TWI235152B - Crystalline Efavirenz - Google Patents

Abstract

The potent reverse transcriptase inhibitor Efavirenz is produced in crystalline form. Crystalline Efavirenz exists in several physical forms which are designated forms 1, 2, 3, 4 and 5 and are characterized by x-ray powder diffraction and differential scanning calorimetry. Pharmaceutical compositions and methods are useful for the treatment of the human immunodeficiency virus (HIV).

Description

I235152 V. Description of the invention (1) Invention of Fei Fei ϊ !! About a kind of effective reverse transcriptase inhibitor made in crystalline form # VII, 7 There are several types of crystal form Effie Frenz, ::: Sweep = amount = type It is characterized by [Light Powder Diffraction Method ;: Medical Immunocompounds and Methods of Human Immunodeficiency Virus (")" that can be used to treat the background of the invention, which is a common feature of viral replication requiring retroviruses. Viral replication and transcriptional effects; ί, ί Reverse transcriptase, through anti-reverse viral replication of the viral RNA genome, the use of reverse transcriptase is a clinically relevant criterion for infection 4 but chemotherapy. # 2 ^ Ryanz is an effective treatment for human immunodeficiency virus 引起 compounds that cause the human immune system to progress (Η 丨 ν) _ transfer mothers and start to form A IDS. Nuclear spine-based inhibitors, such as azide thymus moss, and non-nuclear sphincter VII = and major inhibitors have been shown to be able to reinstate HV reverse transcriptase ^ = treatment. Benzo D's ketones, such as ephedrines, have been found to be a #effective non-nucleoside-based Η IV reverse transcriptase inhibitor. The ephedrine system ^ Chemical name (S) represented by formula (1) -6-gas-4-cyclopropylethynyl-4 difluorofluorenyl-1,4-dihydro-2, -3, 1 —Benzo plowing—2-ketones are famous: ...

Page 4 1235152

Η (I)

Effie Frenz is not just a fairly potent reverse transcriptase inhibitor, effectively combating HIV reverse transcriptase resistance. Thanks to tincture, also

Benzyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzophenone 萼 口 井 ~ 2 \ The importance of radical reverse transcriptase inhibitors, so manufacturing and purification know & ~ Obviously, it is necessary to make the crystal form of J and _ with chemical and physical advantages. / The treatment or prevention of the aforementioned diseases is by privately preventing the need for such treatment

Administration of a medically effective amount of ephedrine by human or animal body is accomplished. Effiferents can be used as individual compounds, as ingredients in pharmaceutical compositions, or in combination with other antivirals, immunomodulators, antibiotics and vaccines. The compounds can be administered parenterally or parenterally in a solid or liquid dosage form. Earlier, I didn't know that there are stable crystalline polymorphs in Ephefreins. Therefore, the manufacture of drugs requires stable crystalline forms and reliable and reproducible steps. Summary of the Invention One aspect of the present invention is directed to a crystalline form of efenez. Its related aspects

1235152 V. Description of the invention (3) Including novel crystalline plastics Izafreenz 'named as Type 1, Type 2, Type 3, Type 4, and Type 5. These types are characterized and distinguished from each other by differential scanning calorimetry (DSC) and X-ray powder diffraction analysis. Another aspect of the present invention includes a crystalline ephedrine pharmaceutical composition and its five forms. The crystalline product of the present invention can be formulated into a general solid pharmaceutical dosage form or made into a liquid dosage form by combining a medically effective amount of a crystalline drug with a pharmaceutically acceptable carrier. The crystalline product may be administered in a pharmaceutical composition in combination with other antiviral agents, immunomodulators, antibiotics or vaccines. Another aspect of the present invention encompasses a method of inhibiting reverse transcriptase, which comprises administering a crystalline ephedrine that is sufficient to cause the reverse transcriptase to contact an inhibitory amount of an active drug substance. The present invention includes, in a particular aspect, a method for treating retroviral infections, such as human immune deficiency viruses and diseases involving viral replication, which includes administering a window treatment containing a quantity of the novel crystalline form of ephedrine of the invention Pharmaceutical composition. Faben i Γ also provides a novel method for treating HIV infection, 4 or 5 including the administration of a medically effective 1,2, transcriptase inhibitor Vl. Phylophrenz to a host in need. The composition is combined with one or more compounds selected from the group consisting of H1 v countersword and HIV protein 1 per inhibitor. … The present invention, the central h, describes fluoromethyl ~ 1.4-type junctions (magic-6 ~ Ga ~ 4-cyclopropylethynyl-4 ~ tri ~ hydrogen-2Η-3, 1-benzopyrene X-ray diffraction

m shows t will be explained with reference to the following drawings. 1235152 V. Description of the invention (6) 6. 0 ± 0. 2 ^ 6. 3 ± 0. 2 ^ 10. 3 ± 0. 2 > 10. 8 ± 0. 2 > 14. 1 ± 0. 2 > 16. 8 ± 0. 2, 20.0 ± 0.2 ^ 20. 5 ± 0. 2, * r 21. 1 ± 0.2 and 24.8 ± 0.2 are characterized by a value of 20, and have scanning by differential The heat map now has another characteristic of peaks from about 138 ° C to about 140 ° C. In another more preferred embodiment, the type 1 crystalline form of ephedrines has the characteristic that the X-ray powder diffraction pattern behaves substantially the same as that of FIG. 1, and it has the characteristic There is another characteristic of peaks from about 1 3 8 ° C to about 1 40 ° C. In a second embodiment, the present invention describes a pharmaceutical composition comprising a medically effective amount of a type 1 crystalline form of ephedrine and a pharmaceutically acceptable carrier. In a preferred embodiment, the pharmaceutical composition is enclosed in a dosage form of a capsule or compressed tablet, wherein the medically effective amount of the crystalline form 1 ephedrine is about 1 mg to about 100 mg . In a more specific embodiment, the pharmaceutical composition is enclosed in a dosage form of a capsule or compressed tablet, wherein the medically effective amount of the crystalline form 1 ephedrine is about 50 mg to about 200 mg . In another more preferred embodiment, the pharmaceutical composition contained in the capsule or compressed tablet contains a disintegrant in an amount of about 10% or more by weight compared to the total dry weight of the dosage form. " Λ In another preferred embodiment, the pharmaceutical composition is in a liquid form. In a more specific embodiment, the liquid type includes a type 1 crystalline form Effie Reinz in a weight ratio of about 0.1% to about 15%, and a weight ratio of about 1%.

Page 9 1235152 V. Description of the invention (7) 50% to about 99% of the medium chain length fatty acid is a liquid excipient of the "combination" in a very good embodiment. * μ J Γ Mouth material is enclosed in soft gel capsules: acid glycerol vinegar ... ', Xi 70 fermented vinegar is basically included. to Cl. fatty acids. it ί: two more: in the two-body embodiment' liquid type The state includes a younger-type crystalline form of ephedrines with a weight ratio of about 々, and contains about 50% to about 99% by weight of a medium-chain-length fat. ^ Liquid excipients of urethane esters include sweeteners with a reset ratio ranging from about 0.1% to about 50%. In another preferred embodiment, the pharmaceutical composition in a liquid form includes a weight ratio of about 0. 1% to about 10% type i crystalline form efenez, and an excipient of vegetable oil in a weight ratio of about 50% to about 99%. In a very specific embodiment, the pharmaceutical composition comprises In a soft gel capsule 'wherein the vegetable oil is soybean oil or peanut oil. In another preferred embodiment, the pharmaceutical composition in a liquid form includes a weight ratio 0% 至。 About 0.1% to about 10% of the first type of crystalline form ephedrine, = and vegetable oil weight ratio of about 50% to about 99% of liquid excipients containing st ratio ranging from about 1.0% to About 50% sweetener. 3 A In the second embodiment, the medical dose of capsules or compressed tablets includes: (a) Type 1 crystallized ephedrines with medical dare ; (B) a surfactant; (c) a disintegrant; (d) a binding agent; and (e) a lubricant.

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V. Description of the invention (8) In a preferred embodiment, the therapeutically effective amount is about 50 mg ^ about 2000 |: the positive type of ephedrine sodium ephedrine sodium sulfate, &% θ ^ The surfactant is Twelve Houses and the lubricant is magnesium stearate. 1 sodium, the binding agent is lactose, and in the fourth specific embodiment, the present invention is one: the method of the reverse transcription enzyme to inhibit virus replication into the virus V caused by HIV reverse transcriptase and can effectively inhibit Enclose the amount that is sufficient to form the crystalline form of ephedrine. Contact with Wu Wuwu In a preferred embodiment, the compound is used to inhibit HIV reverse transcriptase in vivo. In a fifth embodiment, the present invention describes a method of incomplete virus infection, which includes administering a buccal immune-effective amount of a type i crystal form of ephedrine; orally; In a preferred embodiment of the host to be treated, the i-type crystallized ephedrine parent is administered at a dose of about 1 to about 1000 mg. From a more preferred embodiment, the i-type crystalline ephedrine master batch is administered at a dose of about 50 to about 200 mg. From the sixth embodiment, the "i-type crystalline form Effie" is recorded in the seventh embodiment according to the "reformation of efenez by a hydrocarbon solvent recrystallization". Crystalline ephedrine; said ... prepared by the following steps, including: "silk pudding 1) recrystallized ephedrine from a suitable solvent; 2) separating the crystals, and 3) drying the crystals to an appropriate temperature, To generate a substantially pure type i]

Page 11 1235152 V. Description of the invention (9) Crystalline ephedrine. In a more preferred mixture of A ^ i and heptane, diisocyanate, a suitable solvent is heptane or tetrahydrofuran with a degree of about 70 t to about: B, which is separated by filtration, and is moderately mild. The eighth specific embodiment: Real: High quality: Said to be purity 9. %the above. It was prepared by heating Form 2 and Chu 1 i, ,, = crystalline form ifefenez is a mixture. Lane, Type 4 or Type 5 Effie Freundz or its ninth path: # 溶 Dissolve No. / Other: ^ by stirring, Type 1 Crystal Effee Frenz is The mixture # _ ^ ^ ^ is prepared from non-Freinz, type 3 Effie Reinz or in the tenth: C container. Frienz. In the list also, the present invention describes that the second type of crystalline form Effi is in a preferred embodiment where the second type of crystalline form is substantially qualitative. In the two embodiments, the second type of crystalline form Effie Reinz has = :: J in the example, 'Type 2 crystalline form ephedrine 6. 8 ± 0, 2, 9% radiographic pattern performance includes four or more selected from 21.4 + 〇 2 U + 2, 12.3 ± 0.2, 16.2 ±. .2 characteristics. The 20 values of 〇 · 2, 24 · 1 ± 〇 · 2 and 28 · 0 ± 0 · 2 are in another preferred and heterogeneous manner. In the embodiment from X to light in α κ, the second type of crystalline form Effie Foren-Characteristics. a% radiograph performance is essentially consistent with that shown in Figure 2.

