WO2019037591A1 - 盐酸美法仑晶型及其制备方法与应用 - Google Patents

盐酸美法仑晶型及其制备方法与应用 Download PDF

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WO2019037591A1
WO2019037591A1 PCT/CN2018/099076 CN2018099076W WO2019037591A1 WO 2019037591 A1 WO2019037591 A1 WO 2019037591A1 CN 2018099076 W CN2018099076 W CN 2018099076W WO 2019037591 A1 WO2019037591 A1 WO 2019037591A1
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mol
polymorph
amino
phenylalanine
chloroethyl
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李�瑞
夏崇亮
任晋生
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江苏先声药业有限公司
南京先声东元制药有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the invention relates to a crystal form of melphalan hydrochloride and a preparation method and application thereof.
  • Patent document US Pat. No. 3,032,584 A describes the preparation of melphalan compounds by synthesizing melphalan from 4-nitrophenylalanine or L-4-nitrophenylalanine.
  • the amino acid portion of the raw material is protected (ethyl esterification to protect the carboxyl group; phthalic anhydride to protect the amino group) to obtain a relatively stable full-protection substance, and the nitro moiety of the para-position is modified, and then hydrogen is reduced.
  • the hydroxyethylation and chlorination three-step reaction gave the effective group nitrogen mustard of melphalan.
  • the amino acid moiety was deprotected by refluxing with hydrochloric acid to obtain the meruphenone hydrochloride type I crystal product.
  • a first aspect of the invention relates to Compound 1, a Form II polymorph of melphalan hydrochloride, having an X-powder diffraction pattern as shown in Figure 2, having a melting point of 186.2 °C.
  • the heating temperature is preferably 35 to 70 ° C, preferably about 45 to 60 ° C.
  • the drying method is selected to be vacuum drying, and the drying temperature is 30 to 50 ° C, preferably 35 to 45 ° C.
  • the preparation method of the type II polycrystal of the invention the 4-[bis(2-chloroethyl)-amino-]-L-phenylalanine and N,N-dimethylformamide Methyl tert-butyl ether is charged in an amount of 1 g: 1 to 2 ml: 1 to 2 ml, stirred for 10 to 20 minutes, cooled at 5 to 15 ° C, and stirred for 1-3 hours, preferably 1 hour.
  • a third aspect of the invention relates to a process for the preparation of a compound I, a type I polymorph of melphalan hydrochloride, which has an interplanar spacing (CuKa) of an X-powder diffraction pattern at about 20.56 angstroms. .
  • CuKa d-plane spacing of X-ray powder diffraction: 20.568, 10.403, 6.972, 6.816, 5.942, 5.244, 5.025, 4.521, 4.240, 4.035, 3.819, 3.698, 3.637, 3.565, 3.507, 3.380, 3.208 , 3.158, 3.064, 3.006, 2.900, 2.821, 2.778, 2.749, 2.633, 2.547, 2.518, 2.476
  • X-powder diffraction pattern d-plane spacing (CuKa) around the following values: 10.40, 6.97, 6.82, 5.94, 5.24, 5.02, 4.52, 4.24, 4.04, 3.82, 3.70, 3.64, 3.56, 3.50, 3.38, 3.20, 3.16, 3.06, 3.00, 2.90, 2.82, 2.78, 2.75, 2.63, 2.54, 2.52, 2.47, 2.39, 2.32 or 2.29 angstroms.
  • the Form I of the present invention has an X powder diffraction pattern as shown in FIG.
  • the method for preparing a type I polymorph of melphalan hydrochloride according to the present invention comprises: 4 g of [4-(2-chloroethyl)-amino-]-L-phenylalanine and an organic solvent. : Mixing ratio of 1 ⁇ 10ml, heating to a temperature not higher than 70 ° C, adding hydrochloric acid until the reaction is completed, cooling to 0 ⁇ 30 ° C, filtering, drying, that is.
  • the preparation method of the melphalan hydrochloride type I polymorph of the present invention, wherein the ratio of 4 ⁇ [bis(2-chloroethyl)-amino-]-L-phenylalanine to the organic solvent is preferably 1g: 1.8 to 8 ml.
