TW201111351A - Succinate and malonate salt of trans-4-((1R,3S)-6-Chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine and the use as a medicament - Google Patents

Abstract

4-((1R,3S)-6-Chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine hydrogen succinate or hydrogen malonate, pharmaceutical compositions containing these salts and the medical use thereof, including for the treatment of schizophrenia and other psychotic disorders. Also described are methods for the preparation of 4-((1R,3S)-6-Chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine and medical uses thereof.

Description

201111351 VI. Description of the invention: , [Technical field to which the invention pertains] The present invention relates to 4_((1R,3S)·6_chloro_3_phenylindan-1-yl)-1,2 , 2-trimethylpyrazine (especially its hydrogen succinate and hydrogen malonate), 4-((7 π)-6-chloro-3-phenylindan-1-yl) -1,2,2-trimethylpiperidin and methods thereof, pharmaceutical compositions containing these salts, and their medical uses include treatment of schizophrenia or other conditions associated with psychotic symptoms. [Prior Art] The subject compound of the present invention [4-((7/US)-6-gas-3-phenyldihydroandan-1-yl)-1,2,2-trimethylphenyl] has a general Equation (j):

(I) is described in 638 638 073. And is generally described in ΕΡ 63 8 073 ΕΡ 638 073, which covers a group of 3# aryl-1-(1-D-feline-based systems that are described on the dopamine Dl and D forces. άΓ άΓ p >·*,,·*·. The compound knife, and is proposed to be corpse ^,···· schizophrenia. 镜像 的 镜像 镜像 异构 异构 涵盖 涵盖 涵盖 涵盖 涵盖 涵盖 涵盖 涵盖 涵盖 涵盖 涵盖 涵盖 涵盖 涵盖 2- And/or 3-positions are taken (1-dextrinyl) indane and isomers. The amines D1 and 〇2 receptors and the 5·ΗΤ2 receptor have high affinity r -

201111351 was described. The mirror image isomer of the above formula (I) has been described in B. Ges. et al., J. Med. Chem., 1995, 38, pp. 43 80-4392, 'in the form of the anti-succinic acid salt, see Table 5 compound ( -)-3 8. This publication considers the (-)-mirrromer of compound 38 to be a potent D,/D2 antagonist, which shows some D! selectivity in vitro and is equivalent in vivo D! and D2 antagonists. . This compound is also described as a potent 5-HT2 antagonist and has a high affinity for the alpha i adrenergic receptor. It is also mentioned that this compound does not cause a catalepsy in rats. The racemates associated with the compounds of formula (I) above and the anti-succinates are also described in Klaus Ρ. B0ges0, 'Drug Hunting, the Medicinal