Among the other better I have also been listed by Differential Souling, the second type of crystalline form ephedrine. Tian heat chart is now about 116. (: To about 11 9. (: There is a peak value of 1235152 V. Features of the invention description (10). Here are two examples: In the second embodiment, the second type of crystalline ephedrine has a heat map by scanning the difference between- In a more specific embodiment, the features are as follows:-, with the X-ray powder diffraction pattern J $:, ', mouth type Effie Furnitz 6.8 ± 0.2, 9 2 + n 2 = The performance consists of four or more features selected from the group consisting of: 21.4 ± 〇.2; 22 7 ± 0 〇 · 2'16 · 2 ± 〇 · 2 ', and features having a difference of _, ^ 4.1 0 0.2 and 28 · 0 soil 0.2 2 0 value 11 9 ° C Another characteristic has a peak value. I do n’t know if the heat map is now about 11 6 ° c to about 10 = in the example, 'type 2 crystalline form of Effiforn sign, And with ί = another characteristic of the unique peak that is now substantially consistent with Figure 2. The hot summer chart is now about 116 ° C to about the amount = 2 type ten: a crystal body is formed according to two examples in the mountains. -A kind of tablet containing a medically effective medicinal composition. In the example of the tablet containing "Fr & Enz and a medically acceptable carrier," the medicinal composition is encapsulated in a capsule or compressed drug 43%, wherein the first Type 2 crystalline plastic ephedrinz medical Politics = 1 mg to about 1,000 g. 縻 In the preferred embodiment, there is a H-cylinder compound U liquid type ... 1% i about 15% crystalline form A medically effective amount is the reverse transcription of the toxic code. In the embodiment, the present invention describes a method for inhibiting viral replication by incorporating disease. Each method includes providing sufficient

Page 13 On the twelfth 1235152

V. Description of the invention (11) The type 2 crystalline form of ephedrine is connected with ΗIV reverse transcriptase and an effective inhibitory amount of the active drug substance. In a thirteenth embodiment, the present invention describes a method for treating viruses. Diseases, such as human immunodeficiency virus and other symptoms, are as follows: = A medically effective amount of a crystalline form of ephedrine is administered to a host in need of such treatment or prevention. 31

In a preferred embodiment, the crystalline form 2 ephedrine is administered at a dose of about 1 to about 1000 mg per dose. ’'I

In a fourteenth embodiment, the second plastic crystal form of ephedrine is prepared from a saturated alkane solution of ephedrine by a rapid crystallization step ". In a preferred embodiment, rapid crystallization includes: 1) dissolving ephedrine in a suitable solvent at a suitable temperature to form a saturated solution; 2) a saturated solution; and 3) rapidly cooling the saturated solution to produce a first Type 2 crystalline form efenez. In a more preferred embodiment, a suitable solvent is heptane, a suitable temperature is about 70 ° C to 80 ° C, and rapid cooling of the saturated solution includes contacting the saturated solution with the cold interface. In the fifteenth embodiment, the present invention describes the third substantially pure type: · Pear crystal type ephedrine. In another preferred embodiment, the type 3 crystallized ephedrine has an X-ray powder diffraction pattern including four or more selected from the group consisting of: 7 · 1 ± 0 · 2 7.3 ± 0 · 2, 1ΐ.〇 ± 〇 · 2, 13.8 ± 0 · 2,

Page 14 1235152 V. Description of the invention (12) 20. 9 ± 0. 2 > 23. 3 ± 0. 2, 27.9 ± 0.2 and 33 · 5 ± 0 · 2 of 2 0 characteristics. In another preferred embodiment, the type 3 crystallized ephedrine has characteristics that the X-ray powder diffraction pattern behaves substantially the same as that shown in FIG. 3. In another preferred embodiment, the crystalline form 3 ephedrine has the characteristic that the differential scanning calorimeter now has a peak at about 108 ° C to about 110 ° C. In another preferred embodiment, the type 3 crystallized ephedrine has the characteristic that the performance of the differential scanning heat map is substantially the same as that shown in FIG. 7. In a more specific embodiment, the type 3 crystallized ephedrines < has an X-ray powder diffraction pattern representation includes four or more selected from the group consisting of: 7.1 ± 0.2, 7.3 ± 0.2, 11.0 ± 0.2, 13.8 ± 0.2, 20.9 ± 0.2, 23.3 ± 0.2, 27.9 ± 0.2, and 33.5 ± 0.2 of 20, and have characteristics determined by differential scanning calorimetry Another feature is the peak at about 108 ° C to about 110 ° C. In another more preferred embodiment, the type 3 crystallized ephedrine has characteristics that the X-ray powder diffraction pattern behaves substantially the same as that shown in FIG. 3, and __ has a difference The scanning heat map shows another feature with a peak at about 108 ° C to about -11 0 ° C. In a sixteenth embodiment, the present invention describes a pharmaceutical composition comprising a medically effective amount of a type 3 crystalline form of ephedrine and a pharmaceutically acceptable carrier.

I

O: \ 58 \ 58887.ptd Page 15 1235152 Description of the invention (13) In a preferred embodiment, the medicated tablet is in a dosage form, in which the third sentence la, a is contained in a capsule or compressed medicine. The 3rd, 1st, 3rd, and 9th day-of-day-type ephedrine total factors # 殹 上 上 ϊϊ is about 1 mg to about 0 0 0 mg. The medical treatment of the Buddha's heart is in another preferred embodiment, wherein the type 3 crystalline form imitates * μ '/ # and the compound is in a liquid form of 0.1% to about 15%. It is also known that the medically effective amount is about the seventeenth embodiment. Toxic reverse transcriptase inhibits virus replication. I love a kind of HIV reverse transcription by programming the disease. Includes type 3 epidemic infectious virus in contact with an active pharmaceutical substance sufficient to make a crystalline form of ephedrine P4: infection: example: 2: narrative-a host to treat human immunity & Said ^ includes a better specific implementation of the need for such treatment or prevention: 1 Buddha's Enz is based on about 1 to about 1 dose per day, and, every day, if ephedrine It is the i-type yoke 3 ^ ,,, which is dissolved by stirring. Hydrophilic Buddha of Heart-shaped ephedrine or its mixture ^ Heart Record, type-2 ephedrine and separated crystals. Q solvent slurry step to prepare aa

Ϊboring = = = The compound is Geng ... and I is in the tenth and a large y Pfeifferenz. In the spiritual queue, the present invention describes a type 4 crystalline plastic. In a preferred embodiment, a type 4 crystalline efeneze

1235152

5. Description of the invention (14) is essentially pure type. In each case, the type 4 crystalline form of ephedrine U ± 0, 2, 6 includes four or more selected from the group consisting of: 12.7 ± 0.2 to 0;; 9 .: soil. .2, 11 .... earth. .2, 19 · 5 ± 〇 ?, ~ 〇 · 2, 16 · 1 soil 0 · 2, 19 · 2 soil 0 · 2, in., 6 ± 0.2 and 24 · 3 ± 〇 · 2 of 2 Characteristics of Θ values. It is characterized by X-ray μ ϊ Γ type 4 crystal form ephedrine. The pattern of the unpercent shot pattern is substantially the same as that shown in FIG. 4, which is the characteristic of the 'type 4 crystal type ephedrine in the embodiment. "The thermal trace graph now has a peak at about 95 ° C to about 100 t. From:" !! "In the embodiment, the type 4 crystalline form of ephedrine sign.% Thermal trace performance Essentially consistent with the display shown in Figure 8, there are four features in the embodiment of X and light! In the embodiment, the fourth type of crystal form ephedrinz 3 β ± 〇1 the end I-ray pattern performance includes four or Multiple selected from the group consisting of: 12? +0, 6.3 ± 0.2, 9 · γ ± 0.2, 11 · 0 ± 0.2, 19: 5: 〇 ;, :: .2 ± 0.2, 16.1 ± 0.2, 19 · 2 ± 0.2, and has a value of 20 from #_. 6 ± 〇, 2 and 24.3 ± 0.2, while the other special = scanning heat chart is now about 95 ° C to about 100 ° C The peak value ^: In a more specific embodiment, the type 4 crystal type ephedrine /, X-ray powder diffraction pattern performance is substantially consistent with that shown in FIG. 4

Page 17 I235l52 V. The invention; (15) " " " " " " " " " " " " " " Another feature. Effectively, in the twenty-first embodiment, the present invention describes a kind of medical treatment? . In a preferred embodiment of the crystalline form ephedrine and a pharmaceutically acceptable carrier, the pharmaceutical composition is encapsulated in a capsule or compressed: said, within the dagger type, wherein the type 4 crystalline form depends on about 1 mg to about 1000 mg.欣 令 i In another preferred embodiment, the following formula, J: Zhong 筮 4 纴 纴 荆 片 # T ★ The beam composition 疋 is liquid π »〇 /, No. 1, ,," 曰 1 The medically effective amount of efeverenz is about 0.1% to about 15%. 酉 π 3 double miles 疋 is about the twenty-second embodiment Φ, Shifang, viral reverse transcriptase and inhibit The formula of virus rejuvenation,: Ming =: a kind of H1V reverse transcriptase and effective inhibitory amount /, which can be provided by the program to provide sufficient amount of crystalline form of ephedrine. / Sexual pleasure material contact In the twenty-third of the twenty-three specific implementation of the method of immunodeficiency virus infection, Douban t clearly describes the treatment of a host of human defense to medically effective multiplication, including the need for such treatment or in a preferred embodiment. ^ ... Crystalline ephedrines. It is about 1 to about 100,000 milligrams of crystalline ephedrines per dose in the fourteenth embodiment ... It is composed of a mixed solvent system The Chinese crystal i-form ephedrine ^ ^ ^ is prepared by the lamp, the mouth, and the mouth. Day 15 is implemented in the following manner: Preparation out step, said type of said junction type 4 by Feiforuien 'dagger comprising:

Page 18 1235152 V. Description of the invention (18) _______ Causes Η 1 V reverse transcriptase in contact with the amount of active substance that effectively inhibits the amount of crystalline form of ephedrine, the fifth in the twenty-ninth specific implementation In the example, a method of immunodeficiency virus infection, wherein a host for the treatment of human defense is administered a medically effective amount of Type 5 Du Yue, Second, such a mountain is treated or pretreated in a preferred embodiment, the 5 = ephedra ^ enz. In a dose of about i to about 1000 milligrams per dose ^ In the thirtieth embodiment, the positive type of ephedrine is described in the thirtieth embodiment: the last name is recrystallized from a mixed solvent system Preparation is good. In the thirty-first embodiment of the following type of ephedrae, the present day and month #, ten, the method of infection, which includes the effective amount of HIV in need of the treatment: Medical administration together (:): 1; 2'3'4 or 5 crystalline form of ephedrinez () to a compound selected from the group consisting of Η 丨 V trans and white enzyme inhibitors. Transcription inhibitors and Hi V eggs, in the thirty-second embodiment, the present invention teaches the tenth, the first type, the second type, the third type, the fourth type, and the like. Medical composition with medically acceptable carriers. Type or its mixture-ephrenez is a chemical segment represented by the following formula (丨): Cyclopropylethynyl-4-trifluoromethylsense 4: Two (S) +, known for chloro-4- -one : Allow 1 ~ benzo_plowing "2 '1235152 V. Description of the invention (19)