  • the method for preparing a melphalan hydrochloride type I polymorph according to the present invention wherein the heating temperature is preferably 35 to 70 ° C, preferably about 45 to 60 ° C, and the room temperature is 20 to 25 ° C; It means as low as about 0 to 30 ° C, and preferably 5 to 15 ° C.
  • the method for preparing a melphalan hydrochloride type I polymorph according to the present invention wherein the organic solvent is one or more selected from the group consisting of ethanol, methanol, ethyl acetate, isopropyl ether and n-heptane.
  • the method for preparing a melphalan hydrochloride type I polymorph according to the present invention wherein the concentration of the hydrochloric acid is from 6 mol/L to 12 mol/L, preferably at a concentration of from 10 to 12 mol/L; and the added equivalent is 4-[
  • the bis(2-chloroethyl)-amino-]-L-phenylalanine is 0.9 to 2.0 molar equivalents, preferably 1.3 to 1.5 molar equivalents.
  • the drying method is selected to be vacuum drying, and the drying temperature is 30 to 50 ° C, preferably 35 to 45 ° C.
  • a fourth aspect of the invention relates to a non-toxic, pharmaceutical composition
  • a non-toxic, pharmaceutical composition comprising a therapeutically effective amount of a Form II polymorph of Compound 1 and a pharmaceutically acceptable carrier.
  • a fifth aspect of the invention relates to a method of treating multiple myeloma, breast cancer, ovarian cancer, chronic lymphocytic and granulocyte leukemia, malignant lymphoma, multiple myeloma, the method comprising providing a patient with non-toxic, A therapeutically effective amount of Form I and Form II polymorph of Compound 1.
  • a sixth aspect of the invention relates to a process for the preparation of a polymorph of melphalan hydrochloride comprising: 4-[bis(2-chloroethyl)-amino-]-L-phenylalanine and organic
  • the solvent is mixed at a charging ratio of 1 g: 1 to 10 ml, preferably 1 g: 1.8 to 8 ml, and heated to a temperature not higher than 85 ° C, particularly not higher than 70 ° C, hydrochloric acid is added until the reaction is completed, and cooled to 0 to 30 ° C, filtered. Dry, that is.
  • the polymorph comprises Form I or Form II.
  • the method for preparing a polymorph of melphalan hydrochloride according to the present invention wherein the heating temperature is preferably 35 to 70 ° C, preferably about 45 to 60 ° C, and the room temperature is 20 to 25 ° C; the cooling temperature is It is as low as about 0 to 30 ° C, and preferably 5 to 15 ° C.
  • the method for preparing a polymorph of melphalan hydrochloride according to the present invention wherein the organic solvent is selected from the group consisting of ethanol, methanol, ethyl acetate, diisopropyl ether, n-heptane, and N,N-dimethyl One or more of formamide and methyl tert-butyl ether; when the organic solvent is selected from two components, the volume ratio of the component having a large polarity to the component having a small polarity is selected from 4 to 12; 6 to 10; 8.
  • a preferred combination is methanol-isopropyl ether, ethyl acetate-n-heptane, N,N-dimethylformamide-methyl tert-butyl ether.
  • the method for preparing a polymorph of melphalan hydrochloride according to the present invention wherein the concentration of the hydrochloric acid is from 6 mol/L to 12 mol/L, preferably at a concentration of from 10 to 12 mol/L; - [Bis(2-chloroethyl)-amino-]-L-phenylalanine is 0.9 to 2.0 molar equivalents, preferably 1.3 to 1.5 molar equivalents.
  • the drying method is selected to be vacuum drying, and the drying temperature is 30 to 50 ° C, preferably 35 to 45 ° C.
  • the preparation method of the invention has the advantages of convenient operation, short reaction period, less organic solvent for reaction, reduced environmental pollution of three wastes, mild and controllable reaction conditions, good stability, high yield of reaction products and high purity. .
  • Figure 1 is an X-ray powder diffraction pattern of Form I polymorph of melphalan hydrochloride
  • Figure 2 is a X-ray powder diffraction pattern of Form II polymorph of melphalan hydrochloride.
  • the preparation route of melphalan hydrochloride according to the present invention is as follows;
  • Compound 2 is prepared by reference to US Pat. No. 3,032,584.