Chemistry of 1-Piperazino-3-phenylindans and Related Compounds", 1998, /SBN 87-88085-10-4 (see, for example, Table 3 on page 47 and Compound 69 of Table 9A on page 101). Therefore, Formula (I) The compound is a mixed Di/D2 antagonist, a 5-HT2 antagonist, and it also has an affinity for the αι adrenergic receptor. Listed below are different diseases with dopamine Di and A receptors, 5 Ητ2 receptors. Possible association with α! adrenaline receptors. The cause of schizophrenia is unknown, but the dopamine hypothesis of schizophrenia (Carlsson, Am. J. psychiatry 1978, 135, 164 173) was formed in the early 1960s, A theoretical framework is used to understand the underlying biological mechanisms of this condition. In its simplest form, the dopamine hypothesis states that schizophrenia is associated with multiple P a*, M. ceramide, and the support of this insight is all today. The antipsychotic smugglers in the market have some dopamine quinone 2 receptor antagonists 201111351 (Seeman Science and Medicine 1995, 2, 28-37). However, dopamine D2 is generally accepted in the marginal zone of the brain. Antagonism plays an important role in the treatment of positive symptoms of schizophrenia, and blocking the 7-2 receptor in the striate region causes extrapyramidal symptoms (EPS). Mixed dopamine is described in EP 638 073 DJD2 receptor inhibition has been observed in a number of "atypical" antipsychotic compounds, particularly clozapine, which are used to treat patients with schizophrenia. Central alpha 1 antagonism has also been suggested to be useful for improving antipsychotic properties (Millan et al, 2000, 2P2, 38-53). In addition, selective D i antagonists have been incorporated into the treatment of sleep disorders and alcohol abuse (D.N. Eder, Current Opinion in Investigational Drugs, 2002 3 (2): 284-288). Dopamine also plays an important role in the etiology of affective disorders (p. Willner, Brain. Res. Rev. 1983, 6, 21 1-224, 225-236 and 237-246; J. Med. Chem., 1985, 28 ,1817-1828). EP 638 073 describes how compounds having an affinity for 5-HT2 receptors (especially 5-HT2 receptor antagonists) are used to treat different diseases such as schizophrenia, including negative schizophrenia patients. Symptoms, depression, anxiety, sleep disorders, migraine, and Parkinson's disease caused by a neurotropic agent. 5-HT2 receptor antagonism has also been proposed to reduce the incidence of extrapyramidal side effects caused by traditional Zhenshen agents (Balsara et al, Psychopharmacolog; 1979, 62, 67-69). SUMMARY OF THE INVENTION 6 201111351 DETAILED DESCRIPTION OF THE INVENTION The honey of the present invention finds that the hydrogen succinate and the malonic acid hydrogenate of the compound of formula (I) are substantially more water soluble than the corresponding fumarate. As used herein, the term "hydrogen hydrogenate" of the compound of the formula (1) means a salt of a compound of the formula (I) and succinic acid. The "hydrogen malonate" of the compound of the formula (I) used herein means a salt of the compound of the formula (I) and malonic acid of 1··1. The sodium sulphate salt was found to be more stable than the fumarate and hydrogen malonate, and was non-hygroscopic. When exposed to light, the compound's hydrogen malonate was found to have similar stability to fumarate and was more stable when exposed to 60c)c/80% relative humidity (RH) but 9 (rc is less stable than anti-succinate. However, '90.' is a very stressed condition and is not necessarily related to stability under normal conditions. At that time, malonic acid would Gradually absorbed to 1% water, but (hySteresis), therefore considered to be non-hygroscopic, but has good moist properties, showing good solubility properties. In addition: the invention also covers the crystalline salt, hydrate of the present invention And the solvate of the salt of the present invention = water salt does not contain crystal knot human wave > human, ... water molecule private water molecule of the invention, water two refers to the salt of the present invention containing crystal