(I) The synthesis of (S) -6-chloro-4 »cyclopropylethynyl-4—trifluorofluorenyl—l 4—« 3,1-benzohexidine — 2-_ can be synthesized through the use of Sold and completed. Formed after reacting with neopentyl chloride in the presence of hydroxides, and then treated with phenylamine and ethyl trifluoroacetic acid, and then acidified with mineral acid to generate trifluoro salts. (Process Figure 丨). Flow chart 1 ctx neopentyl-Cl

NaOH

A Ο

1) BuLi / EtTFA 2) HCI / HOAc

In the presence of a skirt, it is then reacted with benzyl alcohol to form an amine, which is shown in the figure!) In the presence of an agent, it is reacted with a cyclopropyl ethyl block to form a palmitate, flow chart 2

1235152 V. Description of the invention (20) c

Allyl fluorenol undergoes intramolecular cyclization to form a group, and the free amine undergoes cyclization to form hydrazone / threonine. Remove 卞 Figure 3). ) Represents the active drug substance (flow chart flow chart 3

Break gas THF / heptane

The method of synthetically preparing ephedrinez is further disclosed in commonly designated U.S. Patent Application No. ⑽ / 032, 980, which is incorporated herein by reference 0

Page 23 1235152 V. Description of the invention (21) Five types have been confirmed and named as Type 2, Type 2, and Type 5. Various types can be beneficial to each other #. Health, type 4 and the amount of heat tracing are added with X === ”and differentially pure and high-quality pure types. In addition, the real type 1 can be taught from this article to be thermodynamics The most stable energy on the A. A, 恶, change evil., A n 〇n B 疋 The type of its sad point is about 1 3 ° ° to about 140 C, the highest of the four types. Because of f It is usually used in pharmaceutical formulations. All other types are converted in Type 2: 7 :; = Conversion to Type 1. Conversion and drying are best done in a dryer oven minus: 1 more. About 75 ... to The compound can also be transformed: using a hydrocarbon slurry at a temperature of about 5 ° C to about: 5 ° C. The heptane is the best hydrocarbon in this transformation because the type 4 is at about 7 (rc It is insoluble, so it cannot be transformed into Form 1 under 7 ^ ίΐ. When a saturated solution is seeded at about 60 ° C to about π, and maintained at about this temperature until Form 1 begins to crystallize, Form 1 will Crystallized directly from heptane. $ F can be obtained by rapid crystallization. Rapid crystallization is accompanied by the appearance of a saturated heptane solution of ephedrine at about 70.0%. The crystallization effect with i is best at Pτ where the solution is in contact with the colder surface. The second is observed by the differential scanning calorimetry method. The melting point of the type is about 11 6 ° C to about-1 & 1 9JC ' ~ This has excellent stability. Its needle-like crystals are usually larger than other types. Type 2 does not include f ^, which is common in many steps in the production of efenez. Therefore, type 2 is sold for manufacturing. Freienz, regarding the yield of secondary purification and the batch recovery due to the failure to pass the drug patent application

Page 24 1235152 V. Description of the invention (23) 2 The quality will lead to step advantages. In addition, Type 4 has a better crystalline form. It is therefore particularly suitable for blending. When a cyclic ether such as tetrahydrofuran (THF) is added, a hydrocarbon group (v / v) solvent group η that dissolves about 4 to about 6% of tritium can be obtained from the hydrocarbon slurry of type i or type 2 Thing. Alkanes are best hydrocarbons. From the heptane solution in which about 5% THF was dissolved, the first type was positive. If ephreinz is soluble in THF / heptane mixtures, the degree is usually very high. In order to obtain the maximum yield, it is best to follow certain procedures. Type 4 is crystallized. It is best to change the solvent to heptane. Reduce a T-HF wave to less than about 1%. Type 4 is also obtained from the crystallization of methylcyclohexane at saturation. Recrystallization from linear heptane usually forms the fourth, i, / /, this compound. Because Type 4 is the most common result of the formation of ephedrine from hydrocarbon / THF mixtures, Type 4 is commercially available. The top is separated as a wet cake. Type 4 crystallization by drying ·; c to about 100. . It takes about 12 to about 24 hours, and it is best to be in a vacuum motor, which can be transformed into a cap! type. Type i is prepared in large quantities from type 4 and the type 4 wet cake is heated to about 30 ° c to about 50 ° C in order to remove large wounds, and the temperature is then raised to about The temperature is from 80 ° C to about 100 ° C, and the melting point of the type 5 is observed by differential scanning calorimetry to about 8 ° to about 1 °°. Form J is determined to be the most thermodynamically stable crystalline form below 40 ° C. Type 5 is ^: f crystals' and has the additional characteristic of preferentially removing impurities, so it has the advantage of step ^. Crystallization can be obtained by recrystallizing from a THF / heptane-diluted solution: Crystallization can be obtained from a solution in which the type] or type 4 has been isolated. The possible type transitions in the present invention can be furthered by referring to the flow chart 4 1235152

Page 1235

V. Description of the invention (25) Asian maple '"TMEDA" refers to N'N, N'N'-tetramethylethylenediamine. Including ms: ": lice compound"-the word refers to an alkane solvent. Examples include: Kernel is not limited to solvents such as pentane, hexane, money, octane, nonane, decane, and solvents. The preferred mixed solvent system in the present invention is a mixed solvent system containing tetrahydrofuran and stink bug compounds. The term "slurry" is used to refer to the saturation of ephedrines = additional ephedrines generates a heterogeneous solution of ephedrines and solvents. ,

The present invention describes substantially pure Type 1 Effivrenz, Type 2 Effevrenz, Type 3 Effevrenz, Type 4 Effevrenz and Type 5 Effie Frenz. As used herein, "substantially pure" refers to compounds having a purity of greater than 90%, including 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 100%. When dissolved, ifefenez loses its crystalline structure, so it is called a solution of ifefenez. However, all forms of the invention can be used to prepare liquid formulations in which the drug is dissolved or suspended. In addition, the crystalline form of Eiffelion is incorporated into the solid form.

A medically effective amount of crystalline ephedrine combined with a pharmaceutically acceptable carrier to produce the pharmaceutical composition of the present invention ^ "Medically effective amount" means that it can be effective when administered alone or with other therapeutic agents An amount that prevents, suppresses or slows down a disease or condition or the progression of a disease or condition. The combination of compounds described herein is preferably a synergistic combination. For example, Chou and Tala lay, The Benefits of Enzyme Regulation 22: 2 7-5 5 (1 984), describe when synergistically applied with compounds

Page 28 1235152 V. Description of the invention (26) The effect of the drug (in this case, the inhibition of Η 1 V replication) is greater than the synergistic effect when the compound is applied alone as a single agent. General synergistic effects are most clearly demonstrated at the suboptimal concentration of the compound. In synergy ... π fetch / month 疋 u 呦 Cooperative use can reduce cytotoxicity, increase antiviral effect, or some other excellent effects synergistic compared with the individual ingredients. The compounds of the present invention can be used to inhibit HIV reverse transcriptase, to treat infections caused by human immunodeficiency virus (Η1 V) and to treat pathological conditions resulting therefrom, such as acquired immune deficiency syndrome (AIDS). The definition of treatment or treatment of infections caused by HIV includes' but is not limited to treating and preventing a wide range of HIV infection states: AIDS, ARC (AIDS-related complications), symptoms and no symptoms, and acute or May be through blood transfusion, fluid exchange, bile, accidental needle contact with HIV, or blood during surgery. The compound of the present invention can be taken orally, enterally (including skin by inhalation and injection of the intestinal muscle 2 intrasternal injection or perfusion technique "Ji 'mist, rectum, ^ generally non-toxic medicine can be used as The dosage unit formula of Du 悧 and excipients are given to Ping _ /, and, are familiar with all the dosage forms used, and these are-familiar to the medical arts described in this article by the name of ephedrines a 5: ;; = preventive methods, which are incorporated herein by reference to the "Western Therapy and Predictive Types of the Invention" and one or more than two: two methods include: -Other HIV reverse transcriptase inhibitors, HIV = second-treatment AlDS, such as immunomodulators, antibiotics, anti-infective sm, antiviral agents, as used herein "im reverse transcriptase inhibitor field j and combined use. Η" Refers to ΗIV reverse transcriptase 1235152 V. Nucleotide and non-nucleotide inhibitors (RT) of invention description (27). Examples of nucleotide RT inhibitors include, but are not limited to, AZT, ddC, ddl, d4T and 3TC. Non-nucleotide RT inhibitors include, but are not limited to, delaval bonds (de 1 avi r d 丨 n e)

(Pharmacia and Upjohn U90 1 52S), nevirapine (Boehringer Ingelheim), Ro 1 8,8 93 (Roche), S trovirdine (Lilly), MKC-442 (Triangle), HBY 097 (Hoechst), ACT (Korea Research Agency), UC-781 (Rega Agency), UC-782 (Rega Agency), RD4-2025 (Tosoh Co., Ltd.) and MEN lOgYG ^ Menarini Farmaceutici). As used herein, “ΗIV protease inhibitor” refers to examples of compounds intended to inhibit η IV protease, including, but not limited to, saquinavir (Roche, Ro31-8959), ritonavir (Abbott) , ABT-538), indinavir (Merck, MK-639), amprenavir (Vertex / Glaxo Wellcome), nelfinavir (Agouron, AG-1 343) , Palinavir (Boehringer Ingelhe im), BMS-232623 (Bristol-Myers Squibb), GS3333 (Gilead Sciences), KNI-413 (Japanese Energy), KNI-272 (Japanese Energy), LG-71350 ( LG Chemical), CGP-6 1 75 5 (Ciba-Geigy), PD 1 736 0 6 (Parke Davis), PD 177298 (Parke Davis ,, PD 1 783 9 0 (Parke-Davis), PD 178392 (Parke Davis) , U-140690 (Pharmacia and Up john) and ABT-3 78. Other examples include cyclic protease inhibitors, disclosed in WO 93/0 7 1 28, WO 94/1 9329, WO 94/22840 and PCT. No. US9 6/0 3426.