  • the compound of the formula 1 (10 g) and 20 ml of ethyl acetate and 80 ml of n-heptane were stirred and stirred, heated to 65 ° C, and added with a 10 mol/L aqueous hydrochloric acid solution (1.1 molar equivalent), stirred for 15 min, allowed to naturally cool to room temperature, and cooled to After stirring at 10 ° C for 2 h, it was filtered and dried in vacuo (40 ° C) to give 8.26 g of Compound I crystals of compound 1. The yield was 83.7% and the HPLC purity was 99.7%.
  • the compound of formula 1 (5g) and 5ml of N,N-dimethylformamide and 5ml of methyl tert-butyl ether are mixed and stirred, heated to 70 ° C, 1.3 molar equivalent of 10 mol / L aqueous hydrochloric acid solution is added, the reaction is stirred for 10 min, and the temperature is lowered to After stirring at 5 ° C for 1.5 h, filtration and drying in vacuo (50 ° C) gave 4.50 g of compound crystals of compound 1 as a crystal. The yield was 81% and the HPLC purity was 99.7%.
  • Example 6 X-ray pattern determination of type I and type II polycrystals
  • the relevant X-ray patterns were collected using an X-ray powder diffractometer, and the d-plane spacing of the I and II polymorphs is listed in the table below. In Table 1, the d-plane spacing is expressed in angstroms.

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  • Chemical Kinetics & Catalysis (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

本发明涉及盐酸美法仑的晶型及其制备方法与应用，所述的制备方法操作便捷，反应周期短、反应用有机溶剂少从而减少三废环境污染、反应条件温和可控、反应产物收率高、纯度高。所制备得到的晶型可用于治疗多发性骨髓瘤、乳腺癌、卵巢癌、慢性淋巴细胞和粒细胞型白血病、恶性淋巴瘤、多发性骨髓瘤。

Description

盐酸美法仑晶型及其制备方法与应用 技术领域
本发明涉及盐酸美法仑晶型及其制备方法和应用。
背景技术
4-[双(2-氯乙基)-氨基-]-L-苯丙氨酸盐酸盐，又名盐酸美法仑，是已知的抗肿瘤药，其化学结构式如下：
Figure PCTCN2018099076-appb-000001