conjugate is usually prepared by The solvate refers to the form of the salt of the present invention, the solvate, the solvate of the solvate, and the solvent of the solvate. The formation of sulphate 201111351 acid salt in the presence of solvent The solvent molecule may be one or two or more different solvents. The solvate may include water as one of two or more organic solvents, or just a non-aqueous solvent. One specific example of the present invention relates to 4·-4- ((Μ,π) - k chloro-3-phenyl-hydrogen|g small group) {2,2-trimethyl hydrazine (ie, compound of formula (1)) and crystalline anhydrous form of succinic acid 1 : i salt. The inventors of the present invention found two crystal forms of the compound I of the succinate hydrogen salt (named Alpha and Beta) β, a specific example of the compound I succinate hydrogenation of the opening y 's The form is named Alpha' and is characterized by one or more: (I) a χ-ray powder diffraction pattern as shown in Figure 1; (II) a χ-ray powder diffraction pattern as shown in Table I It is obtained by using copper U radiation (λ=1.54〇6Α) to (4), showing the main peak at 2Θ-angle; (III) having DSC (differential scanning calorimetry) pattern showing endotherm at 139_141 °C. Another specific example is the crystalline form of the hydrogen succinate salt of Compound I, which is known as beta and is characterized by - or More: () X-ray powder diffraction pattern shown in Figure 2; • (U) X-ray powder diffraction pattern as shown in Table 1, using copper κα1 radiation (λ = 1 54 〇 6 The result is that the main peak is at 2Θ-angle; (111) has a DSC (differential scanning calorimetry) pattern shown at 135-138. (: Starts endotherm. 201111351 Another specific example is about compound i The crystal of hydrogen malonate is characterized by one or more: (Ο X-ray powder diffraction pattern as shown in Figure 3; (1) χ-ray powder diffraction pattern as shown in Table I It was obtained using copper κα1 radiation (human = 1.54 〇 6 persons), showing that the main peak is at 2 Θ-angle. Table I. Characteristics of the crystalline form of the hydrogen sulphate of Compound I obtained using the copper Κα1 radiation (λ=1 54〇6 Α), the characteristics of the crystallized form of Alpha and Beta and the hydrogen malonate of Compound I, X-ray powder diffraction Figure. Referring also to Figures 1, 2 and 3', representative XRPD patterns of the succinate polymorphic forms of compound I and alpha and beta and malonate are provided, respectively. The salt represents the _sexual reflection-main peak (expressed at a diffraction angle of 2 ) degrees) succinate Alpha 9.36; 10.23; 11.81; 13.45; 16.21; 16.57; 17.49; 18.89; 19.20; 19.63; 20.01; 20.30; 21.15; 21.93; 22.34; 24.37; 25.34; 27.27· 29 65 succinate beta 8.1; 10.5; 11.4; 14.0; 14.6; 15.6; 15.7; 16.2; 17.2; 17.5; 17.9; 18.4; 18.9; 19.2; 20.3; 21.0; 22.5; 23.3; 26.3 Malonate 8.3; 10.6; 11.5; 12.8; 14.2; 14.5; 14.7; 15.8; 16.5; 17.4; 17.6; 18.0; 18.6; 19.2; 21.2; 22.0; 22.9; 23.7: 24.7; 28.8 The crystalline form of the specific salt of Compound I is characterized in that its X-ray powder diffraction pattern is shown in Figure (1)" means that the crystalline form of the salt of Compound I in question has substantially similar to Figure (1). X-ray powder diffraction pattern, which shows an X-ray powder diffraction pattern substantially as shown in the figure, and under the comparable conditions described herein or by any method comparable to 201111351 Measurement. Tong 10, all data in this paper should be understood as an approximation, due to normal measurement error (example The squirrel & say μ + u 』 as used in the instrument and other parameters) affects the peak position and peak intensity. The present invention also relates to - a solid compound of the sulphate hydrogen salt, wherein the solid salt is mainly composed of the alpha form (Compared to the total amount of salt). In a specific example, the term "main I," is intended to mean that the succinic acid salt of Compound I of the solid is from 75% to the crystalline form of Alpha Composition, such as at least 8%,