Page 30 1235152 V. Description of the invention (28) For example, tablets and dolphins: (Freuri: crystalline form can be administered at oral doses, prescription), pills Λ include a sustained release or timed release emulsion. 1 powder, granules, brewing agent, s Ding 1 liquid suspension, syrup and k and · solid dosage form f contains about 1 mg $ ^ ΠΛΛ > + 弋 (edge 糸, and 5 things) generally per dosage unit Oral administration: mg of crystallized efenez. Mouth type such as tablets or capsules, the company said Xinxuanxuan b and a non-toxic pharmaceutically acceptable inert carrier /; ifefofo powder, sucrose, gi s ^ m ^ ^ carriers, such as lactose, starch廿: methylcellulose, magnesium stearate, diphosphoric acid, 'max = mannitol, sorbitol, and the like-applied together. External ingredients: In addition, the solid dosage form in this article contains some amount of biform. " These excipients include other diluents,: St ... thinners are added in large amounts to the formula :. Zhile tablets cure. Examples of diluents are lactose and cellulose. The "binding agent" used here is used to increase the quality of the powder to adhere to the powder to ensure that the tablet will remain dense after compression, and to improve the quality of the free flowing powder. Typical binding agent examples include lactose, sugar, and various sugars. The "lubricant" used herein has several functions, including preventing the sticking of tablets and compression devices, and improving particle flow before compression or encapsulation. Lubricants are examples of the most common hydrophobic substances. Excessive use of lubricants can lead to reduced disintegration in the formulation and / or delay dissociation of the drug substance. The "G1 idants" used in this article are substances that will improve the flow characteristics of particulate matter. Examples of G 1 i d a n t s include talc and colloidal polymer; oxidized oxygen dioxide. 1235152 V. Description of the Invention (29) "Peptone" as used herein is a substance or a mixture of substances that is added to the formulation to promote S-shaped separation or disintegration of the solid agent after application. Examples of disintegrating agents include starch, clay, cellulose, ammonium alginate, gums, and crosslinked polymers. A group of disintegrants refers to "super disintegrants", which are usually used in low concentrations as body preparations. The amount type is generally 1% to 10% by weight compared to the total weight of the dosage unit.Croscarmelose, Crosopvidone and sodium starch glycolate ^ Represents crosslinked cellulose, crosslinked polymer and Examples of cross-linked starch. Sodium starch glycolate swells 7 to 12 times in 30 seconds, thus effectively disintegrating the contained granules. The disintegrant used in the present invention is preferably selected from the group consisting of modified starch, aoscamallose sodium, calcium carboxymethyl cellulose, and crospovidone. The more preferred disintegrant of the present invention is modified starch, such as sodium starch glycolate. . j, Jiazai I include tablets containing the solid pharmaceutical uniform amount described herein. The preferred capsule or compressed tablet type is usually = in terms of the effective amount of ephedrinez and one or more of the total weight of the capsules or tablets, the amount is about 10% Disintegrant. A preferred capsule formulation contains efefrenz in an amount of about 5 to about 1000 milliliters per capsule. The preferred compressed tablet formulation is from mg to about 8. 〇mg of ephedrinez. Better. : Capsule f has about 5 per tablet. To about, milligrams. Preferably, the medicinal dosage form of capsules or stilbene tablets includes a medically effective amount of Dig, 2, or 4 ephedrines; surfactants; disintegrating agents; binding agents; emollients

Page 32 1235152

V. Description of the invention (30) Lubricants; and optionally added pharmaceutically acceptable excipients, such as diluents gl idants and the like; wherein the disintegrating agent is selected from the group consisting of modified powder; θ croscarmallose sodium, carboxyl Basic fiber words and crospov i done ° Generally speaking, a liquid pharmaceutical composition for oral administration contains two HIV reverse transcriptase inhibitors capable of varying within a range of about 0.1 to about 15% by weight (wgt). The content of the drug substance in the total compound ranges from about i to about 10% by weight. ^ M α, gen, water, and polyhydric alcohols that are included in the package, such as special bonds, are sold and sold on the market. According to fatty acids, When the general combination medium is in the form of the best ratio for oral administration, the crystalline ephedrine can be combined with any non-toxic pharmaceutically acceptable inert carrier, such as ethanol, glycerol, and the like. In a preferred liquid composition, the liquid excipient is a polyol ester containing a medium chain fatty acid. This medium-chain fatty fatty alcohol ester is intended to include glycerol, propylene glycol, or other polyethylene glycols with chain breaks. It reacts with mixed fatty acids in which the acid chain length is 6 and fatty acids of 2 carbon atoms. . A particularly good composition is a triglyceride or diglyceride of C8_C1G fatty acid sold from coconut oil with "_ 一" 一 " 00 ": Quotient = Ciba has about 68% c8 fatty acid (caprylic acid) triglyceride. About 28% (hexamethylene) diglyceride with a small amount of ce and. One of fatty acid triglycerides. α is a polyol ester component of a chain-length fatty acid. When the solvent excipient for formulating the hair-promoting agent appears, its composition is "Lai to Lai" but the weight ratio is 70% to 99; The liquid composition will contain a sweetener, which can be used 1235152 V. Description of the invention (31) is used to reduce the oily taste of medium chain fatty acid vinegar, so it is an important method for the preparation of the compound. "Π 之 # Sweetener optional Auto-sugars, such as sucrose, mannitol, sorbose, lactose, etc., or sugar substitutes, such as cycumate, saccharin, ... If bran substitutes are used as sweeteners, the amount of glutamate used in the present invention will be less than if sugar is used. With this in mind, the range of sweeteners that can be used in the composition is from 0.1 to 50% by weight, and denier is better than 0.5 to 30%. The sweetener is more sugar than sugar, and sucrose in particular. It was found that the particle size used has a significant effect on the physical appearance and taste of the final composition. Use better sucrose granules: Xiaowei is 20%. Screens below 325 U.S. standard sieves are larger in the preferred liquid pharmaceutical composition, and are selected from the group consisting of: arachis, peanut oil, and soybeans. can〇ia oil or walnut oil-grade vegetable oil. 'Some vegetable oils can be purchased from this source "and a second source of interest from some sources known to this artist. When the composition of the present invention is formulated as a solvent, the weight ratio of the solvent in the tongue ranges from 50 to "%, and the weight 1 is more preferably from 70 to 99%. The best Chinese herbal medicine containing vegetable oil "^ a ^ ^ ^ ^ I. The mouth liquid also contains a 'liquid composition' that can be used to reduce vegetable oils. The liquid composition also contains: J =: an important method of mouth composition. Serving. Examples of such ingredients adjust other components of the composition to a weight ratio of "5 to fat." In the composition of the present invention, it is used as an emulsifier in a dry range, and the weight ratio is 0.1.

1235152 on page 34, description of the invention (32) to 0.5% Lecithin, which can be used to improve the absorption of active pharmaceutical agents. Other examples of ingredients that can be used are antibacterial preservatives, such as paraben dihydroxybenzoate. Benzene; suspending agents such as colloidal polysiloxane dioxide; inhibitors; local oral anesthetics; flavoring agents; and coloring agents. The choice of these ingredients and their use amounts in the composition of the present invention is within the range familiar to those skilled in the art ', and is more easily understood from the working examples provided below. The crystalline efenez can also be combined with soluble polymers as the target fun carrier. Such polymers include poly (vinyl) bipyridine piranine copolymer, polyhydroxypropyl isobutyleneamine-phenol, polyhydroxyethyl-asparagine, or polyethylene oxide-hexadecane Poly-amino acids substituted with residues. In addition, the crystalline form of ephedrine can be coupled with a biodegradable polymer that can be used to achieve controlled releases, such as polylactic acid, polyglycolic acid, copolymers of polyacids and polyglycerols, Lactone, polyhydroxybutyric acid Λ, ortho: ester, polyacetal, polydihydropyran, polycyanoacrylate, and amphiphilic blocking copolymer of hydrogel. = Crystalline ephedrine gel capsules contain liquid or solid compositions as described by ephedrine and J. Gel capsules also contain powders II: lactose, powder, cellulose derivatives, magnesium stearate, hard moon purpose. Similar diluents can be used to make compressed tablets. Liao Fufu Jiu release products to k for continuous release for several hours ^ It can be coated with sugar coating or film to cover any discomfort i J. Le tablets will be selected in the gastrointestinal tract when it is in the atmosphere or in the intestine. Capsule protection

Page 35 1235152 V. Description of the invention (33) '------- Related = Sugar solution and glycol, for example propylene glycol or polyethylene glycol are suitable carriers for enteral administration. The solution of the enteral solution is prepared by adding the crystalline ephedrine: bismuth / phenanthrene in a carrier, and if necessary, adding a buffer substance. Antioxidants, such as sodium bisulfite, sulfite or ascorbic acid, used alone or in combination are suitable stabilizers. Can also make «ΜΑ 纳. The enteral solution also contains preservatives, such as benzikQnium cloride, methyl- or propyl-paraben, and chlorobutanol. Appropriate peony carriers are described in Remington, S.M.Sciences, Mack, and Division, which are standard reference books within the scope of the present invention. The effective pharmaceutical dosage form for administering the compound of the present invention is explained as follows: Capsules> = Li unit capsules can be used for bolus of 1000 mg of powdered active ingredient, 1 M =! Win 5: ”and 6 mg stearic acid It is prepared by per-tablet two-knee capsules.

Soft gel glue I The ingredients are dissolved in easily digestible oils, such as soybean oil, cottonseed oil, coffee oil, and oil mixture. A mixture is prepared and injected into the gel by a positive displacement pump to form a soft gel capsule containing 10 0¾ active ingredients. The capsules should be rinsed and dried.

Pills., Large = tablets can be prepared using traditional procedures, so the dosage unit is _mL Γ27, 0.2 mg colloidal polysiloxan dioxide, 5 mg hard moon magnesium, 275¾ g microcrystalline cellulose, u mg Starch and 98 8 mg of lactose. Appropriate coating can increase edibility or delay absorption.

1235152 V. Description of the invention (34) The suspension solution of the floating liquid in the dish can be prepared for oral administration, so each 5 ml contains 25 mg of finely divided active ingredient, 200 mg of sodium carboxyfluorene-based fiber, and 5 mg of stearic acid. Sodium, 1.0 g of sorbitol solution, U.SP., and 025 mg of vanilla. WA injection is suitable for injectable administration. The intestinal composition can be prepared by stirring the active ingredient in a weight ratio of 1.5% by weight and dissolving it in 10% by volume of propylene glycol and water. This solution is often sterilized by technology. »I spray is prepared as an aqueous solution, so that every milliliter contains 0 mg of active ingredient, ^^ g of methacrylate, rraben, 0.2 mg of propyl paaben, and 10 mg of methyl, travidin. This> cereal solution is scattered in the 丨 ml vial. The lung aspirator was prepared as a homogeneous mixture with polyethoxy ether 8 0, so that the final concentration of live was heavy, and the polyethoxy ether 80 in the capacity was made into a valve shape, which was dispersed in the dr system. Can β 'Add the required amount of jin at 1% of the full force on the can-1 part of lice and 4 rat ethane. Type I and Type 2 of the present invention, ingredient (a) Kexing Wudi 1 Type 3 ^ Type 4 and Type 5 Therapeutic Agents-Cheng cut U) Already used alone in any dosage form as described above Combination applicator: Hai, the above, but also-solution will have the aforementioned-or more in the following description, component (b) according to simultaneous or separate treatment of H. Therefore, if ingredients (a) and (b) are the agents for wounding (b), they can be used simultaneously or separately.

