure (bath temperature 30 degree to 35 degree) to 20% to 30% of original volume;

C) use ice-water bath to cool surplus solution, wait for that Compound I crystal is separated out;

D) leach solid, by cold toluene wash, room temperature dries to obtain white needle-like crystals.

3rd object of the present invention is to provide the crystal C of (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate, it is characterized in that, its X-ray powder diffraction figure is 8.82 in 2theta value; 15.27; 16.18; 16.82; 17.32; 17.67; 18.34; 19.01; 21.26; 22.58; 23.10; 23.31; 23.54; 25.32; 26.05; 26.55; 28.62; 32.21; 36.21 place has characteristic peak.

Further, the crystal C of (2S) provided by the invention-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate, be further characterized in that, Fig. 4 is consistent for its X-ray powder diffraction.

Further, the crystal C of (2S) provided by the invention-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate, it is characterized in that, start to occur endotherm(ic)peak near being heated to 137.6 DEG C, start to occur exothermic peak near being heated to 142.8 DEG C, its dsc analysis chart is basic consistent with Fig. 5.

Further, the crystal C of (2S) provided by the invention-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate, it is characterized in that, when being heated to 300 DEG C, have the weightlessness of about 86.5%, its thermogravimetric analysis figure is basic consistent with Fig. 6.

4th object of the present invention is to provide the preparation method of crystal C, comprises following process:

E) under zero degree, be dissolved in by Compound II per in acetonitrile solvent, drip the trifluoroacetic acid of 10 times of molar weights, after TLC observes Compound II per spot disappear, reaction completes;

F) by reaction soln with spin concentration instrument concentrating under reduced pressure (bath temperature 30 degree to 35 degree, under this temperature range, the epoxy-functional of product can not be degraded) to 45% to 55% of original volume;

G) add in the reaction solution after concentrated isopyknic toluene stir after with ice-water bath cooling, wait for that Compound I crystal is separated out;

H). leach solid, by cold toluene wash, room temperature dries to obtain white needle-like crystals.

The advantage of the inventive method is mainly

1) easy and simple to handle, be easy to industry and amplify;

2) solvent boiling point used in preparation process is medium, easy recovery;

3) crystal purity obtained by preparation method is higher than the method for existing bibliographical information, the crystal purity of (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate that the preparation method using WO2009045497 to report obtains is about 95%, as the intermediate as API also needs further crystallization purifying, and the crystal purity using preparation method provided by the present invention to obtain reaches more than 99%, without the need to being further purified, HPLC detects spectrogram as Fig. 7.

4) crystal stability of new crystal is higher than the crystal formation had been reported.

The stability of crystal form comparative study that table 1 is reported for crystal form B and C and patent WO2009045497.

White solid is before the crystal formation that WO2009045497 reports and crystal form B of the present invention and C stability test.Temperature 40 DEG C ± 2 DEG C, place 3 months under the condition of relative humidity 75% ± 5%, investigate the stability of crystallization, the results are shown in following table:

Accompanying drawing illustrates:

Fig. 1 is X-ray diffraction (X-PRD) collection of illustrative plates of the new crystal B of (2S) of the present invention-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate.

Fig. 2 is differential scanning calorimetry (DSC) collection of illustrative plates of the new crystal B of (2S) of the present invention-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate.

Fig. 3 is thermogravimetric analysis (TGA) collection of illustrative plates of the new crystal B of (2S) of the present invention-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate.

Fig. 4 is X-ray diffraction (X-PRD) collection of illustrative plates of the new crystal C of (2S) of the present invention-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate.

Fig. 5 is differential scanning calorimetry (DSC) collection of illustrative plates of the new crystal C of (2S) of the present invention-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate.

Fig. 6 is thermogravimetric analysis (TGA) collection of illustrative plates of the new crystal C of (2S) of the present invention-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate.

The HPLC of the new crystal B of (the 2S)-2-amino-4-methyl isophthalic acid of Fig. 7 prepared by embodiment 1-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate detects spectrogram.

Embodiment:

Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.

Raw material used in embodiment or reagent except special instruction, all commercially.

