WO2021244555A1 - 一种手性中间体及其制备方法 - Google Patents
一种手性中间体及其制备方法 Download PDFInfo
- Publication number
- WO2021244555A1 WO2021244555A1 PCT/CN2021/097789 CN2021097789W WO2021244555A1 WO 2021244555 A1 WO2021244555 A1 WO 2021244555A1 CN 2021097789 W CN2021097789 W CN 2021097789W WO 2021244555 A1 WO2021244555 A1 WO 2021244555A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- deuterated
- compound
- general formula
- deuterium
- Prior art date
Links
- 0 *c(cc1)ccc1C(OC(C(C(O)=O)OC(c1ccc(*)cc1)=O)C(O)=O)=O Chemical compound *c(cc1)ccc1C(OC(C(C(O)=O)OC(c1ccc(*)cc1)=O)C(O)=O)=O 0.000 description 3
- YONLFQNRGZXBBF-KBPBESRZSA-N OC([C@H]([C@@H](C(O)=O)OC(c1ccccc1)=O)OC(c1ccccc1)=O)=O Chemical compound OC([C@H]([C@@H](C(O)=O)OC(c1ccccc1)=O)OC(c1ccccc1)=O)=O YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N CC1OCCC1 Chemical compound CC1OCCC1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- OZCLSBCDFQXGGX-UHFFFAOYSA-N CCC(C)CC(c1nccc(C)c11)[O]=C(NC(c2c3)=O)N1c2nc(Cl)c3Cl Chemical compound CCC(C)CC(c1nccc(C)c11)[O]=C(NC(c2c3)=O)N1c2nc(Cl)c3Cl OZCLSBCDFQXGGX-UHFFFAOYSA-N 0.000 description 1
- KWWCVCFQHGKOMI-UHFFFAOYSA-N COc(cc1)ccc1C(OC(C(C(O)=O)OC(c(cc1)ccc1OC)=O)C(O)=O)=O Chemical compound COc(cc1)ccc1C(OC(C(C(O)=O)OC(c(cc1)ccc1OC)=O)C(O)=O)=O KWWCVCFQHGKOMI-UHFFFAOYSA-N 0.000 description 1
- KWWCVCFQHGKOMI-HOTGVXAUSA-N COc(cc1)ccc1C(O[C@@H]([C@@H](C(O)=O)OC(c(cc1)ccc1OC)=O)C(O)=O)=O Chemical compound COc(cc1)ccc1C(O[C@@H]([C@@H](C(O)=O)OC(c(cc1)ccc1OC)=O)C(O)=O)=O KWWCVCFQHGKOMI-HOTGVXAUSA-N 0.000 description 1
- KWWCVCFQHGKOMI-HZPDHXFCSA-N COc(cc1)ccc1C(O[C@H]([C@H](C(O)=O)OC(c(cc1)ccc1OC)=O)C(O)=O)=O Chemical compound COc(cc1)ccc1C(O[C@H]([C@H](C(O)=O)OC(c(cc1)ccc1OC)=O)C(O)=O)=O KWWCVCFQHGKOMI-HZPDHXFCSA-N 0.000 description 1
- FMLPQHJYUZTHQS-QMMMGPOBSA-N C[C@@H](C1)NCCN1C(OC(C)(C)C)=O Chemical compound C[C@@H](C1)NCCN1C(OC(C)(C)C)=O FMLPQHJYUZTHQS-QMMMGPOBSA-N 0.000 description 1
- CMIBUZBMZCBCAT-UHFFFAOYSA-N Cc(cc1)ccc1C(OC(C(C(O)=O)OC(c1ccc(C)cc1)=O)C(O)=O)=O Chemical compound Cc(cc1)ccc1C(OC(C(C(O)=O)OC(c1ccc(C)cc1)=O)C(O)=O)=O CMIBUZBMZCBCAT-UHFFFAOYSA-N 0.000 description 1
- CMIBUZBMZCBCAT-HOTGVXAUSA-N Cc(cc1)ccc1C(O[C@@H]([C@@H](C(O)=O)OC(c1ccc(C)cc1)=O)C(O)=O)=O Chemical compound Cc(cc1)ccc1C(O[C@@H]([C@@H](C(O)=O)OC(c1ccc(C)cc1)=O)C(O)=O)=O CMIBUZBMZCBCAT-HOTGVXAUSA-N 0.000 description 1
- CMIBUZBMZCBCAT-HZPDHXFCSA-N Cc(cc1)ccc1C(O[C@H]([C@H](C(O)=O)OC(c1ccc(C)cc1)=O)C(O)=O)=O Chemical compound Cc(cc1)ccc1C(O[C@H]([C@H](C(O)=O)OC(c1ccc(C)cc1)=O)C(O)=O)=O CMIBUZBMZCBCAT-HZPDHXFCSA-N 0.000 description 1
- YONLFQNRGZXBBF-UHFFFAOYSA-N OC(C(C(C(O)=O)OC(c1ccccc1)=O)OC(c1ccccc1)=O)=O Chemical compound OC(C(C(C(O)=O)OC(c1ccccc1)=O)OC(c1ccccc1)=O)=O YONLFQNRGZXBBF-UHFFFAOYSA-N 0.000 description 1
- YONLFQNRGZXBBF-ZIAGYGMSSA-N OC([C@@H]([C@H](C(O)=O)OC(c1ccccc1)=O)OC(c1ccccc1)=O)=O Chemical compound OC([C@@H]([C@H](C(O)=O)OC(c1ccccc1)=O)OC(c1ccccc1)=O)=O YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
Definitions
- the invention specifically relates to a class of chiral drug intermediates and their application in the synthesis of anti-tumor drug molecules.