1235152 Description of the invention (35) Treatment. The ingredients (a) and (b) of the present invention can be formulated together into a single dosage unit (i.e., 'combined into a capsule, tablet, powder or liquid, etc.) as a combined product. When ingredients (a) and (b) are not formulated together into a single dosage unit, ingredient (a) can be administered at the same time as ingredient (b) is added or in any order; for example, ingredient (a) of the present invention can be administered first , Followed by ingredient (b), or in the reverse order. If ingredient (b) contains more than one therapeutic agent, such as an RT inhibitor and a protease inhibitor, these therapeutic agents may be administered together or in a sequence of, =. When the application is not performed at the same time, it is preferable that the application of the components (a) and (b) is completed within 1 hour. The best route of application of ingredients (a) and (1)) is: take. As used herein, an oral therapeutic agent, an oral inhibitor, an oral compound, or a compound refers to a compound that can be administered orally. Although it is best that both ingredient (a) and ingredient (b) are administered by the same route (ie, for example, if necessary, they can each be administered by different routes (ie: = substance: dose, and the other ingredient is administered by dose). Intravenous administration) or agents such as those practiced by practitioners familiar with the art can be caused by various factors such as :: == The combination treatment method and application route, age, mechanical properties and other factors of the present invention The type and degree, the type of simultaneous treatment, and the secondary education of treatment: the weight, the nature of the sacrum vary. "The number and the desired effect as described above according to this article, the present invention ... by the practitioners familiar with the art: ㈠. And the daily dose of the mother ingredient is about 100%. It is usually guided by ordinary heart, and generally sees about 1.5 grams. If ingredient (b)

Page 38 1235152 V. Description of the invention (36) When it represents more than one compound, the daily dosage of each therapeutic agent of the general ingredient (b) is about 100 mg to about 1.5 g. According to the general guidelines, when the ingredients (a) and (b) are administered together, the synergistic effect of using them together will show that the dosage of each ingredient will be more than that of a single agent as a single treatment. IV The general dose at the time of infection is about 70-80% lower. Although the active ingredients are combined in a single dosage unit, the cost of the compound product of the invention can be adjusted to minimize the contact between the substance and the active ingredient. To reduce exposure, for example when the product is administered orally, an active ingredient may be enteric-coated. By enteric coating, one of the active ingredients may not only reduce the contact between the combined active ingredients, but also may be in the gastrointestinal tract, making the release of one of these ingredients so that one of these compounds will not be released by the stomach To the intestine. In another specific embodiment of the present invention, oral administration ^ It is hoped that one of the active ingredients is coated with a substance that can release a long-lasting substance = substance 'that can be sustained-released in the entire gastrointestinal tract, and the towel also reduces the contact of the compound with active soluble matter. "In addition to the dagger, the sustained-release ingredients can also be released intestinal only in the small intestine. There is still another ingredient coated with a long-lasting and / or enteric polymerized polymer base: it is also coated with a layer of polymer M like a low-viscosity progression-cellulose or other Known suitable substances, with which each ingredient is part. The admixture coating is used to form an outer barrier private layer with (a) and (b). In each formula, the ingredients of each ingredient of the two ingredients: coatings or other substances to prevent contact, and contact between ingredients ^ ^ should also be avoided. One of the active ingredients in the dosage form of the product of the present invention, ^. ^, Is

Page 35 1235152 V. Description of the invention (37) Enteric coating in the form of tablets, so that the components of the intestinal coating and other active ingredients are combined into dust and tablets, or the components of the intestinal coating are compressed into a tablet Layer while the other active ingredients are compressed into another layer. To further open the two layers, one or more placebo layers can be added as appropriate so that the placebo layer is between the active ingredient layers. In addition, the dosage form of the present invention can be in the form of a capsule, in which one of the active ingredients is compressed into a tablet or in the form of many small medicines, granules, granules, or non-per ils, and then coated with enteric-coated enteric, coated Small tablets, granules, granules or non-peri Is are then placed in capsules or compressed into capsules. k two ways and other ways to reduce the contact between the components of the compound product of the present invention: ground: is administered in a single dose or =: =: medicine, according to this article, these medicines that are familiar with 丄 can be used to treat Η IV infection medicine The kit includes a sterile container containing a compound of the compound ⑷ and a therapeutically effective amount of a pharmaceutical composition of one or more compounds, which is also included in the wound (b). The disinfection of the container can be accomplished using the toxic method described herein. Ingredients ⑷ and ingredients ㈦; "knowledge" eliminates the individual sterile containers. The sterile container of the substance will not be effective or one or more containers that require multiple parts. Ingredients u) 3 individual containers or one opened, Or a single-dose form component can be synthesized on a substance basis if necessary. This set also includes ... multiple upper "units. ^ For example, one or more medically acceptable specialized medical kits are composed of additional vials, etc. ′ Those skilled in this art will easily understand the mixed ingredients. instruction,

Page 40 Ϊ235152

: A single sheet or label indicating the amount of ingredients to be applied, instructions for application, and / or instructions for the ingredients are also included in this set. Obviously, according to the above teachings, the present invention may have many improvements and changes. Therefore, it should be understood that within the scope of the patent application in the appendix, the present invention can be carried out in other ways besides the special records in this article.

Y-End Diffraction Method X-Ray Powder Diffraction Method by Effie Freienz. Data obtained from Philips Model 37 0 Automatic Powder Diffractometer. Samples are run in batch mode with pW 1 7 7 5 multi-position sample exchange. The diffractometer is equipped with a variable slot (Θ — compensation slot), a scintillation counter, and a graphite monochromator. The emission is CuK α (40 kV, 30 mA). Data were collected at room temperature from 2 to 60 degrees 2Θ; the step size was 0 · 02 degrees' and the counting time was 0.5 seconds per step. A sample of a thin layer of powder-free substance containing no solution was prepared on a glass specimen holder. Calorimetric method The thermal properties of ephedrinez were analyzed by differential scanning using TA instrument Dsc 9 110. The calorimetric characteristics were determined, and the data was analyzed by TA instrument thermal analysis 2 丨 〇 〇 The sample was placed in a sealed aluminum pan, and the empty aluminum pan was used as a reference value for analysis. In the temperature range of 2 5 ° C to 200 ° C ', at a rate of 5 ° c per minute or 10 ° C per minute. Calibrate the instrument with standard indium. The following examples are taught (S)-6-gas-4-cyclopropylethynyl-4-trifluorofluorenyl-1, 4-dihydro-2H-3, benzobenzofluorene-2- Preparation of ketones.

O: \ 58 \ 58887.ptd Page 41 1235152 V. Description of the invention (39) Examples of pain _ 1. Preparation of N-(4-phenyl) -2,2-dimethylpropanamide will be 4- Chloroaniline (52.7 kg, 413 moles) was dissolved in tertiary butyl methyl ether (180 kg) at 30 ° /. Sodium hydroxide solution (61.6 kg, 463 ^ ears) and water (2 4 · 2 kg) in a mixture, and then cooled to 15 it. It took 1 hour to add trimethylacetamidine (52.2 kg, 448 moles) to the resulting slurry to keep the temperature below 40 ° C. After 308 was decanted at 30 ° C, the slurry was cooled to -10 r and maintained for 2 hours. Use filtration as the second product, rinse with 90/10 water / methanol (1 75 kg) solution, and then dry under vacuum to produce 85 kg (97% yield) of crystalline solid title compound, melting point 1 52-1 53 ° C: 1 !! NMR (300 MHz, CDC13) 6 7 48 (d J = 9 Hz '2H) 7.28 (d, J = 9 Hz, 2H); uc (7; CDC13) d 1 76.7, 1 36.6 , 1 29.1, 1 28.9, 1 21. 4, 39 > 6 5 2 7.6. ,,, Example 2: 4-chloro-2 -trifluoroacetone cage face, prepare a ag ak, makeup, lice hydrate hydrate (N-U-chlorophenyl) -2, 2_ Dimethylpropanamine (36 7 kg moles) in TEDDA (20.2 kg, 174 moles) / Yi 'Yi 曱 Tintin Bell's sautéed (1109 kg, 39) Stem, 4, each

Keep the temperature below 5 at the same time. . . The solution was in the range of 0 to 1, and the ear Λ Γ reacted with ethyltrifluoroethane (34.5 g / f, 243 mol). After 30 minutes, the Zen Institute; ^ Shi Cong, Qi, 589, Mo) Suo A Gan only surname, w Mingcheng Luoye quenched in 3 N HC1 (196 liters, ears) and keep the temperature low At 25 t. Concentrate organic by distillation of about 200 liters of solvent. "Afterwards, the right item" / mixture. Add acetic acid (352 kg:

1235152 V. Description of Invention (41)

Hz, 1H), 4.43 (d, J = 6 Hz, 2H), 3.79 (s, 3H); 13C NMR (75 MHz, CDC13) (5 1 80.5, 1 5 9.2, 1 5 1.9, 1 37.4, 130.8, 128.9, 128.4, 119.9, 117.0, 114.5, 114.4, 111.3, 55.3, 46.6. Example 3a: Synthesis of (1R, 2S) -pyrrolidinyl norephedrine. (1R, 2S) -desulfurization Ephedrine (68.6 kg, 454 mol) was added to a mixture of water (144 kg), carbonic acid (144 kg '1043 mol) and n-butanol (227 kg). The mixture was heated to 90 ° C, and it took 2 hours to add 1,4-dibromobutane (11 3.4 kg, 525 mol). The reaction was cooled to 40 ° C after 5 hours of reflux. Water (181 kg) was added and the temperature was 30 ° C. The phases were separated. 12 N HC 1 (54.3 kg, 543 mol) was added to the organic phase. The solution was heated to reflux and 150 liters of distillate was removed at 200 to 300 mm. At 70 Toluene (39.5 kg) was added at ° C, and the resulting slurry was cooled to 0-5 C for crystallization. The product was collected, washed twice with toluene (3 g kg each), and purged with nitrogen Drying to produce 83.6 kg of hydrochloride Salt of the title compound. Fill the hydrochloride salt into toluene (392 kg) and water (42 kg) with t12 or more at 30% 仏 〇} 1 (about 55 kg, 414 moles). After removing the lower aqueous phase, the organic solution was partially concentrated with 140 liters of solvent in the steam room to produce a stomach with 20% by weight of the title compound. The calculated yield was 50 kg (75%). Under vacuum · The toluene solution of the title compound was concentrated and recrystallized from heptane to a melting point of 46-48 ° C. Preparation of L 3 ": Preparation of cyclopropylacetylene 5chloro-1-pentyne (23.0 kg, 224 moles) and anhydrous THF (15 gfm p. 44)