1964年1月17日，2mg美法仑片剂在美国上市，其活性成分为美法仑；1992年11月18日，盐酸美法仑注射剂ALKERAN在美国上市，活性成分为美法仑盐酸盐。由于苯丙氨酸基团的存在，其易于进入肿瘤细胞内发生作用，从而有效地抑制和阻止恶性肿瘤细胞的增生和成熟。美法仑及其盐酸一盐的应用十分广泛，可用于多发性骨髓瘤、乳腺癌、卵巢癌、慢性淋巴细胞和粒细胞型白血病、恶性淋巴瘤、多发性骨髓瘤。
专利文献US3032584A记载了美法仑化合物的制备方法，以4-硝基苯丙氨酸或L-4-硝基苯丙氨酸为原料合成美法仑。在该合成方法中，首先要对原料的氨基酸部分进行保护(乙酯化保护羧基；苯酐保护氨基)得到一个较稳定的全保护物，将对位的硝基部分修饰后，再通过加氢气还原，羟乙基化，氯化三步反应得到美法仑的有效基团氮芥，最后采用盐酸回流的方法对氨基酸部分进行脱保护，得到盐酸美法仑I型晶型产品。
Figure PCTCN2018099076-appb-000002
根据目前已有的文献报道，尚未有文献记载美法仑的II型晶型及其制备方法。
发明内容
本发明的第一方面涉及化合物1即盐酸美法仑的II型多晶合物，该II型具有如图2所示的X-粉末衍射图谱,其熔点为186.2℃。
本发明的第二方面涉及盐酸美法仑的II型多晶合物的制备方法，包括：将4-[双(2-氯乙基)-氨基-]-L-苯丙氨酸与N,N-二甲基甲酰胺、甲基叔丁基醚按投料量1g：1～3ml：1～3ml混合，加热至温度不高于80℃，加入盐酸水溶液搅拌反应至反应完毕，并冷却到0～30℃，搅拌结晶，过滤、干燥，即得，其中所述盐酸水溶液与4-[双(2-氯乙基)-氨基-]-L-苯丙氨酸摩尔当量比为0.9～2.0：1摩尔当量，优选1.3～1.5:1摩尔当量。
本发明所述的II型多晶合物的制备方法，所述的加热温度优选为35～70℃，优选约45～60℃。
本发明所述的II型多晶合物的制备方法，其中所述的盐酸水溶液的浓度为为5mol/L～12mol/L，优选为5～11mol/L，进一步优选为6～10m mol/L。
本发明所述的II型多晶合物的制备方法，所述的干燥的方式选择为真空干燥，干燥的温度为30～50℃，优选35～45℃
本发明所述的II型多晶合物的制备方法，所述的4-[双(2-氯乙基)-氨基-]-L-苯丙氨酸与N,N-二甲基甲酰胺、甲基叔丁基醚按投料量1g：1～2ml：1～2ml，搅拌反应10～20min，冷却温度为5～15℃，搅拌结晶的时间为1-3h，优选为1h。
本发明的第三方面涉及的化合物1即盐酸美法仑的I型多晶合物的制备方法，该I型多晶物在于具有在约20.56埃的X-粉末衍射图d面间距(CuKa)。具备以下物理性质：X射线粉末衍射的d面间距(CuKa)：20.568，10.403，6.972，6.816，5.942，5.244，5.025，4.521，4.240，4.035，3.819，3.698，3.637，3.565，3.507，3.380，3.208，3.158，3.064，3.006，2.900，2.821，2.778，2.749，2.633，2.547，2.518，2.476，2.392，2.317，2.291。进一步至少一个在以下数值周围的X-粉末衍射图d面间距(CuKa)：10.40，6.97，6.82，5.94，5.24，5.02，4.52，4.24，4.04，3.82，3.70，3.64，3.56，3.50，3.38，3.20，3.16，3.06，3.00，2.90，2.82，2.78，2.75，2.63，2.54，2.52，2.47，2.39,2.32或2.29埃。特别的，本发明所述的I晶型具有如图1的X粉末衍射图谱。
本发明所述的盐酸美法仑的I型多晶型物的制备方法，包括：将4‐[双(2‐氯乙基)‐氨基‐]‐L‐苯丙氨酸与有机溶剂按1g：1～10ml的投料比混合，加热至温度不高于70℃，加入盐酸至反应完毕，并冷却到0～30℃，过滤、干燥，即得。
本发明所述的盐酸美法仑I型多晶型物的制备方法，其中4‐[双(2‐氯乙基)‐氨基‐]‐L‐苯丙氨 酸与有机溶剂的投料比优选为1g：1.8～8ml。
本发明所述的盐酸美法仑I型多晶型物的制备方法，所述的加热温度优选为35～70℃，优选约45～60℃，室温为20～25℃；所述的冷却温度是指低至约0～30℃，并优选5～15℃。
本发明所述的盐酸美法仑I型多晶型物的制备方法，所述的有机溶剂选自乙醇、甲醇、乙酸乙酯、异丙醚、正庚烷、的一种或几种。