- Axial chirality is a special form of chirality, which is caused by covalent bonds that cannot rotate freely due to steric hindrance or electronic effects. Axial chirality also has a wide range of effects on the pharmacological activity and metabolic properties of compounds, but it is easy to be overlooked because there is no chiral center in the molecule. Drug development is a long and expensive process, so sufficient attention should be paid to axial chirality in the early stage to minimize the risk of late drug development and clinical trials.
- the present invention provides a compound composed of general formula (I) and general formula (II):
- X 1 , X 2 , R 1 , R 2 ,, R 3 , R 4 , R 5 ,, R 6 are selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, deuterated alkyl, alkene Group, deuterated alkenyl, alkynyl, deuterated alkynyl;
- R 7 and R 8 are selected from alkyl acyl, aromatic acyl, aromatic sulfonyl, wherein the aromatic group is substituted by alkyl, deuterated alkyl, alkoxy, deuterated alkoxy;
- R 9 and R 10 are selected from hydrogen, deuterium, alkyl, deuterated alkyl, aryl, heterocyclic group;
- X, Y, Z are carbon atoms or nitrogen atoms
- M and Q are selected from oxygen atom or nitrogen atom;
- the complex does not include a complex composed of the following two compounds:
- the present invention provides a compound composed of the general formula (I) and the general formula (II), and the compound also includes a compound of the general formula (VI):
- R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 are selected from hydrogen and deuterium.
- the present invention provides a compound composed of the general formula (I) and general formula (II), which includes the following general formula compound:
- X 1 , X 2 , R 1 , R 2 ,, R 3 , R 4 , R 5 ,, R 6 are selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, deuterated alkyl, alkene Group, deuterated alkenyl, alkynyl, deuterated alkynyl;
- R 7 and R 8 are selected from alkyl acyl, aromatic acyl, aromatic sulfonyl, wherein the aromatic group is substituted by alkyl, deuterated alkyl, alkoxy, deuterated alkoxy;
- R 9 and R 10 are selected from hydrogen, deuterium, alkyl, deuterated alkyl, aryl, heterocyclic group;
- R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 are selected from hydrogen and deuterium;
- X, Y, Z are carbon atoms or nitrogen atoms
- M and Q are selected from oxygen atom or nitrogen atom;
- the present invention provides the compound composed of the general formula (I) and the general formula (II), which includes the compound composed of the general formula (III) and (V):
- X 1 , X 2 , R 5, and R 6 are selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, deuterated alkyl, alkenyl, deuterated alkenyl, alkynyl, deuterated alkyne base;
- R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are selected from hydrogen, deuterium, alkyl, deuterated alkyl, alkoxy, deuterated alkyl ⁇ oxy;
- Z is a carbon atom or a nitrogen atom.
- the present invention provides the compound composed of the general formulas (III) and (V), which includes the following general compound:
- X 1 , X 2 , R 5, and R 6 are selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, deuterated alkyl, alkenyl, deuterated alkenyl, alkynyl, deuterated alkyne base;
- R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are selected from hydrogen, deuterium, alkyl, deuterated alkyl, alkoxy, deuterated alkyl ⁇ oxy;
- R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 are selected from hydrogen and deuterium;
- Z is a carbon atom or a nitrogen atom
- the present invention provides the compound of general formula (III), including the following compounds,
- the present invention provides the compound of general formula (V), including the following compounds:
- the present invention provides a compound having the following structure:
- the present invention provides a method for preparing a composite, which includes the following steps:
- Step (1) The temperature is preferably minus 50°C to minus 150°C;
- Step (1) The temperature is preferably minus 50°C to minus 150°C;
- Step (3) The temperature is preferably minus 50°C to above zero 150°C, and the reverse phase solvent is selected from C5-C12 alkane solvents, preferably n-hexane, n-pentane, and n-heptane; other types of reverse phases are also preferably from tert-butyl methyl ether, One or more of ether, tetrahydrofuran, dioxane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, dichloroethane, acetone, methyl ethyl ketone, ethyl acetate, toluene, benzene, xylene kind.