1235152 V. Description of the invention (42) kg) The mixture is cooled to -2 ° C. Hexane in which n-hexane (2 3 ♦ I · 58 kg) was dissolved was added to the mixture at a rate that did not increase the temperature by 5 t (2, 2 scoops). The temperature must be maintained above -5 ° C during the second half of the positive-convergence period to avoid the accumulation of organolithium and the dangerous exothermic reaction. The reaction was aged at -5 to 0 t for 2 hours until the analysis showed that at least 99% of the conversion was complete. Then toluene (35 to 40 kg) was added, and the reaction was concentrated under vacuum until the volume was reduced to the original volume of / 3. The mixture was heated (to ~ 400c) throughout the concentration process to maintain a good steaming rate. Next, the mixture is cooled to 15 to -20, and it is added to 50 to 60 liters of an aqueous solution of chlorinated to 12 kg) at a rate that the temperature rises above 10 ° C. ◦After separation of the water layer (about 70 kg): 100 parts circulate in the entire tower containing 15 kg of 3 A molecular sieve holes until the amount of water u is ~ 300 ppm or lower as determined by Kari Fisher analysis Value so far. Each desired organic solution was then distilled at atmospheric pressure through a tube filled with net cotton, and the cyclopropylacetylene dissolved in THF / toluene / hexane was collected. The calculated yield was 14.0 kg. / All [mask ^ 1_4: (S) -5-chloro-α-(cyclopropylacetylene) —2- [曱 5 + yl) fluorenyl] -amino] α- (trifluorofluorenyl) phenyl alcohol Yangtuben originally filled triphenylmethane (100 g) with solvent, 2S) —Hawha. Determining in ephedrine (80 kg, containing 60 · 7 mol QR, 2S) -pyrrolidine ^ dipentan. Yellow test) in the toluene solution. Concentrate the solution under vacuum to approximately the initial soil volume of spines ::: Add anhydrous sulphur (3 kg), and set to. 〇Bay cooling tank cold part solution. When the temperature reaches -20 ° C, put it in n-hexyl lithium (dissolved in hexane, 33.4 kg, U9.5 mole), and keep the temperature low on the same day ^

1235152 V. Description of the invention (43) 0 ° C. Cyclopropylacetylene solution (30% in THF / hexane / toluene; containing about 4 kg of '65 Mo earring propyl ethylene) was added to the resulting red solution while maintaining the internal temperature below -2 °. 〇. The resulting solution is between -45 and -50. (: Aged for 1 hour. N _ ((4'_methoxy) benzyl) _4-chloro-2_trifluoroacetamidoaniline solution (43% in THF / toluene; containing about 10 kg, 28 8 mol) U'-methoxy) -4-chloro_2-tribenzylanilide in the ear, while maintaining the reaction temperature below -40t. At -43 + /-3. After aging the mixture for 1 hour, the reaction was quenched and 140 kg of 1N HC1 was added, pre-cooled to 0 ° C. The organic layer was separated and extracted twice with 25 kg portions of 1N HC, and then separated with 40 kg of water and Extract twice, and then concentrate to about 29 liters under vacuum. Toluene (47 kg) is added and the solution is concentrated to a volume "to 30 liters. Charge heptane (23 kg) and cool the mixture and maintain at -5 it 4 hours. The product was filtered, washed twice with a 10 kg portion of heptane, and dried under vacuum to yield 10 kg (85%) of the title compound 1 63- 1 6 5 ^ C; [a] ^ D + 8.15〇 (C j.ooe, Me〇H); NMR ^ (300 MHz, CDC13) 5 7.55 (brs, ih), 7.23 (d, J = 8 Hz, 2H), 7.13 (dd, J = 3, 9 Hz, 1H), 6.86 (d, J: 8

Hz, 2H), 6.59 (d, J = 8 Hz, iH), 4.95 (bs5 1H), 4.23 (s, 2H), 3.79 (s, 3H), 2.39 (m, 1H), 1.34 (m, 1H), 0.84 (m, 2H), _0.76 (m, 2H); i3C, NMR (75 MHz, CDCl3) ... 5 1 58.9, 1 45.5, 1 30.6, 1 30.3, 1 30.2, 1 28.6, 1 25.9 , 1 22.0, 1 2 1.6, 1 1 9.5, 1 1 4.8, 1 1 4.1, 94.0, 75.2, 74.7, 70.6, 55.3, 48.0, 8.6, 8.5, Ό. 6; 19F NMR (282 MHz, CDC13) 3 1 8〇 19. · ’

1235152 on page 46 5. Description of the invention (44) f_ Example 5: (S) -6 —chloro-4 — (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) Preparation of -2- (4'-Methoxyphenyl) -3, 1-benzopyrene The ortho-aeroquinone (57 kg, 232 mol) and (s) -5 -chloro-α-( Cyclopropylethynyl) -2-[(4-methoxyphenyl) methyl] -amino] -j-trimer)) Benzobinol (89 kg '217 mole) was added to ethyl acetate @ 1 (32.5 kg) and heptane (2 9 5 · 5 kg) solution. After the mixture was fully refluxed & 5 hours, it was diluted with ethyl acetate (64. 1 kg) and cooled to 30. 〇. Tetrahydrogen | Kun 'was removed by filtration and rinsed with a mixture of heptane (104.7 kg) and ethyl acetate (31 kg). The filtrate was partially concentrated by distillation to 260 liters of solvent, then diluted with heptane (177 kg) and cooled to -10 to -15 ° C. The resulting slurry was filtered through t, the product was rinsed with heptane (41 kg), and dried on filter paper to less than 20% heptane by weight (by loss during drying). The yield was calculated by .HPLC as 71 kg (80%). Analytical samples were prepared from IN NaOH and recrystallized from heptane / ethyl acetate: melting point-130- 131.7 ° C. JH NMR (300 MHz, DMS0-d6) 5 7.46 (d, J 2 9 Hz, 2H), 7.28-7.21 (m, 3H), 7.0 (d, J 9 Hz, 2H), 6.85 (d, J-9 Hz, 1H), 5.52 (s, 1H), 3.78 (s , 3H), 1.52-1.47 (m, 1H), 0.90-0.84 (m, 2H), 0.72-0.68 (m, 1H); 13C NMR (75 MHz, DMS〇-d6) (5 160.3, 143.8, 129.6, 129.3, f2 8.9, 1 25.8, 123.1, 1 2 1.7, 1 1 8.1, 1 1 7.8, 1 1 3.8, 93.6, 80.9, 74.1, 70.3, 5 5.2, 8.5, 8.4,-1.07; 19F NMR (282 MHz, CDC13) < 5 -157.5. Example 6: (S) -5 -chloro-α- (cyclopropylethynyl) -2-amino-α- (tri

Page 1212 35152

The crude (S) -5 -chloro-4- (cyclopropylethynyl) -1; [, 4-dihydro-4- (trifluoroZyl) -2- (4, -methoxyphenyl) ) -3, 1_benzopyrene (dry weight is calculated as 71 kg) into a mixture of methanol (301 kg) and 30% NaOH (121 kg) spear water (6 liters). The mixture was heated to tritium to form a clear solution and then cooled to 30 ° C. It took more than 20 minutes to add a solution of 0.2N NaOH (29 liters) in which sodium borohydride (3.2 kg '84.2 mol) was dissolved into the methanol solution, maintaining the temperature below 35 ° C. After 30 minutes, the excess borohydride was quenched with propylene '(5.8 kg), and the solution was diluted with water (175 liters) and then neutralized to pH 8 to 9 with acetic acid. The resulting slurry was cooled to about 0 ° C, and after filtering and rinsing the product with water, it was dried under vacuum at 40 ° C. The crude product was stirred at 25 ° C again with a mixture of toluene (133 kg) and heptane (106 kg) to form a slurry, and then cooled to below -10 ° C. The product was filtered, rinsed with heptane (41 kg), and dried under vacuum at 40 ° C, yielding 44.5 kg (88%) of off-white / light yellow crystalline solid. The analytical sample was recrystallized from tert-butyl methyl ether / heptane: melting point 141-143. (:; [3] 250-28.30 (〇0.106, MeOH); ^ NMR (300 MHz, CDC13) δ 7.54 (d, J 2 Hz, 1H), 7 · 13 (dd, J 2 9, 2 Hz , 1H), 6.61 (d, J 2 9 Hz, 1H), 4.61 (brs, 1H), 4.40 (brs, 1H), 1.44-1 35 (m, -1H), 0.94-0.78 (m, 2H ): 13C NMR (75 MHz, DMS0-d6) (5 1 46.7, 1 29.4, 1 29.0, 1 24.3, 1 1 8.4, 1 1 8.0 7, 1 1 8.0 5, 92.3, 7 2.6, 7 1.0, 8.2, 8.1, -1 · 1; 19F NMR (282 MHz CDC13) δ -80.5. Example 7 · (S) -6 -Ga_4- (phosphinopropylethoxy) -1,4-dihydro-4 -(three /

1235152 on page 48 5. Description of the invention (46) Dun methyl) -2H-3, 1-benzopyrene-co--2 ketone Preparation of hydrazone-5-gas-α_ (cyclopropyl ethyl block) _2 _Amine 1- (difluoromethyl) benzyl alcohol (15.7 kg, 54.3 mol (32 kg) and THF (52 kg) in a mixture. Fei Li Xiaoyu in the Geng table said Directly feed the slave lice (~ 8.0 kg, 80 mol) 'to maintain the temperature below: Allow the resulting slurry to warm to 20 — 2 5 t and hold for i hours. Add methanol (6.5 kg , 203 moles) and stir the solution for about 30 minutes. Add heptane (97 kg) and distill ~ 140 liters of solvent under reduced pressure. Add heptane (9 kg) and THF (22 kg), and first Rinse the solution with 5% aqueous sodium bicarbonate solution (15 liters) and then with water (15 liters). The solution was warmed to 500c and filtered in a clean reactor, followed by wetting with 40 kg of heptane. The solution was concentrated under reduced pressure, diluted with heptane (22 kg), and cooled to -10. The product was filtered, rinsed with heptane (37 kg), and dried under vacuum at 90-100 ° C to produce 16.0 kg (95%) Gray To slightly pink solid. HPLC: 99.8 area%: melting point 139-141 ° C; [a] 25D-94.1. (C 0.30 0, MeOH); iH nmr (400 MHz, DMS〇-d6) 5 11.05 ( s, 1H), 7.54 (dd, J = 2.5, 7 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 6.99 (d J 2 7 Hz, 1H), 1.58 (m, 1H), 0 · 92 (m, 2H), 0.77 (m, '2H); 13C NMR (100 MHz, DMS0-d6) 1 46.23, 134 · 71 ,, 132.04, 126.93, 126.57, 122 · 2¾, 116 · 83, 114 · 〇8, ...