At least 9 G%' or at least 95%, compared to the total amount of the compound present. The present invention is also directed to a solid succinate salt of Compound I, wherein the solid salt is mainly derived from the beta form and is (compared to the total amount of salt). In a specific example, the term "mainly, 仫社-m is intended to entangle the solid compound I of succinate consisting of at least 75% of crystalline carbendazole. β, , Q $, such as at least 80 〇 / 〇, at least 90 ° /., or at least 95%, compared to the total amount of hydrogen succinate of Compound I present in comparison to the total amount of succinate present in the compound I. Mix of beta crystal forms

The invention also relates to the invention of the invention, such as the succinate hydrogen salt of the compound I. The salt which is not poorly obtained is obtained. The acid salt according to the present invention can be freely tested by treating the compound of the formula (1) with an acid in an inert solvent, followed by precipitation, separation and, if necessary, recrystallization. If necessary, it can be ground or dry milled or used.日 瓜 乂 乂 乂 乂 乂 方便 方便 方便 方便 方便 方便 方便 方便 方便 方便 方便 方便 方便 方便 方便 方便 方便 方便 方便 方便

The precipitation of the succinate of the present invention is preferably carried out by dissolving the compound of the formula (n) in a suitable solvent such as acetone or toluene, and then in a suitable solvent such as acetone, aqueous acetone or toluene. This solution is mixed with a succinic acid suspension or solution. In one embodiment, the solvent is a mixture of propylene 1 and water, for example substantially from acetone and from about 2% to about 1% (preferably about 5%, A mixture of water based on the weight of the mixture. The resulting suspension may be heated or solvent added until all of the succinic acid has dissolved. The succinate salt of the compound of the invention preferably sinks as the solution cools. The succinate may be recrystallized one or more times as needed, and separated by filtration, rinsed (e.g., with acetone), and dried. The present invention is also directed to the preparation of a compound! Formal method 'This method involves slowly evaporating the solvent of the compound k-sodium succinate solution in ambient conditions. The malonate can be obtained using a similar method, thus obtaining a root The malonate salt of the invention can be subjected to a free test of a compound of the formula: i) by treatment with malonic acid in an inert solvent, followed by precipitation, separation and, if necessary, re-rumination: if, after the use of the crystalline salt The precipitation of the malonate of the present invention can be carried out by hydrazine or dry milling, "the method of microparticulation by its convenient method" or from the solvent emulsification method. (for example, 2-propanol), and then in a suitable solvent (for example, a suspension of 2 - malonic acid or a solution, suspension - internal acid dissolution. The compound of the present invention = heat = all until C The diterpenoid salt is preferably precipitated in solution cooling called 201111351. The malonate salt of the invention may be recrystallized one or more times as needed and separated by filtration, rinsed (eg with 2-propanol) and Preparation of the compound of formula (I) The racemic form of the compound of formula (1) can be prepared as described in EP 638 073 and B0geS0 et al. J. Med. Chem., 1995, 38, page 438_4392, which describes How to obtain racemization by crystallization of a non-image isomer salt The optical solution of the compound, thereby obtaining the formula (the mirror image isomer of hydrazine. The improved synthesis method of the invention is developed) < (1) The mirror image isomer is a V from the image isomerically pure (ie, a compound) Obtained in the synthetic sequence of Va (-6-gas-3.phenyldihydrogen + alcohol, see below). So 'in this method., < V intermediates are analyzed (for example by Tomographic or enzymatic method to obtain sVa mirror isomers

The synthesis method for obtaining the compound of the formula (1) is more efficient than the above-mentioned crystalline final product: the non-image-isomerized salt, in particular, the yield of the final money by crystallization of the non-image mirror salt (22% corresponds to racemization) The amount of starting material, ie the maximum theoretical yield is 50%. (4) Crossing, the yield of the new method is substantially higher (Russ is equivalent to the amount of racemic starting material), ie the largest theory Yield $乡). Another advantage of the present invention is that the image isomer purity of (I) is higher when synthesized according to the present invention than the use of crystalline non-image salt isomer synthesis (95.4% ee) (higher than the other, intermediate (4) Non-final products will result in a more efficient synthesis, since only the correct mirror image isomers are used for the next step, resulting in, for example, a slower volume yield and less reagent consumption. Therefore, the formula (1) Mirror isomers can be obtained by the 12 201111351 method involving the following steps:

The cyanide moiety is reacted with 2,5-dichlorobenzene cyanide in the presence of a suitable solvent (t-Bu〇K) in a suitable solvent such as dioxime ether (DME). Reacts with the gas acetate (MCA) to form a spontaneous ring closure and a single tank to form the compound of formula (II). The compound of the formula (Π) is then subjected to acid hydrolysis to form a compound of the formula (ΠΙ) which is suitably heated by heating in a mixture of acetic acid, sulfuric acid and water, followed by a suitable solvent (such as containing triethylamine or N_曱). The toludolone-containing toluene is subjected to a lysine reaction by heating the compound of the formula (5) to form a compound of the formula (IV).

C1

. ', Dessert, such as ethanol or isopropanol) Reduction ") Compounds are suitably by NaBH J to +30. (: Between the ranges, such as the best degree of the shirt - 30, such as less than 30 ° C, less than 20. 〇 low; ^ 1 () or better than 5 ^ 10 C, to form cis structure Compound of formula (V): 13 201111351

The compound of formula (v) is isolated to give the desired mirror image isomer (formula Va), which is also C in the cis configuration ("(6)·6_chloro-3-phenyldihydrofuran):