- the reverse phase solvent is selected from C5-C12 alkane solvents, preferably n-hexane, n-pentane, and n-heptane; other types of reverse phases are also preferably from tert-butyl methyl ether, One or
- the present invention provides a crystalline form of the compound represented by formula IX:
- the compound IX crystal uses Cu-Ka radiation to express the characteristic peaks of X-ray powder in 2 ⁇ angles, and the X-ray powder diffraction pattern is at 7.0° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.7°
- the diffraction angle (2 ⁇ ) of ⁇ 0.2°, 16.0° ⁇ 0.2°, 19.0° ⁇ 0.2° has characteristic peaks.
- Figure 1 shows the single crystal diffraction results of Compound IX.
- Figure 2 shows the X-ray powder diffraction pattern of Compound IX.
- Example 2 compound with KRAS G12C inhibitory activity and having axial chirality was prepared by the following scheme.
- the specific scheme is as follows:
- the compound provided by the present invention has stable properties, is beneficial to the storage and transportation of the intermediate, and is convenient to use.
- step 1
- the water phase was added to the reaction kettle, 0.33 kg of disodium hydrogen phosphate was added, the pH of the water layer was adjusted to about 7, and 12 L of methyl tert-butyl ether was added, stirred at room temperature, stood still, and separated. The water phase was extracted once with 6L methyl tert-butyl ether;
- the filter cake was rinsed with 4.5L of ethyl acetate: petroleum ether, drained, and the filter cake was air-dried to dryness to obtain a white solid.
- the solid was compound IX and had a certain crystal form.
- the crystal form It has an X-ray powder diffraction pattern similar to Figure 2 for characterization.
- the X powder diffraction pattern of the crystalline form of Compound IX is shown in Figure 2. It can be seen that the crystalline compound IX uses Cu-Ka radiation to express the characteristic peaks of X-ray powder in 2 ⁇ angles.
- the X-ray powder diffraction pattern is at 7.0° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.7° ⁇ 0.2 °, 16.0° ⁇ 0.2°, 19.0° ⁇ 0.2° diffraction angle (2 ⁇ ) has characteristic peaks.
- the crystalline compound IX with the above characteristics is stable in nature, which is conducive to the transportation, storage and use of pharmaceutical production.
- intermediate XI was prepared, and then synthesized by the following steps.
- Example 4 Pharmacodynamic test of nude mouse tumor cell MIA PaCa-2 xenograft tumor model
- Test sample compound N-1;
- Test group blank solvent group; compound N-1 (20mg/kg, QD ⁇ 15 days);
- Animal model establishment Culture and collect MIA paca-2 tumor cells in logarithmic growth phase in vitro, and inoculate them subcutaneously on the right back of nude mice at 5 ⁇ 10 6 cells/unit, and wait until the tumor volume grows to 150 ⁇ 300mm 3 When the tumor-bearing nude mice were randomly grouped. Subsequently, each group of animals was administered, and the day of the first administration was defined as the first day of the experiment;
- observation time and frequency once a day
- observation indicators or content including but not limited to animal administration, appearance signs, general behavioral activities, mental status, death, and other abnormal manifestations.
- TGI (%) [1-(average tumor volume at the end of the treatment group-average tumor volume at the beginning of the treatment group) / (average tumor volume at the end of the control group-average tumor volume at the beginning of the control group )] ⁇ 100%.
- Compound N-1 has a significant inhibitory effect on the growth of pancreatic cancer MIA paca-2 cells transplanted subcutaneously in nude mice.
- reaction solution was poured into water, extracted with ethyl acetate, separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid, which was directly used in the next reaction.