95.63, 77.62, 65.85, 8. 48, 8. 44, -1.32; 19F NMR (282 MHz, DMSO-d6) 6 -81 · 1. Examples 8-1 6 specifically teach the preparation of various types of ephedrines of the present invention, and a method for completing the conversion between these types (flow chart

I

Page 49 1235152 V. Description of the invention (47) 5). The following examples are intended to illustrate the invention and are within the scope of the invention. Flowchart 5 But it should not be brown because of this Example 11 Type 3 f Example Example '\ 1612 Type 3

Example 11

Example 10 Example 13 Type 2 Type 2 Type 1

Example 16 Saturated solution Type 4 Example 17 Dilution solution-^ Type 5 Example 18 Type 1 i-Example i / · Type I direct crystallization 4 ... Gram, 2.5 mol) was dissolved in thF (1.2 liters) and heptane (6.8 liters). The solution was cleared by filtering through Whatman filter paper. Then, when the THF was removed by distillation under atmospheric pressure, the fresh HG was replaced on the one side to maintain the volume. When the amount of THF < 1%, the solution is cooled

Page 50 1235152 V. Description of the invention (48) --- Tian 0 C ί? The solution was cooled to 64 ° C. . Crystallization begins. The samples are shown as X-rays by XRD. In addition, the slurry was cooled to 3 ° C. and 3 ° C. under a vacuum oven with nitrogen to remove the dry wet filter, until 0.36% of the dry refining was lost, resulting in 640 grams of product (80% yield). 1 ^-例 ^ •• The crystallization of type 2 was changed to type 1. The ephedrine (450 g, 1.4 mol) was stirred in heptane (3.5 liters) to form a slurry, and heated to reflux. Until completely dissolved. Allow the solution to cool to 73 ° C while filtering the solution through # 1 Whatman filter paper, and cool to 6 ° C. Filter the slurry and rinse the wet cake with 300 ml of heptane. 1 0 0 C Wet cake (389 grams) was dried in a vacuum tray oven for 5 hours, and 388 grams (86% yield) of type 1 was produced. [Mask 1Q: The crystallization of type 4 changed to the first Dissolve efefrenz (32 g, mol) in 60 ml of heptane and 20 ml of THF at 60 C. Allow the solution to cool down and inject 50 mg of DMP 2 at 45τ 6 6. After crystallization occurred, the solvent was removed under vacuum, and the solvent was replaced with fresh heptane. The slurry was cooled to 00C and filtered. XRD showed type IV Dry in a vacuum oven at 80 ° C for 16 hours to produce 26 grams of Type 1 (82% yield).: The crystallization of Type 2 changes to Type 3 and turns to Type 1 — Λ ... Ryanz (105 g, 0.33 mol) was blended into a slurry in 1.2 liters of heptane and heated to reflux until completely dissolved. The solution was cooled to 75 ° C while passing through # 1 Whatman Filter paper filters the solution and cools down. Formation; 4 layers of catastrophic material crystallize 'transition sample. Revealed by X-ray powder diffraction method

Page 51 1235152 V. Description of the invention (49) Alkanes: Π: After stirring the slurry at room temperature for 24 hours, a thick layer of 200 ml of heptamine 82 i W% was filtered and filtered under vacuum at room temperature and Dried raw 9 (TC.3 =. The solid is confirmed to be type 3 by X-ray powder diffraction. After the diffraction is confirmed to be / = 24 hours', the resulting solid is transformed by X-ray powder: type 1 For type 3, the i-type efenez (10.5 g, 0.33 mol) was added to the temperature at the highest temperature, and the mixture was stirred from the sixth liter of heptane for 7 days to become a slurry. XRD showed that there was no type I in the sample. Although the relative density was slightly different: Φ type 2 obtained the same peak.: Type 2 changed to type 4 (0.16 mol) at 580 ml Type 2 efenez (50 grams,… ”/… heart.), Add =, to 40 C, and after 50 minutes filter the slurry sample, X-ray powder diffraction) still shows the first Type 2. Add THF in 4 parts (28 ml, 32 liters in total to produce 5% THF in heptane). After adding the last aliquot, the mixture is cooled to 2 generations while forming a very thick slurry Material, confirmed by XRD as type 4 Fosun of "4: Type 1 Type 4 will be converted to Type 1 by 菲佛瑞恩兹 ⑴ g, dagger square 3 mole) was stirred in ⑽ slurried. The aggregate was heated to 35. 〇. Add a 2 ml portion of THF. After adding a total of 6 liters (the resulting solution ~ 6% THF), the slurry became very viscous. XRD is shown as type 4. J ^ ^ 1 5 • Change the type 2 to the first by heating the slurry to M ° C

Page 52 1235152

Zhongyi / Frynn'z (3g, ο.01 mole) in Gengshao (42ml cold * heated to 7 (rc ') and maintained for 2 hours. Make the destruction two / to fox., And use XRD filtered samples, showing only type i. 16 • By heating the slurry to 70. (:, to change the type 3 to the number J in the middle ϊ Γ molding Frienz (3 g '0. 01 mol ) Geng roast (42 ml) hours. The soup is shown as type 3. Then add the mass: and-for 2 hours, cool to room temperature, and filter the sample with XRD

Ben 'is shown as type 1 via X R D. Heart: Direct crystallization of type 5 Put the type 1 efenez (approximately 70 g) at 1 liter at 1 liter 1% V / ^ T ^ F / heptane and stir to a slurry. Undissolved solids were removed by filtration and the Type 5 seed was seeded into the mother liquor at room temperature. After the crystals slowly formed, they were separated by filtration. The solid was confirmed to be type 5 by the [light powder diffraction method].

In addition, the type 1 efenez (approximately 70 grams) was placed in a 5 liter 1% v / v THF / heptane and stirred to form a slurry, and the temperature was returned to 40. The solution was filtered at ambient temperature (40) to remove any insoluble solids, and a Type 5 seed was seeded into the mother liquor at 40 ° C. When the solution is cooled to room temperature, "type 5 forms crystals. At room temperature, solids (9.43 g) are separated by filtration at room temperature. Also, 2 type 1 efenez (approximately 70 g) ) Put in i-heptane and stir to form a polymer, and add 10 ml of THF to adjust the solvent ratio to 1% v / v THF / heptane, and then heat the slurry at 8 5 C until all is dissolved.

Page 53 1235152 V. Description of the invention (51) When the solution is cooled, type 5 seeds are periodically implanted until the seeds no longer dissolve (63 ° C), and then cooled to 45 ° C and filtered. The separated solid was type 1. The solution was then cooled to room temperature overnight and the type 5 crystals (15.41 g) were collected by filtration. Example 18 8: Type 5 was changed to Type 1 The Type 5 was dried in a 9 5 t vacuum oven with nitrogen for 3 days to produce Type 1 confirmed by the X-ray powder diffraction method.

Page 54

Claims (1)