Separation (V) to (Va) can be carried out using palmar chromatography (preferably liquid chromatography), and it is suitable to use a gel to the palm of the hand, which is covered with a dry The preferred polymer, such as modified amylose, is preferably an amylose tris (3,5-dimercaptophenyl urethane) overlaid on a ruthenium gel. Suitable solvents are used in palm chromatography, such as, for example, alcohols, nitriles, ethers or paraffins or mixtures thereof, suitably ethanol, methanol, isopropanol, acetonitrile or decyl tributyl. The ether or a mixture thereof is preferably methanol or acetonitrile. For palm liquid chromatography, suitable techniques can be used to expand ', for example, simulated moving bead technology (SMB). Alternatively, the compound of the formula (V) can be isolated by enzyme isolation to obtain the compound Va. It has been found that the preparation of the image-isomerically pure compound Va or its deuterated derivative can selectively oxidize the hydroxyl group of the racemic compound V by an enzyme image to obtain a compound Va having high optical purity or its deuterated derivative. 14 201111351 Objects. Alternatively, the image-isomerically pure compound v a can also be obtained by converting the racemic compound v to the corresponding ester at the hydroxyl group position and then selectively deactivating the enzyme image. The use of enzyme mirror selective deuteration has been reported for other compounds. Therefore, the isolation of the compound V to the compound v) can be carried out by selective enzyme deuteration. Selective enzyme deuteration refers to a particularly efficient conversion of a cis-mirror isomer of compound v to an enzyme deuteration, while other cis-mirror isomers of compound V in the reaction mixture are unchanged. Alternatively, the isolation of the compound V to the compound Va can be carried out by selective enzyme depurification. Selective enzyme deuteration refers to an ester of a compound of formula (v) that is particularly effective in the deacetylation of an enzyme, while the other cis-mirror isomers of the ester of the compound of formula (V) in the reaction mixture are unchanged. .

Enzyme, e.g. Novozym 435 V

For example vinylbutyrate toluene

Suitable esters (Vb) of the compound of formula (v) are, for example, acetate, propionate, butyrate, valerate, hexanoate, benzoate, laurate, isobutyrate, 2-methyl Esters of butyrate, 3-methylbutyrate, pivalate, 2-methylvalerate, 3-methylvalerate, 4-methylvalerate. 15 201111351

Vb (1R.3R) Va wherein R (for example) is acetic acid vinegar vinegar, benzoic acid granules, lauric acid vinegar 3-methylbutyric acid vinegar, pivalic acid vinegar, 2_ 4-methylvaleric acid vinegar, C Acid esters, butyrate, valerate, isobutyrate, 2-methylbutyrate, methylvalerate, 3-methylvalerate, therefore, there is a specific example regarding the preparation A method of (SS)- or (R,R).an image isomer (ie, cis configuration) of a V compound, comprising: oscillating compound V for mirror-selective enzyme deuteration, using a oximation agent, or And b) subjecting the racemic compound Vb to a mirror-selective enzyme de-masting to form a mixture of the deuterated compound Va. Mirror selective enzyme deuteration means that the enzymatic deuteration is particularly effective in converting the mirror image isomer of the compound of formula (V) in the reaction mixture without converting another mirror image isomer of the compound of formula (V). Mirror selectivity = deuteration means that the enzyme lysing is particularly effective in converting anti-mixing. A mirror image isomer of the compound of formula (Vb) is not converted to another mirror image isomer of the 1 (Vb) compound. The mixture obtained by enzyme isolation may not be completely pure, ::::, in addition to a large number of desired mirror image isomers (Va), may contain a small amount of other mirror image isomers or The composition mixture according to the present invention obtained after deuteration depends on the hydrolyzing enzyme of the specific 201111351 used in (u), and the depurination reaction of the reaction is carried out according to the enzyme deuteration/species image of the present invention. := When most of the image isomers are converted more than the other brothers. ^ Sexual deuteration will result in a combination of the formula (Vb) mainly containing (Rr according to the mirror image selection of the present invention and (s, y,) _ to a mixture containing a compound of the formula (Va) (or a mixture) a compound of the formula (Vb) of the formula (Va) and a (R,R)-type de-massing action; a mixture of the main components. Similarly, the mirror-selective enzyme and the second=containing (S, S)_ The form of the formula (Vb) combines a mixture of the main compounds of the formula (V), or a mixture of the compound of the formula (Va) and the form of the (s, s) form of the compound of the formula (V) by the optical separation of the invention. The optical purity of the method 95 is usually at least 9〇%, preferably at least ^ _ more preferably at least 97% ee and most preferably at least 98 ° / ee. ..., 'lower value optical purity is Acceptable. Water 2 In the present invention, the image-selective enzyme deuteration is carried out under the condition of substantially suppressing the reaction. The hydrolysis is caused by the presence of water in the reaction of the reaction, so the mirror image Selective fermentation machine solvent into organic solvent without water or almost anhydrous (Enzymes usually require some water to be active and active.) Such as 'one: agents include meridians, such as hexane, gargene, pen and toluene; shouted tetrahydrofuran, dioxane, tributyl butyl ethane , ketones such as acetone, diethyl ketone, butyl ketone and ethyl ketone 1 · * 匕 jut m , 酉曰 blocking such as decyl acetate, ethyl acetate, ethyl butyrate, ethyl butyrate, s 曰 and ethyl formate Toothed hydrocarbons such as di-methane, gas and l, l, h 17 201111351 tri-ethane ethane; secondary and tertiary alcohols such as tert-butanol; gas-containing solvents such as dimethylformamide, acetamidine Amines, amides, acetonitriles and propionitriles; and aprotic: polar solvents such as dimethyl hydrazine, N field m Ν fluorenyl pyrrolidone and hexamethylene phosphorus tridecylamine for use in enzyme deuteration轫社 <The preferred organic solvents are organic solvents such as toluene, hexanol, Gengyuan, dioxane and tetrahydrofuran (THF). Suitable irreversible thiol suppliers are, for example, such as ethylene 2-propenyl-ester or 2,2,2-tridentate-ethyl-ester.