Abstract
本发明公开了一种合成手性药物的复合物中间体原料,及其制备方法。本发明公开的合成中间体生产成本较低,物理化学性质稳定,制备操作简单,非常易于工业化生产。
Description
本发明具体涉及一类手性药物的中间体,及其在抗肿瘤药物分子合成中的应用。
在早期的药物研发过程中,由于当时条件和认识的局限,常将对映异构体当成单一光学纯化合物处理。随着手性拆分技术的发展以及人们对于手性药物认识的提高,手性对于药物的药理活性,毒性,代谢性质的影响逐渐被重视,一些与手性相关的不良反应事件发生,如欧洲“反应停”事件,使药物研发人员对药物中的手性因素更加关注。
轴手性是手性的一种特殊形式,是由于空间位阻或电子效应导致共价键不能自由旋转而产生。轴手性对于化合物的药理活性、代谢性质也有广泛的影响,但由于分子中不具手性中心,而容易被忽视。药物研发是一个漫长而昂贵的过程,因此在早期阶段就应该给予轴手性足够的重视,最大的降低药物后期研发和临床试验的风险。
药物合成制造工业中,如何实现具有轴手性中间体的分离和纯化,一直是药物科学家亟待解决的难题。
发明内容
本发明提供一种由通式(I)和通式(II)组成的复合物:
其中,X
1,X
2,R
1,R
2,,R
3,R
4,R
5,,R
6选自氢,氘,氟,氯,溴,碘,烷基,氘代烷基,烯基,氘代烯基,炔基,氘代炔基;
R
7,R
8选自烷基酰基,芳香酰基,芳香磺酰基,其中芳香基团被烷基,氘代烷基,烷氧基,氘代烷氧基取代;
R
9,R
10选自氢,氘,烷基,氘代烷基,芳基,杂环基;
X,Y,Z为碳原子或者氮原子;
M,Q选自氧原子或者氮原子;
且,该复合物不包括以下两个化合物组成的复合物:
本发明提供所述的通式(I)和通式(II)组成的复合物,该复合物还包括通式(VI)结构的化合物:
其中,R
21,R
22,R
23,R
24,R
25,R
26,R
27,R
28,R
29,R
30选自氢,氘。
本发明提供所述的通式(I)和通式(II)组成的复合物,其中包括以下通式复合物:
其中,X
1,X
2,R
1,R
2,,R
3,R
4,R
5,,R
6选自氢,氘,氟,氯,溴,碘,烷基,氘代烷基,烯基,氘代烯基,炔基,氘代炔基;
R
7,R
8选自烷基酰基,芳香酰基,芳香磺酰基,其中芳香基团被烷基,氘代烷基,烷氧基,氘代烷氧基取代;
R
9,R
10选自氢,氘,烷基,氘代烷基,芳基,杂环基;
R
21,R
22,R
23,R
24,R
25,R
26,R
27,R
28,R
29,R
30选自氢,氘;
X,Y,Z为碳原子或者氮原子;
M,Q选自氧原子或者氮原子;
且,不包括以下复合物:
本发明提供所述的通式(I)和通式(II)组成的复合物,其中包括由通式(III)和(V)组成的复合物:
其中,X
1,X
2,R
5,,R
6选自氢,氘,氟,氯,溴,碘,烷基,氘代烷基,烯基,氘代烯基,炔基,氘代炔基;
R
11,R
12,R
13,R
14,R
15,R
16,R
17,R
18,R
19,R
20选自氢,氘,烷基,氘代烷基,烷氧基,氘代烷基氧基;
Z为碳原子或者氮原子。
本发明提供所述的由通式(III)和(V)组成的复合物,其中包括以下通式复合物:
其中,X
1,X
2,R
5,,R
6选自氢,氘,氟,氯,溴,碘,烷基,氘代烷基,烯基,氘代烯基,炔基,氘代炔基;
R
11,R
12,R
13,R
14,R
15,R
16,R
17,R
18,R
19,R
20选自氢,氘,烷基,氘代烷基,烷氧基,氘代烷基氧基;
R
21,R
22,R
23,R
24,R
25,R
26,R
27,R
28,R
29,R
30选自氢,氘;
Z为碳原子或者氮原子;
且,不包括以下的复合物:
本发明提供所述的通式(III)化合物,包括以下化合物,
本发明提供所述的通式(V)化合物,包括以下化合物:
本发明提供具有以下结构的复合物:
本发明提供一种复合物的制备方法,包括下列步骤:
(1)在一定温度下,化合物I溶解于IV中;
(2)在一定温度下,化合物II溶解于IV中;
(3)在一定温度下,将以上两种溶液混合,并滴加入反相溶剂,有固体析出,过滤,干燥得复合物产品。
本发明所述一种复合物的制备方法,其特征在于:
步骤(1)温度优选零下50℃至零上150℃;
步骤(1)温度优选零下50℃至零上150℃;
步骤(3)温度优选零下50℃至零上150℃,反相溶剂选自C5-C12烷烃溶剂,优选正己烷,正戊烷,正庚烷;其他类型反相也优选自叔丁基甲基醚,乙醚,四氢呋喃,二氧六环,二氯甲烷,三氯甲烷,四氯化碳,乙腈,二氯乙烷,丙酮,丁酮,乙酸乙酯,甲苯,苯,二甲苯中的一种或多种。
本发明提供一种如式IX所示化合物结晶形态:
其特征在于,所述的化合物IX晶体,使用Cu-Ka辐射,以2θ角度表示的X-射线粉末特征峰,X-射线粉末衍射图在7.0°±0.2°,10.5°±0.2°,13.7°±0.2°,16.0°±0.2°,19.0°±0.2°的衍射角(2θ)具有特征峰。
利用本发明提供的中间体制备得到,具有抑制KRAS G12C突变细胞活性的分子,当母核分子含有“氯原子”取代时,该类分子活性优于或者不劣于,对应的母核分子含有“氟原子”取代的分子。
图1显示化合物IX的单晶衍射结果。
图2显示化合物IX的X射线粉末衍射图。
下面用实施例来进一步说明本发明,但本发明并不受其限制。下述反应方法及合成步骤提供了用于合成本发明化合物以及关键中间体的可能途径。关于个别反应步骤的更详细说明,参见下述实施例。本领域技术人员应理解,本发明化合物也可以通过其它的合成途径获得。虽然下文反应流程中使用了特定的起始原料和试剂,但是这些起始原料和试剂可以被其它类似的起始原料或试剂所取代,以提供各种衍生物。此外,在本说明书的指导下, 通过下述方法制得的许多化合物可以通过本领域技术人员所熟知的常规化学方法进行进一步修饰。