Room temperature described in embodiment all refers to 20 ~ 35 DEG C.Unless otherwise indicated, the not purified direct use of described reagent.The equal available from commercial supplier of all solvents, such as aldrich (Aldrich), and not treatedly just can to use.

X-PRD spectrum gathers on Bruker D8Advance diffractometer (copper target, ), the method parameter of described X-ray powder diffraction is as follows:

X ray reflection parameter: Cu, K α

1.540598；1.544426

K α 2/K α 1 intensity: 0.50

Voltage: 45 KVs (kV)

Electric current: 40 milliampere(mA)s (mA)

Divergent slit: automatically

Scan pattern: continuously

Sweep limit: from 3.0 to 40.0 degree

Sampling step length: 0.013 degree

DSC spectrum collects on TA Instruments DSC Q2000 instrument, and the method parameter of described differential scanning calorimetric analysis is as follows:

Scanning speed/DEG C/min: 10 DEG C/min

Shielding gas: nitrogen

TGA spectrum collects on TA Instruments TGA Q500 instrument, and the method parameter of described thermogravimetric analysis is as follows:

Scanning speed: 10 DEG C/min

Shielding gas: nitrogen

Embodiment 1

The preparation of Compound I crystal form B:

By molten for [(1S)-3-methyl isophthalic acid-[[(2R)-2-methyl epoxy ethyl] carbonyl] butyl] t-butyl carbamate (21g 77.4mmol) to 20mL in, 200mL trifluoroacetic acid is dripped, stirring at room temperature under room temperature.After 2h, TLC detection raw material reaction is complete, and 30 degree, under 35 degree, with spin concentration instrument concentration of reaction solution to 20% to 30% of original volume, with ice-water bath cooling reaction solution crystallization, are filtered, obtain 15.7g white needles, yield 85% after filter cake oven dry.

The X-ray powder diffraction data of the crystal form B that the present embodiment obtains are as shown in table 1.

The X-ray powder diffraction data of table 1 crystal form B

2-Theta	D interval	Relative intensity %
			8.44	10.46774	46.4
8.82	10.01798	100
			14.924	5.93151	12.2
15.303	5.7852	18.1
			16.238	5.45428	46
16.793	5.27528	60.2
			17.318	5.11632	12.2
17.669	5.01562	38.7
			18.341	4.83342	27.4
19.129	4.63592	29.2
			21.32	4.16432	28.8
22.605	3.93041	44.3
			23.101	3.84705	18.1
23.335	3.80905	22.2
			23.539	3.77643	21.4
24.736	3.59627	7.5
			25.35	3.51064	15.1
26.051	3.41775	10.8
			26.635	3.34411	40.3
28.65	3.11332	9.4
			30.139	2.96277	6.4
30.49	2.9295	7.8
			32.271	2.77174	12.3
36.272	2.47465	11.8

Embodiment 2

The preparation of Compound I crystal C:

By molten in 20mL acetonitrile for [(1S)-3-methyl isophthalic acid-[[(2R)-2-methyl epoxy ethyl] carbonyl] butyl] t-butyl carbamate (21g 77.4mmol), 200mL trifluoroacetic acid is dripped, stirring at room temperature under room temperature.After 2h, to detect raw material reaction complete for TLC, 30 degree under 35 degree, with spin concentration instrument concentration of reaction solution to 45% to 55% of original volume, add 400mL toluene, with ice-water bath cooling reaction solution crystallization, filter, filter cake obtains 15.7g white needles, yield 80% after drying.The X-ray powder diffraction data of the crystal C that the present embodiment obtains are as shown in table 2.