The image-selective enzyme de-ingulation is preferably carried out in water or a mixture of water and an organic solvent, suitably in the presence of a buffer. Suitable organic solvents A (for example) water-miscible solvents such as alcohol, acetonitrile '-methylformamide (DMF), dimethyl sulphide (DMS 〇), dioxin, DME and diethyl Dimethyl dimethyl ether (diglyme). It has been found that the enzyme deuteration according to the present invention can be used 435 (Candida Antarctica Lipase B, from Novozymes A/s, Fluka

Cat. No. 73 940) In general, the enzymatic fermentation or depurination according to the present invention is preferably carried out using a lipase, an esterase, a hydrazinease or a protease. An enzyme useful according to the present invention is an enzyme capable of performing R_selective deuteration or S-selective deuteration of a hydroxyl group of a racemic compound of formula (v), or capable of R-selective depurination or 8_selection The enzyme β of the sulfhydryl group of the racemic compound of the formula (Vb), especially a fixed form of the enzyme, is useful according to the invention 'including cross-linked enzyme crystals (CLEC). A preferred embodiment relates to the use of lipase for the enzymatic isolation of Compound V. The best lipid li is Candida an tare tica lipase (Fluka Cat. - No. 62299); Pseudom〇nas cepacia lipase (Fluka Cat. -No. 62309); 18 201111351

Novozym CALB L (Candida antarctica) (Novozymes A/S); Novozym 435 (Candida antarctica lipase B) (Novozymes A/S); or Lipozyme TL IM (Thermomyces lanuginosus lipase) (Novozymes A/S) Preferably, it is in a fixed form. The alcohol group of the cis-alcohol of formula (Va) is converted to a suitable cleavage group such as, for example, a halogen (e.g., C1 or Br, preferably ci) or a sulfonate (example)

Such as a decanoate or a phthalic acid ester, suitably by means of an inert solvent such as an ether, suitably tetrahydrofuran, such as sulfinium chloride, methyl hydrazine or toluene sulfonium chloride. Reaction, the resulting compound has the formula (VI) 'where LG is a leaving group:

In a preferred embodiment, the gasification: LG is C1, that is, the formula (Vla) cis_C1