下文通过实施例与制备进一步解释并列举本发明化合物及相应的制备方法。应了解,尽管具体实施例中给出了典型或优选的反应条件(如反应温度、时间、反应物的摩尔比、反应溶剂以及压力等),但是本领域技术人员也可以使用其它反应条件。最佳反应条件可随所用的特定反应底物或溶剂而发生改变,但所述条件可由所属领域的技术人员通过常规优化而确定。
实施例1
化合物A(按照WO2020050890,WO2019051291制备)称量5.00g于250mL圆底烧瓶中,加入50mL甲基四氢呋喃,于氮气保护下,75℃条件下保温搅拌30min,待溶解完全成为澄清溶液,加入溶解有10g的(+)-DBTA的20mL甲基四氢呋喃,将以上两个甲基四氢呋喃溶液混合后,继续在75℃条件下,滴加入50mL正庚烷,然后将以上混合物于25℃条件下,继续搅拌8小时,过滤固体,50℃条件下,鼓风干燥5h,得到目标复合物4g(>99%ee)。
1H NMR(400MHz,DMSO-d6)δ12.31(br.s,1H),8.60(s,1H),8.53-8.52(m,1H),7.99-7-96(m,2H),7.71-7-67(m,1H),7.57–7.53(m,2H),7.29–7.28(m,1H),5.77(s,1H),3.86-3.72(m,2H),3.58–3.52(m,1H),2.94–2.84(m,1H),2.05(s,3H),1.97–1.90(m,1H),1.85–1.74(m,1H),1.36-1.24(m,1H),1.13-1.12(m,3H),1.09-1.07(m,3H),1.02-1.00(m,3H);
13C NMR(100MHz,DMSO-d6)δ168.0,165.2,164.6,160.5,151.7,150.1,149.9,149.7,146.3,139.7,134.1,129.8,129.6,129.3,128.7,124.4,124.1,112.8,74.8,72.0,67.2,33.2,30.0,25.9,22.7,22.3,21.4,17.5。
文献WO2019051291中,第61页至67页,化合物Example2化合物制备,首先采用超临界二氧化碳手性柱色谱(AD)分离方法,得到轴手性纯的中间体化合物Intermediate C(结构如下),然后制备得到Example2化合物,该方法成本极高,不适宜工业化生产。
采用本发明制备得到的轴手性化合物复合物,采用以下的方案,制备得到具有KRAS G12C抑制活性的具有轴手性的化合物Example 2化合物,具体方案如下:
本发明提供的复合物,制备文献WO2019051291中Example2类化合物的优势在于:
(1)不需要使用超临界二氧化碳手性柱色谱分离轴手性中间体,利于工业化生产成本降低。
(2)采用廉价的市售拆分材料(酒石酸衍生物),以较高收率制备得到具有轴手性的中间体,用于WO2019051291中Example2类似化合物的制备,利于目标分子工业化生产的实现。
(3)本发明提供的复合物,性质稳定,有利于该中间体的储存和运输,便于使用。
实施例2:化合物IX的特征晶型产品的制备
步骤1:
向100L反应釜中依次加入3kg的AK-47和30L甲基叔丁基醚,搅拌均匀。另外,向塑料桶中加入21L水和1.36kg磷酸氢二钠,搅拌溶解后,加入100L釜中,常温搅拌至AK-47完全被游离,静置,分液;
水相加入反应釜中,加入0.33kg磷酸氢二钠,调节水层PH至7左右,加入12L甲基叔丁基醚,常温搅拌,静置,分液。水相再用6L甲基叔丁基醚萃取一次;
合并有机相,加入磷酸氢二钠水溶液(0.225kg溶于21L水中),常温搅拌,静置,分液。浓缩成固体,取出固体鼓风干燥,得类白色固体,即是Intermediate C。
步骤2:
向干燥的100L反应釜中依次加入3kg的Intermediate C,6.39kg N,N-二异丙基乙胺,1.65kg(S)-4-N-叔丁基羰基-2-甲基哌嗪和75L四氢呋喃,氮气保护下,滴加三氯氧磷,滴加完三氯氧磷,然后反应;
继续加0.825kg(S)-4-N-叔丁基羰基-2-甲基哌嗪至釜中,继续反应;
将反应液倒入装有30L的10%氯化铵溶液的桶中搅拌淬灭,淬灭液于减压浓缩至断流且有大量固体析出;
减压过滤,滤饼和21L二氯甲烷加入50L釜中,常温搅拌溶解,加入水,继续搅拌,静置,分液。水相再用6L二氯甲烷萃取一次,合并有机相。浓缩掉大部分二氯甲烷,再加入1.5L四氢呋喃浓缩至干;
将浓缩干的固体和24L四氢呋喃加入100L釜中,保温搅拌至所有大颗粒全部分散开,缓慢加入96L水,加完之后,继续搅拌;
减压过滤,滤饼抽干。将滤饼和24L乙酸乙酯加入釜中,常温搅拌。缓慢将石油醚加入釜内,加毕,继续常温搅拌;
减压过滤,滤饼用4.5L的乙酸乙酯:石油醚淋洗,抽干,滤饼鼓风干燥至干,得白色固体,该固体为化合物IX,并具有一定晶形的固体,该晶型有类似图2的X射线粉末衍射图表征。
化合物IX的其他结构表征数据如下:
(1)化合物IX的核磁共振氢谱数据如下表:
化学位移(ppm) | 多重性(J值/Hz) | 质子数 |
8.57 | d(4.9) | 1 |
8.05 | s | 1 |
7.14 | dd(4.9,0.6) | 1 |
5.01-4.64 | m | 1 |
4.45-3.82 | m | 3 |
3.68 | br s | 1 |
3.44-2.91 | m | 2 |
2.72-2.54 | m | 1 |
2.03 | s | 3 |
1.51 | s | 9 |
1.49 | d(6.8) | 3 |