本发明所述的盐酸美法仑I型多晶型物的制备方法，所述盐酸的浓度为6mol/L～12mol/L,优选的浓度为10～12mol/L；加入的当量为4-[双(2-氯乙基)-氨基-]-L-苯丙氨酸的0.9～2.0摩尔当量，优选1.3～1.5摩尔当量。
本发明所述的盐酸美法仑I型多晶型物的制备方法，所述的干燥的方式选择为真空干燥，干燥的温度为30～50℃，优选35～45℃。
本发明的第四方面涉及无毒、含有效治疗量的化合物1的II型多晶型合物和药学上可接受的载体的药用组合物。
本发明的的第五方面涉及治疗多发性骨髓瘤、乳腺癌、卵巢癌、慢性淋巴细胞和粒细胞型白血病、恶性淋巴瘤、多发性骨髓瘤的方法，所述方法包括向病人提供无毒、治疗有效量的化合物1的I型及II型多晶型合物。
本发明的第六方面，涉及一种盐酸美法仑的多晶型物的制备方法，包括：将4‐[双(2‐氯乙基)‐氨基‐]‐L‐苯丙氨酸与有机溶剂按1g：1～10ml优选1g：1.8～8ml的投料比混合，加热至温度不高于85℃，特别是不高于70℃，加入盐酸至反应完毕，并冷却到0～30℃，过滤、干燥，即得。所述多晶型物包括晶型I或晶型II。
本发明所述的盐酸美法仑的多晶型物的制备方法，所述的加热温度优选为35～70℃，优选约45～60℃，室温为20～25℃；所述的冷却温度是指低至约0～30℃，并优选5～15℃。
本发明所述的盐酸美法仑的多晶型物的制备方法，所述所述的有机溶剂选自乙醇、甲醇、乙酸乙酯、异丙醚、正庚烷、N,N-二甲基甲酰胺和甲基叔丁基醚的一种或几种；当有机溶剂选自两种成分时，极性大的成分与极性小的成分其体积比选自4～12；8，优选自6～10；8。优选的组合为甲醇-异丙醚、乙酸乙酯-正庚烷、N,N-二甲基甲酰胺-甲基叔丁基醚。
本发明所述的盐酸美法仑的多晶型物的制备方法，所述所述的盐酸的浓度为6mol/L～12mol/L,优选的浓度为10～12mol/L；加入的当量为4-[双(2-氯乙基)-氨基-]-L-苯丙氨酸的0.9～2.0摩尔当量，优选1.3～1.5摩尔当量。
本发明所述的盐酸美法仑的多晶型物的制备方法，所述所述的干燥的方式选择为真空干燥，干燥的温度为30～50℃，优选35～45℃。
本发明所述的制备方法的有益效果是：操作便捷、反应周期短、反应用有机溶剂少从而 减少三废环境污染、反应条件温和可控、具有良好的稳定性、反应产物收率高、纯度高。
附图说明
附图1为盐酸美法仑的I型多晶合物的X-射线粉末衍射图
附图2为盐酸美法仑的II型多晶合物X-射线粉末衍射图
具体实施方式
本发明将于下文通过实施例更加详细的描述，这些实施例示例性地用于进一步说明，且不应当视为对本发明的限制。
本发明所述的美法仑盐酸盐的制备路线如下；
Figure PCTCN2018099076-appb-000003
其中化合物2参考专利US3032584制备得到。
实施例1：I型多晶合物
式2化合物(1g)和8ml无水乙醇混合搅拌，加热至60℃，加入浓盐酸，搅拌30min，自然冷却至室温，并降温至15℃，搅拌2h后，过滤，真空干燥(30℃)后得到0.72g化合物1的I晶型多晶合物，收率为79.2％，HPLC纯度99.6％。
实施例2：I型多晶合物
式2化合物(5g)和10ml无水甲醇、8ml异丙醚混合搅拌，加热至65℃，加入6mol/L的盐酸水溶液(1.0摩尔当量)，搅拌15min，让其自然冷却至室温，并降温至10℃，搅拌1h后，过滤，真空干燥(50℃)得到4.02g化合物1的I晶型多晶合物，收率为81.7％，HPLC纯度为99.7％。
实施例3：I型多晶合物
式1化合物(10g)和20ml乙酸乙酯、80ml正庚烷混合搅拌，加热至65℃，加入10mol/L的盐酸水溶液(1.1摩尔当量)，搅拌15min，让其自然冷却至室温，并降温至10℃，搅拌2h后，过滤，真空干燥(40℃)得到8.26g化合物1的I晶型多晶合物，收率为83.7％，HPLC纯度为99.7％。
实施例4：II型多晶合物
式1化合物(5g)和6mlN,N-二甲基甲酰胺、8ml甲基叔丁基醚混合搅拌，加热至75℃，加入1.1摩尔当量的10mol/L的盐酸水溶液，搅拌15min，让其自然冷却至室温，并降温至10℃，搅拌2h后，过滤，真空干燥(50℃)得到3.65g化合物1的II晶型多晶合物，收率为79.2％，HPLC纯度为99.6％。