123 ^ 152 ly \ ^, __case | fe ^ 810_ zp year / month date __ VI. Patent application scope ^-丨 1. A type 2 crystalline form of Effie Frenz, which is characterized by having Contains five or more selected from the group consisting of: 6 · 8 ± 0 · 2, 9 · 2 ± 0 · 2, 12 · 3 ± 0 · 2, 16 · 2 ± 0 · 2, 21 · 4 ± 0 · 2, X-ray powder diffraction pattern with a value of 22 · 7 ± 0 · 2, 24.1 ± 0 · 2, 28. 0 ± 0.2, and 0. 2. According to the second type of crystallized ephedrine of claim 1 in the scope of the patent application, it is characterized by a peak represented by a differential scanning heat map at 1 16 t to 1 19 ° C. 3. — A type 5 crystalline form of ephedrinez, characterized by having six or more selected from the group consisting of: 10 · 2 ± 0 · 2, 11. · 4 ± 0 · 2, 11.6 soil 0. 2 、 12 · 6 ± 0 · 2, 19 · 1 ± 0 · 2, 20.6 ± 0.2, 21.3 ± 0 · 2, 22 · 8 ± 0.2, 24 · 8 ± (K2, 27 · 4 ± 0.2, 28 · 2 ± 0.2 X-ray powder diffraction pattern with a value of 20 of 31.6 ± 0.2 of 20. 4.According to the 5th type of crystallized ephedrinz of the scope of patent application, it is characterized by 1 0 8 ° C to 110 ° C has a peak represented by a differential scanning heat map. 5. A pharmaceutical composition comprising a virus code-reverse transcriptase to inhibit viral replication, comprising a medically effective amount According to the scope of the patent application, item 1 of the crystal type 2 ephedraelz or the scope of the patent application scope of the type 5 crystal efenez, and a pharmaceutically acceptable carrier. 6. According to the application The pharmaceutical composition according to item 5 of the patent, which is enclosed in a capsule or a compressed tablet dosage form, wherein the medically effective amount refers to a crystalline form 2 or 5 of ephedrafur from 1 mg to 100 mg Enz. 7. On application The pharmaceutical composition according to item 5 of the patent is for the animal or human to inhibit ΗIVV reverse transcriptase in vivo. O: \ 58 \ 58887-940128.ptc Page 56 1235152 _Case No. 88109817_f4 Year / Month __ VI. Application for Patent Scope 8. —A method for preparing the first type of crystalline ephedrine, 1st The crystalline form of ephedrines is characterized by having four or more selected from the group consisting of: 6.0 ± 0.2, 6.3 ± 0.2, 10.3 ± (K2, 1 (Κ8 ± (Κ2, 14.1, ± 0.2), 16 · 8 ± 0 · 2, 2 (Κ0 ± 0.2, 20 · 5 ± 0 · 2, 21 · 1 ± 0 · 2 spear mouth 2 4. 8 ± 0. 2 of 2 0 light powder diffraction pattern , Which is prepared by heating type 2 crystalline form ephedrines, type 3 crystalline form ephedrins, type 4 crystalline form ephedrins, or mixtures thereof, of which Type 2 crystal type Effie Frenz is characterized by having five or more selected from the group consisting of: 6 · 8 ± 0 · 2, 9.2 ± 0 · 2, 12 · 3 ± 0 · 2, 16 · 2 X-ray powder diffraction pattern with a value of 0.2, 2 · 21 ± 4 (K2, 22.7 ± 0.2, 24 · 1 ± 0.2, 28.0 ± 0.2, 2; type 3 crystallized ephedrine Enz is characterized by having four or more elements selected from the group consisting of: 7.1 ± 0.2, 7.3 ± 0 · 2, 11.0 ± 0 · 2, 13.8 ± 0.2, 20 · 9 ± 0 2, 23 · 3 ± 0.2, 27 · 9 ± 0 · 2 2 of spear mouth 33 · 5 ± 0 · 2 (9-valued X-ray powder diffraction pattern; and type 4 crystal type ephedrine It is characterized by having four or more selected from the group consisting of: 3.6 ± 0.2, 6.3 ± 0.2, 9.7 ± 0.2, 11.0 ± 0.2, 12.7 ± 0.2, 13.2 ± 0.2, 16. 1 ± 0 · 2, 19 · 2 ± 0 · 2, 1 5 ± 0 · 2, 2 0. 6 ± 0 · 2 Spear mouth 2 4. 3 ± 0 · 2 of 2 0 value of X-light meter end Diffraction pattern. 9 · A method for preparing Type 1 crystalline ephrenz, the type 1 crystalline ephefrenz is characterized by having four or more selected from: 6. 0 ± (K2, 6.3 ± (K2, 10.3 ± 0.2, 1 (K8 ± (K2, 14.1 ± 0.2, 16.8 ± 0.2, 2 (K0 ± (K2, 2 (K5 ± 0.2, 21.1 ± (K2 Shoukou 24.8 soil O: \ 58 \ 58887-940128.ptc Page 57 1235152 _ Case No. 88109817 f4 year / month date __ VI. Patent application range 0.2-2 (9-value light powder diffraction pattern, which is through stirring Type 2 crystallized ephedrinez, type 3 crystallized ephedrinez, or a mixture of them in a hydrocarbon solvent slurry, of which type 2 crystallized ephedrinez It is characterized by having five or more elements selected from the group consisting of: 6.8 ± 0 · 2, 9 · 2 ± 0 · 2, 12.3 ± 0 · 2, 16.2 soil 0.2, 2 · 4 ± 0.2, 22 · X-ray powder diffraction pattern of 20 values of 7 ± 0.2, 24 · 1 ± (K2 ^ 28 · 0 ± 0.2-20); Type 3 crystal form Eiffelionz is characterized by having four or more it from Ι: 7 · 1 ± (K2, 7 · 3 ± (K2, 11 · 0 ± (K2, 13.8 ± 0.2, 20 · 9 ± (K2, 23 · 3 ± 0 · 2, 27 · 9 ± (K2 X-ray powder diffraction pattern with a 20 value of 33 · 5 ± 0 · 2 at the mouth of the spear. 1 0. — A method for preparing the first crystal type according to Effie Reinz, the first crystal type Effie Frenz is characterized by having four or more selected from the group consisting of: 6 · 0 ± 0 · 2, 6 · 3 ± 0 · 2, 10 · 3 ± 0 · 2, 10 · 8 ± 0 · 2 14.1 ± 0 · 2, 16.8 ± 0.2, 20.0 soil 0.2, 20.5 ± 0.2, 21.1 ± 0.2 spear mouth 24.8 ± 0. 2 of the value of the light powder diffraction pattern, which includes The type 4 crystalline form of ephedrines is heated at 80 ° C to 100 ° C, wherein the type 4 crystalline form of ephedrines is characterized by having four or more selected from: 3.6 ± 0.2, 6.3 ± 0.2, 9.7 ± 0.2, 11.0 ± 0.2, 12.7 ± (K2, 13.2 ± (K2, 16.1 ± 0.2, 19.2) X-ray meter diffraction pattern of 20 values of ± 0 · 2, 19 · 5 ± 0.2, 20 · 6 ± 0.2, spear mouth 24 · 3 ± 0.2, 1 1 .According to item 10 of the scope of patent application The method wherein the heating is performed under suction. O: \ 58 \ 58887-940128.ptc Page 58 1235152 _Case No. 88109817 f Millennium / Month / Day Amendment_ VI. Application for Patent Scope 1 2. The method according to Item 11 of Patent Application Scope, where the heating is performed for 1 2 to 24 hours. 1 3. The method according to item 10 of the scope of patent application, wherein the type 4 wet cake is first heated to 30 ° C to 50 ° C to discharge the solvent, and then heated to 80 ° C to 100 ° C. ° C. 1 4. A method for preparing a type 2 crystalline form of ephedrinez, the type 2 crystalline form of ephedrinez is characterized by having five or more selected from the group consisting of: 6.8 ± 0.2, 9 · 2 ± 0.2, 12.3 ± 0.2, 16.2 ± 0.2 > 21.4 ± (Κ2, 22.7 ± (K2, 24 · 1 ± (K2 spear 28.0 ± 0.2, 20 values of X-ray powder diffraction pattern, It is prepared by the rapid crystallization method of saturated alkanes solution of ephedrine. 1 5. The method according to item 14 of the scope of patent application, wherein the rapid crystallization includes: (1) ephedrine at a suitable temperature Ryanz is dissolved in a suitable solvent to obtain a saturated solution; (2) filtered, the saturated solution; and (3) the saturated solution is rapidly cooled to obtain the type 2 crystalline form of Effie Reinz. 1 6. According to The method of claim 15 in which the suitable solvent is heptane, the suitable temperature is 70 ° C to 80 ° C, and the rapid cooling of the saturated solution includes contacting the saturated solution with a cold surface 1 7. —A method for preparing type 3 crystalline form of ephedrinez, the characteristic of type 3 crystalline form of ephedrinez is There are four or more selected from the group consisting of: 7 · 1 ± 0 · 2, 7 · 3 ± 0.2, 11 · 0 ± 0 · 2, 13.8 ± 0 · 2, 20 · 9 ± 0 · O: \ 58 \ 58887-940128.ptc page 59 1235152 _ case number 88109817 f leap year (monthly day amendment _ VI) patent application scope 2, 2 3. 3 ± 0 · 2, 2 7. 9 soil 0 · 2 X-ray powder diffraction pattern with a value of 3 3 · 5 ± (K 2 -20 value, which is obtained by stirring the first crystal type ephedrine and the second crystal ephedrine It is prepared by using a slurry of a hydrocarbon solvent or a mixture thereof in a hydrocarbon solvent, and isolating the crystal, wherein the type 1 crystalline form of ephedrine is characterized by containing four or more from I: 6.0 soil (K2 , 6.3 ± 0.2, 1 (K3 soil (K2, 10.8 soil 0.2, 14.1 ± (Κ2, 16.8 ± 0.2, 20.0 ± (Κ2, 20.5 ± 0.2), 21.1 ± 0.2, and 24.8 ± A light powder diffraction pattern of a value of 20 to 0.2; and a type 2 crystalline form of Effie Frenz is characterized by having five or more selected from: 6.80.2, 9 · 2 ± 0 · 2, X-ray powder diffraction pattern with 12 values of 12 · 3 ± 0 · 2, 16.2 soil 0.2, 21.4 ± 0.2, 22.7 ± (K2, 24 · 1 ± 0.2, 28.0 soil 0.2, 0.2 1 8. The method according to item 17 of the scope of patent application, wherein the hydrocarbon is heptane and the crystal It is isolated by filtration. 19. A method for preparing a type 5 crystalline form of ephedrinez, a type 5 crystalline form of ephedrinez is characterized by having six or more options. Self-contained: 10 · 2 ± (K2, 11.4 ± (K2, 11.6 ± (K2, 12 · 6 ± 0 · 2, 19.1 ±) (K2, 2 (K6 ± (K2, 21.3 ± 0.2, 22 · 8 ± 0.2, 24.8 ± 0.2, 27 · 4 ± (K2, 28 · 2 ± 0.2, Spear 31 · 6 ± (K2 of 20 value of X-ray powder diffraction pattern, which is obtained by self-mixing) Solvent system is recrystallized from Philippines. 2 0. —A method for preparing type 1 crystalline ephedrines. Type 1 crystalline ephedrines is characterized by containing Four or more selected from the group consisting of: 6 · 0 ± 0.2, 6.3 ± 0.2, 1 (K3 ± 0.2, 1 (K8 ± 0.2, 14.1 ± 0 · O: \ 58 \ 58887-940128.ptc Page 60 1235152 Amendment_Case No. 88109817 VI. Patent application scope 2, 16.8 ± 0.2, 20.0 soil 0.2, 20.5 ± 0.2, 21.1 ± 0.2 Net mouth 24.8 A light powder diffraction pattern with a value of ± 0.2 to 20, including: (1) crystallized from a THF / heptane solution, a type 4 crystalline form of ephedrine, wherein the THF / heptane solution has 5% concentration of THF and then reduced to 1% concentration of THF; and (2) heating type 4 crystalline form ephedrine to 80 ° C to 100 ° C; where Type 4 crystalline form Eiffelionz is characterized by having four or more selected from the group consisting of: 3.6 ± 0.2, 6.3 ± 0.2, 9.7 ± 0.2, 11.0 ± 0.2, 12.7 ± 0 · 2, 13.2 ± 0 · 2, 16.1 ± 0 · 2, 19.2 ± 0.2, 19.5 ± 0.2, 2 (K6 ± (K2 and 24 · 3 ± 0.2 of 2 of 2 0 values of X-rays Powder Diffraction Pattern. 2 1. — A method for preparing Type 1 crystalline form ephedrinez. Type 1 crystalline form ephedrinz is characterized by having four or more selected from: 6 · 0 ± 0.2, 6 · 3 ± 0 · 2 ,: 10 · 3 ± 0 · 2, 10 · 8 ± 0 · 2, 14 · 1 ± 0 · 2, 16 · 8 ± 0.2, 2 (K0 soil ( L2, 2 (K5 ± 0.2, 21.1 ± 0.2, tooth opening 24.8 ± 0. 2 of the value of the light powder diffraction pattern, which is based on the application of the scope of patent application of the first category of the second type of crystal ephedra Freienz, Type 3 crystalline form Ifrevrenz, Type 4 crystalline form Ifrevrenz or patent application scope 3 Type 5 crystalline form Ifrefreuz, or mixtures thereof And obtained, wherein the type 3 crystalline form of Effie Freunds is characterized by having four or more # 1 selected from the group containing ·· 7.1 1 ± (Κ 2, 7 · 3 ± 0 · 2, 11 · 0 ± (K 2, 1 3 · 8 soil 0.2, 2 (K9 ± (K2, 23.3 ± (K2, 27.9 ± (K2 # port 33 · 5 ± 0 · 2 of 2 O: \ 58 \ 58887-940128.ptc Page 61 1235152 _ Case No. 88109817 VI. Patent application scope leap year / &X; light powder diffraction pattern with monthly correction of 0 value; and type 4 crystal form Pfefferienz is characterized by having four or more elements selected from the group consisting of: 3 · 6 ± 0.2, 6.3 ± 0.2, 9.7 ± 0.2, 11.0 ± 0.2, 12.7 ± (Κ2, 13.2 soil (Κ2, 16 · 1 ± 0 · 2 ,: 1.9 · 2 ± 0 · 2, 19.5 ± 0 · 2, 2 (K 6 ± (K 2 and 24. 3 ± 0 · 2 of 2 0 values of X-ray powder) Diffraction pattern. O: \ 58 \ 58887-940128.ptc Page 62