1.22 | d(6.8) | 3 |
1.13 | d(6.7) | 3 |
(2)化合物IX的核磁共振碳谱数据如下表:
(3)化合物IX高分辨质谱数据如下:
项目 | 实测值 | 理论值 |
m/z | 547.2004 | 547.1991 |
离子 | [M+H] + | [M+H] + |
分子式 | C 26H 33Cl 2N 6O 3 | C 26H 33Cl 2N 6O 3 |
(4)化合物IX的晶型形态的X粉末衍射图如图2。可见,具有晶型的化合物IX,使用Cu-Ka辐射,以2θ角度表示的X-射线粉末特征峰,X-射线粉末衍射图在7.0°±0.2°,10.5°±0.2°,13.7°±0.2°,16.0°±0.2°,19.0°±0.2°的衍射角(2θ)具有特征峰。
具有以上特征的晶型的化合物IX性质稳定,利于药品生产的运输储藏和使用。
实施例3:化合物N-1制备
参考化合物IX的制备方法,制备得到中间体XI,然后进行以下步骤合成。
在的单口瓶中加入化合物XI,碳酸铯,甲苯,[1,1'-双(二苯基膦)二茂铁]二氯化钯和2-(6-乙烯基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷,加毕后氮气置换,升温反应。将反应液倒入水中,乙酸乙酯萃取,分液,无水硫酸钠干燥,过滤,减压浓缩,硅胶柱层析纯化,得黄色固体,直接用于下一步反应。
在50ml单口瓶中,加入上步产物,二氯甲烷,室温下滴加三氟乙酸,加完室温反应。反应完毕,降温至0℃,缓慢加入饱和碳酸氢钠水溶液,调节pH至7~8,二氯甲烷萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩至干。向剩余物加入二氯甲烷,N,N-二异丙基乙胺,冰浴降温,缓慢滴加丙烯酰氯的二氯甲烷溶液,加完继续反应。反应完毕,缓慢倒入饱和氯化铵水溶液淬灭,二氯甲烷萃取,合并有机层,饱和食盐水洗涤一次,无水硫酸钠干燥,过滤,滤液浓缩,硅胶柱层析纯化,得类白色固体即是化合物N-1。MS:m/z 591.2,[M+H]
+。
实施例4:裸鼠肿瘤细胞MIA PaCa-2异种移植瘤模型药效学试验
模型建立和给药方案:
动物种属及数量:Balb/c Nude;每组6只;
供试样品:化合物N-1;
试验组别:空白溶剂组;化合物N-1(20mg/kg,QD×15天);
动物模型建立:体外培养并收集对数生长期的MIA paca-2肿瘤细胞,以5×10
6个细胞/只数量皮下接种于裸鼠的右侧背部皮下,待瘤体积生长至150~300mm
3时对荷瘤裸鼠进行随机分组。随后,对每组动物进行给药,并将首次给药当天定义为试验第1天;
给药途径和频率:口服灌胃;每天1次;
一般状态观察:观察时间与频率:每天1次;观察指标或内容:包括但不限于动物给药局部、外观体征、一般行为活动、精神状态、死亡等情况及其它异常表现。试验结束后对动物实施安乐死。
肿瘤体积计算:V=1/2×长径×短径
2(mm
3)。用肿瘤生长抑制率TGI(%)评价化合物的抑瘤疗效。TGI(%)=[1-(治疗组给药结束时平均瘤体积-治疗组给药开始时平均瘤体积)/(对照组给药结束时平均瘤体积-对照组给药开始时平均瘤体积)]×100%。
“+”表示抑瘤率<60%;“++”表示抑瘤率60%~120%;“+++”表示抑瘤率>120%。
化合物 | 抑瘤率(%) |
N-1 | +++ |
实验结果:
化合物N-1,对胰腺癌MIA paca-2细胞裸小鼠皮下移植瘤生长具有显著抑制作用。
实施例5:化合物N-2制备
第一步
在的单口瓶中加入化合物IX的晶型产物(其X射线粉末衍射图表征主要峰:7.0°,10.5°,13.7°,16.0°,19.0°),碳酸铯,甲苯,[1,1'-双(二苯基膦)二茂铁]二氯化钯和2-(6-乙烯基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷,加毕后氮气置换,升温至80℃反应。将反应液倒入水中,乙酸乙酯萃取,分液,无水硫酸钠干燥,过滤,减压浓缩,硅胶柱层析纯化,得黄色固体,直接用于下一步反应。
第二步
在50ml单口瓶中,加入上步产物,二氯甲烷,室温下滴加三氟乙酸,加完室温反应。反应完毕,降温至0℃,缓慢加入饱和碳酸氢钠水溶液,调节pH至7~8,二氯甲烷萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩至干。向剩余物加入二氯甲烷,N,N-二异丙基乙胺,冰浴降温,缓慢滴加丙烯酰氯的二氯甲烷溶液,加完继续反应。反应完毕,缓慢倒入饱和氯化铵水溶液淬灭,二氯甲烷萃取,合并有机层,饱和食盐水洗涤一次,无水硫酸钠干燥,过滤,滤液浓缩,硅胶柱层析纯化,得类白色固体即是化合物N-2。MS:m/z 561.2,[M+H]
+。
参考实施例3和实施例5的制备方案,可以制备得到以下的化合物:
其中,N-3分子,MS:m/z 612.3,[M+H]
+;
N-4分子,MS:m/z 598.3,[M+H]
+;
N-5分子,MS:m/z 586.2,[M+H]
+。
同理,可以制备得到N-4的类似物M-4分子:
采用实施例4类似的“裸鼠肿瘤细胞MIA PaCa-2异种移植瘤模型药效学试验”,结果表明,化合物N-4(抑制率165%)的活性优于化合物M-4(128%)。
Claims (11)
- 根据权利要求1和2所述的通式(I)和通式(II)组成的复合物,其中包括以下通式复合物:其中,X 1,X 2,R 1,R 2,,R 3,R 4,R 5,,R 6选自氢,氘,氟,氯,溴,碘,烷基,氘代烷基,烯基,氘代烯基,炔基,氘代炔基;R 7,R 8选自烷基酰基,芳香酰基,芳香磺酰基,其中芳香基团被烷基,氘代烷基,烷氧基,氘代烷氧基取代;R 9,R 10选自氢,氘,烷基,氘代烷基,芳基,杂环基;R 21,R 22,R 23,R 24,R 25,R 26,R 27,R 28,R 29,R 30选自氢,氘;X,Y,Z为碳原子或者氮原子;M,Q选自氧原子或者氮原子;且,不包括以下复合物:
- 一种复合物的制备方法,包括下列步骤:(1)在一定温度下,化合物I溶解于IV中;(2)在一定温度下,化合物II溶解于IV中;(3)在一定温度下,将以上两种溶液混合,并滴加入反相溶剂,有固体析出,过滤,干燥得复合物产品。
- 权利要求9所述一种复合物的制备方法,其特征在于:步骤(1)温度优选零下50℃至零上150℃;步骤(1)温度优选零下50℃至零上150℃;步骤(3)温度优选零下50℃至零上150℃,反相溶剂选自C5-C12烷烃溶剂,优选正己烷,正戊烷,正庚烷;其他类型反相也优选自叔丁基甲基醚,乙醚,四氢呋喃,二氧六环,二氯甲烷,三氯甲烷,四氯化碳,乙腈,二氯乙烷,丙酮,丁酮,乙酸乙酯,甲苯,苯,二甲苯中的一种或多种。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202180005951.6A CN114585624A (zh) | 2020-06-02 | 2021-06-01 | 一种手性中间体及其制备方法 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010487022 | 2020-06-02 | ||
CN202010487022.0 | 2020-06-02 | ||
CN202011415708.5 | 2020-12-05 | ||
CN202011415708 | 2020-12-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2021244555A1 true WO2021244555A1 (zh) | 2021-12-09 |
Family
ID=78830662
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2021/097789 WO2021244555A1 (zh) | 2020-06-02 | 2021-06-01 | 一种手性中间体及其制备方法 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN114585624A (zh) |
WO (1) | WO2021244555A1 (zh) |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019213516A1 (en) * | 2018-05-04 | 2019-11-07 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
WO2020050890A2 (en) * | 2018-06-12 | 2020-03-12 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
CN110997668A (zh) * | 2017-05-22 | 2020-04-10 | 美国安进公司 | Kras g12c抑制剂及其使用方法 |
CN111051306A (zh) * | 2017-09-08 | 2020-04-21 | 美国安进公司 | Kras g12c的抑制剂及其使用方法 |
WO2020102730A1 (en) * | 2018-11-16 | 2020-05-22 | Amgen Inc. | Improved synthesis of key intermediate of kras g12c inhibitor compound |
CN112159405A (zh) * | 2020-02-04 | 2021-01-01 | 广州必贝特医药技术有限公司 | 吡啶并嘧啶酮类化合物及其应用 |
WO2021081212A1 (en) * | 2019-10-24 | 2021-04-29 | Amgen Inc. | Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer |
WO2021097212A1 (en) * | 2019-11-14 | 2021-05-20 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
WO2021097207A1 (en) * | 2019-11-14 | 2021-05-20 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
-
2021
- 2021-06-01 WO PCT/CN2021/097789 patent/WO2021244555A1/zh active Application Filing
- 2021-06-01 CN CN202180005951.6A patent/CN114585624A/zh active Pending
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110997668A (zh) * | 2017-05-22 | 2020-04-10 | 美国安进公司 | Kras g12c抑制剂及其使用方法 |
CN111051306A (zh) * | 2017-09-08 | 2020-04-21 | 美国安进公司 | Kras g12c的抑制剂及其使用方法 |