(Via) Compound VI (for example, LG is chlorine) Ketone (such as 丫心 y曱# in σ suitable solvent such as isobutyl ... and: base B (four) is better thiol ~ methyl. (d) reaction, in the test ( Example 201111351 The presence of a compound of formula (VII):

Homolation of the secondary amine functional group (suitable by reductive amination, using suitable reagents such as, for example, formaldehyde, paraformaldehyde, =, two yoke or diethoxy decane (DEM) )) to get the formula (;[) compound_

Or 'when ruthenium with compound VI (for example, when LG is C 1 ), it can be directly substituted by using I,2,2-trimethylpiperane (the following formula VIII) instead of 2 2 dimethyl Into the methyl group, thus shortening the synthesis effect by a '2 j 4 cleavage step,

Furthermore, the morphine moiety of the molecule can be incorporated by reacting the compound νι with a compound of the formula (IX) wherein PG is a protecting group such as, but not limited to, for example, phenylmethoxycarbonyl (commonly referred to as Cbz) Or Z), Chu Yi', brother three 20 201111351

Butoxycarbonyl (usually referred to as BOC), ethoxycarbonyl or benzyl, thus obtaining a compound of the following formula (X).

The product is deprotected to (VII) after the thiolation as described above to give the final product compound I. Alternatively, the protecting group such as, for example, an ethoxycarbonyl group can be directly converted to a methyl group using a suitable reducing agent such as a hydrogenation clock. Some of the compound I cis non-image isomers are formed during the synthesis (ie, 4_((1&lt;S,3lS)-6-chloro-3-phenylindan-1-yl)-1,2,2 - Triterpene), an impurity in the final product. This impurity is mainly due to the formation of some (VI) and form forms in the step of forming compound vi, such as (15·, 3/〇_3, 5_di gas) phenyl dihydroanthracene (when lg is (1) &amp; nx by crystallization from the mixture of trans and cis &lt; (VI)

Chemical. The cis form of the substance VI can reduce impurities; in the case where the LG of the compound VI is C1, __ 'T is achieved by mixing the mixture with a suitable solvent (hydrocarbons such as gadolinium, city w Α 70 ). 'The desired VI cis form precipitates the undesired compound ντ

The i 1 trans form is in solution. The desired compound VI cis form (for example, ΤΓβ 1 dried to be separated, 疋C1) is obtained by filtration, solvent washing and drying if the compound VI ||5 is explicitly present in the compound for the synthesis of νπ 21 In the 201111351 (VI) batch, an impurity compound v (trans-form) is obtained in (νπ) (ie, (1S, 3S) _6_gas_3·phenyldiazoyl)_33_dimethyl (four) This is the second choice for the cis form of the compound to be present in the final product: it has been found that the cis form of compound VII can be precipitated by a suitable salt of a compound of formula VI1, such as an organic acid salt (such as an organic diacid). 'Car pure is the compound of formula (VII), anti-succinate or cis-butane hydrogen salt) to remove, if necessary, re-crystallization again. ... In addition, found (1) (ie 4- ((U, called winter gas · 3_phenyldihydroindole_1_yl)-i, 2,2-trimethyl oleyl) in the cis non-image isomer form, Lu ^ impurities can be effectively excluded 'A suitable salt thereof by precipitation of a compound of the formula (I), for example an organic acid salt such as an organic diacid, preferably a fumarate, for example (1) a hydrogen fumarate of the compound, optionally followed by one or more recrystallizations. Another aspect of the invention also relates to an intermediate described herein for the synthesis of a compound of the formula (丨), That is, especially the intermediate (Va), VI, such as via and νπ, or the salt of the compound νπ. It should be understood herein that when the stereoisomeric form is specified, the main constituent of the stereoisomer compound, especially when referring When the Lumin mirror image isomer form, the compound has the mirror image isomer β mentioned in the excess of the mirror image. Therefore, a specific example of the invention relates to the compound of formula (Va), preferably having mirror image isomerism. An excess of at least 6〇% (6〇% of the image isomer exceeds S means that the ratio of Va to its mirror image isomer in the mentioned mixture is 80:20), at least 7〇%, at least 8%, at least 85%, at least 9 〇〇 /., at least 96%, preferably at least 98%. In addition, the non-image isomer 22 of the compound 201111351 is preferably at least 70% excess (70% of non-image isomer excess) Means the compound Va and (1R,3S) -6-gas-3-phenyldihydroindole_丨_ The proportion of alcohol in the mentioned mixture is 85: 15), at least 80%, at least 85%, at least 90° or at least 95°. A specific example relates to the substantially pure compound Va. A specific embodiment of the invention relates to a compound of formula (VI), preferably having at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, in excess of the image isomer. Good at least 98%,