实施例5：II型多晶合物
式1化合物(5g)和5mlN,N-二甲基甲酰胺、5ml甲基叔丁基醚混合搅拌，加热至70℃，加入1.3摩尔当量的10mol/L的盐酸水溶液，搅拌反应10min，降温至5℃，搅拌1.5h后，过滤，真空干燥(50℃)得到4.50g化合物1的II晶型多晶合物，收率为81％，HPLC纯度为99.7％。
实施例6：I型、II型多晶合物的X-射线图谱测定
使用X-射线粉末衍射仪收集相关的X-射线图，下表分别列出了I和II型多晶型合物的d面间距。在表1中d面间距以埃表示。
表1.X-射线粉末衍射d面间距(埃)
I型 II型
20.720 11.581
10.437 8.110
6.986 6.826
6.827 6.185
5.950 5.891
5.251 5.748
5.030 5.511
4.523 5.254
4.244 5.027
4.208 4.813
4.037 4.550
3.821 4.453
3.701 4.373
3.640 4.226
3.568 4.137
3.511 4.014
3.381 3.930
3.209 3.914
3.161 3.840
3.065 3.630
3.007 3.567
2.900 3.472
2.822 3.379
2.779 3.156
2.751 3.107
2.635 3.036
2.548 2.949
2.520 2.911
2.476 2.762
2.393 2.592
2.317 2.436
2.292

Claims (10)

  1. 一种盐酸美法仑的II型多晶型物，具有如图2所示的X射线粉末衍射图谱。
  2. 权利要求1所述的多晶型物的制备方法，包括：将4‐[双(2‐氯乙基)‐氨基‐]‐L‐苯丙氨酸与N,N‐二甲基甲酰胺、甲基叔丁基醚按投料量1g：1～3ml：1～3ml混合，加热至温度不高于80℃，加入盐酸水溶液搅拌反应至反应完毕，并冷却到0～30℃，搅拌结晶，过滤、干燥，即得，其中所述所述盐酸水溶液与4-[双(2-氯乙基)-氨基-]-L-苯丙氨酸摩尔当量比为0.9～2.0：1摩尔当量，优选1.3～1.5:1摩尔当量。
  3. 权利要求1所述的多晶型物的制备方法，其中所述的盐酸水溶液的浓度为5mol/L～12mol/L，优选为5～11mol/L，进一步优选为6～10m mol/L。
  4. 权利要求1所述的多晶型物的制备方法，所述的干燥的方式选择为真空干燥，干燥的温度为30～50℃，优选35～45℃。
  5. 本权利要求1所述的多晶型物的制备方法，所述的4‐[双(2‐氯乙基)‐氨基‐]‐L‐苯丙氨酸与N,N‐二甲基甲酰胺、甲基叔丁基醚按投料量1g：1～2ml：1～2ml，搅拌反应10～20min，冷却温度为5～15℃，搅拌结晶的时间为1-3h，优选为1h。
  6. 一种4-[双(2-氯乙基)-氨基-]-L-苯丙氨酸盐酸盐的多晶型物的制备方法，包括：将4‐[双(2‐氯乙基)‐氨基‐]‐L‐苯丙氨酸与有机溶剂按1g：1～10ml，优选1g：1.8～8ml的投料比混合，加热至温度不高于70℃，加入盐酸至反应完毕，并冷却到0～30℃，过滤、干燥。
  7. 权利要求6所述的多晶型物的制备方法，所述的加热温度优选为35～70℃，优选约45～60℃；所述的冷却温度是指低至约0～30℃，并优选5～15℃。
  8. 权利要求6所述的多晶型物的制备方法，所述的有机溶剂选自乙醇、甲醇、乙酸乙酯、异丙醚、正庚烷、N,N-二甲基甲酰胺和甲基叔丁基醚的一种或几种。
  9. 权利要求6所述的多晶型物的制备方法，所述的盐酸的浓度为6mol/L～12mol/L,优选的浓度为10～12mol/L；加入的当量为4-[双(2-氯乙基)-氨基-]-L-苯丙氨酸的0.9～2.0摩尔当量，优选1.3～1.5摩尔当量。
  10. 权利要求6所述的多晶型物的制备方法，所述的干燥的方式选择为真空干燥，干燥的温度为30～50℃，优选35～45℃。
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