WO2019213516A1 (en) * | 2018-05-04 | 2019-11-07 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
WO2020050890A2 (en) * | 2018-06-12 | 2020-03-12 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
WO2020102730A1 (en) * | 2018-11-16 | 2020-05-22 | Amgen Inc. | Improved synthesis of key intermediate of kras g12c inhibitor compound |
WO2021081212A1 (en) * | 2019-10-24 | 2021-04-29 | Amgen Inc. | Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer |
WO2021097212A1 (en) * | 2019-11-14 | 2021-05-20 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
WO2021097207A1 (en) * | 2019-11-14 | 2021-05-20 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
CN112159405A (zh) * | 2020-02-04 | 2021-01-01 | 广州必贝特医药技术有限公司 | 吡啶并嘧啶酮类化合物及其应用 |
Also Published As
Publication number | Publication date |
---|---|
CN114585624A (zh) | 2022-06-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112300153B (zh) | 一种杂环化合物、药物组合物和用途 | |
JPH11503412A (ja) | 三置換フェニル誘導体 | |
AU2020201527A1 (en) | Phosphoramidate compound and preparation method and crystal thereof | |
CN111848607B (zh) | 一种新型bcl-2/bcl-xl抑制剂、药物组合物及用途 | |
CN111704646B (zh) | 甾体类化合物及其制备方法和用途 | |
CN108947949B (zh) | 抗焦虑氘代化合物及其医药用途 | |
CN116102615A (zh) | 制备细胞毒性苯二氮䓬衍生物的方法 | |
CN111635449B (zh) | 一种羽扇豆醇吡啶季铵盐衍生物及其制备方法与应用 | |
WO2021244555A1 (zh) | 一种手性中间体及其制备方法 | |
Huang et al. | Synthesis, characterization and antitumor activity of novel amide derivatives containing ferrocenyl pyrazol-moiety | |
CN106986871B (zh) | 一种氘代Palbociclib的晶型及其制备方法和应用 | |
CN111018772A (zh) | 一类具有抗肿瘤活性的5-磺酰胺基取代的靛红类衍生物 | |
CN110156817B (zh) | 双吴茱萸碱分子抗肿瘤衍生物及其制备与应用 | |
CN112334458B (zh) | 3-吲唑啉酮类化合物、其制备方法及其在医药学上的应用 | |
WO2008093853A1 (ja) | マクロライド系化合物の固体およびその製造法並びにその医薬組成物 | |
CN108530337B (zh) | 一种可选择性抑制胃癌细胞的吲哚酰胺类化合物 | |
CN109516926B (zh) | 一种荜茇明碱衍生物制备及用途 | |
CN112174958B (zh) | 一种吡啶并[2,3-d]嘧啶类化合物及其制备方法和用途 | |
CN112225745B (zh) | 一种具有抗肿瘤活性的异片螺素类化合物、制备方法及用途 | |
CN115785189B (zh) | 一种5α,8α-过氧化甾醇-17-苯基噻唑衍生物及其合成方法和应用 | |
CN111138361B (zh) | 取代苯氧基-2-氮杂双环[3.2.1]辛烷类化合物及其制备方法和应用 | |
CN109761993A (zh) | 螺苯并呋喃-3,3′-喹啉衍生物及其合成方法和应用 | |
CN115073547B (zh) | 一种甾体咔啉衍生物及其制备方法和应用、抗肿瘤药物组合物 | |
CN111170940B (zh) | 一种1,4-二氢喹啉以及1,4-二氢吡啶类化合物的合成方法及其在抗肿瘤药物中的应用 | |
WO2024067542A1 (zh) | 一种含螺环类衍生物的盐、晶型及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21816918 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 21816918 Country of ref document: EP Kind code of ref document: A1 |