The X-ray powder diffraction data of table 2 crystal C

2-Theta	D interval	Relative intensity %
			8.82	10.01798	100
15.274	5.7962	20.1
			16.179	5.47384	4.4
16.822	5.26619	18.3
			17.318	5.11632	7.9
17.669	5.01562	37
			18.341	4.83342	4
19.012	4.66414	3.4
			21.261	4.17562	5.7
22.575	3.93542	18.9
			23.101	3.84705	11.1
23.305	3.81376	9.7
			23.539	3.77643	17.4
25.321	3.51462	5.9

26.051	3.41775	6.7
			26.547	3.35495	40.5
28.621	3.11643	3.7
			32.213	2.77663	12.7
36.214	2.4785	4.4

Claims (10)

1. the crystal form B of (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate, it is characterized in that, its X-ray powder diffraction figure is 8.44 ± 0.2 ° in 2theta value; 8.82 ± 0.2 °; 14.92 ± 0.2 °; 15.30 ± 0.2 °; 16.24 ± 0.2 °; 16.79 ± 0.2 °; 17.32 ± 0.2 °; 17.67 ± 0.2 °; 18.34 ± 0.2 °; 19.13 ± 0.2 °; 21.32 ± 0.2 °; 22.61 ± 0.2 °; 23.10 ± 0.2 °; 23.34 ± 0.2 °; 23.54 ± 0.2 °; 24.74 ± 0.2 °; 25.35 ± 0.2 °; 26.05 ± 0.2 °; 26.64 ± 0.2 °; 28.65 ± 0.2 °; 30.14 ± 0.2 °; 30.49 ± 0.2 °; 32.27 ± 0.2 °; 36.27 ± 0.2 ° of places have characteristic peak.

2. crystal form B according to claim 1, is characterized in that, its X-ray diffractogram is substantially consistent with Fig. 1.

3. crystal form B according to claim 1, is characterized in that, its differential scanning calorimetric thermogram is substantially consistent with Fig. 2.

4. crystal form B according to claim 1, is characterized in that, its thermogravimetric analysis figure is substantially consistent with Fig. 3.

5. a preparation method for the crystal form B of (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate, is characterized in that comprising following steps a-d:

A) under zero degree, be dissolved in by Compound II per in acetonitrile solvent, drip the trifluoroacetic acid of 10 times of molar weights, after TLC observes Compound II per spot disappear, reaction completes;

B) by reaction soln with spin concentration instrument concentrating under reduced pressure (bath temperature 30 to 35 degree) to 20% to 30% of original volume;

C) use ice-water bath to cool surplus solution, wait for that Compound I crystal is separated out;

D) leach solid, by cold toluene wash, room temperature dries to obtain white needle-like crystals.

6. the crystal C of (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate, it is characterized in that, its X-ray powder diffraction figure is 8.82 ± 0.2 ° in 2theta value; 15.27 ± 0.2 °; 16.18 ± 0.2 °; 16.82 ± 0.2 °; 17.32 ± 0.2 °; 17.67 ± 0.2 °; 18.34 ± 0.2 °; 19.01 ± 0.2 °; 21.26 ± 0.2 °; 22.58 ± 0.2 °; 23.10 ± 0.2 °; 23.31 ± 0.2 °; 23.54 ± 0.2 °; 25.32 ± 0.2 °; 26.05 ± 0.2 °; 26.55 ± 0.2 °; 28.62 ± 0.2 °; 32.21 ± 0.2 °; 36.21 ± 0.2 ° of places have characteristic peak.

7. crystal C according to claim 1, is characterized in that, its X-ray diffractogram is substantially consistent with Fig. 4.

8. crystal C according to claim 1, is characterized in that, its differential scanning calorimetric thermogram is substantially consistent with Fig. 5.

9. crystal C according to claim 1, is characterized in that, its thermogravimetric analysis figure is substantially consistent with Fig. 6.

10. a preparation method for the crystal C of (2S)-2-amino-4-methyl isophthalic acid-[(2R)-2-methyl oxirane base]-1-pentanone trifluoroacetate, is characterized in that comprising following steps e-h:

E) under zero degree, be dissolved in by Compound II per in acetonitrile solvent, drip the trifluoroacetic acid of 10 times of molar weights, after TLC observes Compound II per spot disappear, reaction completes;

F) reaction soln spin concentration instrument is evaporated to 45% to 55% of original volume;

G) add in the reaction solution after concentrated isopyknic toluene stir after with ice-water bath cooling, wait for that Compound I crystal is separated out;

H) leach solid, by cold toluene wash, room temperature dries to obtain white needle-like crystals.