Wherein LG is a potential cleavage group, preferably selected from a pheromone (e.g., a carbene) or a sulfonate. A specific example relates to the non-image isomer purity of compound VI; that is, the compound has a non-mirror different shopping excess, preferably Φ at least 1% (10% of the non-image isomer excess means compound VI and cis non The ratio of the mirror image isomer (for example, (1S, 3R) -3,5-diqi-buphenyl dihydrogen, when LG = C1) in the mentioned mixture is 5 5 : 45 ), At least 25% or at least 50%. A specific example relates to substantially pure compound VI. Therefore, the present invention also relates to a compound having the following formula (Via) 23 201111351

Preferably, there is an excess of at least 6 G°/〇, at least 70%, less than 80%, at least βςο/ s λ 85%, at least 90%, at least 96%, preferably at least 98%. 0 厶 ', the body example is about the non-image isomer purity of the compound, that is, the σ H non-image isomer excess is preferably at least i 〇% ((4) non-mirror, sputum excess refers to the compound and cis The non-image element isomer (the ratio of monochlorobenzindane in the mentioned mixture is 55:45), up to 25% or at least 5%. A specific example relates to the substantially pure compound VI' Wherein lg is ci. The present invention also relates to a compound having the following structure (νπ)

Preferably, there is at least 60% excess of the image isomer (60% of the image isomer excess means that the ratio of VII to its mirror image isomer in the mixture mentioned is 80:20) 'at least 70%, at least 8〇 %, at least 85%, at least 9〇〇/〇, at least 96. /. Preferably at least 98%, or a salt thereof, such as, for example, a fumarate such as fumaric acid or a cis-succinate such as maleic acid. A specific example is 24 201111351 regarding the purity of the non-image isomer of compound 32VII, that is, the compound has a non-image mixture excess of at least (1G% (four) like an isomer excess refers to the compound νπ and cis _ ( The ratio of non-image isomers of the ls state to the mixture of ten mentioned is 55:45), at least 25%, at least 5%, at least 70%, at least, brain, at least 9%, at least 95%, at least 97 %, at least (four). A specific example relates to a substantially pure compound π or a salt thereof. In another aspect, it relates to a compound salt, a malonate or a succinate, the method of the invention described

I or a salt thereof, especially fumaric acid, especially obtained by the salts herein, may be obtained on the other hand with respect to the compound νπ or a salt thereof, in particular by the description herein, for example, The physical properties of the pharmaceutically acceptable salt of the method of the present invention of enedionic acid show that it is particularly useful as a pharmaceutical of the present invention.

Thus, the present invention is further described in the context of _^, the substance m丄' is a pharmaceutical composition of a species of succinate, the hydrogen succinate or carbazine π^, 虱| described herein (for example, as described herein) Malonate Is®, a compound of formula (I) such as used in, "medical use of this 4-salt and composition, for the treatment of the central nervous system ^ mental disorders, including mental illness (especially spiritual Diseases such as lobes, schizophrenic disorders, neonatal cerebral palsy u #丨月A cleavage, paranoia, disease or disease, subtype psychosis, and other psychotic symptoms Mental rickets' such as manic episodes of bipolar disorder. C a? 25 201111351 Antagonist activity shows that in addition to this, the 5- oxime compound of the present invention has a relatively low risk of side diameters of the outer diameter of the cone. With regard to the use of the succinate or malonate of the invention, it is more preferred to use a hydrogen succinate salt of the compound of formula (I) (for example crystalline form Apha) or hydrogen malonate for the treatment of a composition selected from the group consisting of Group of diseases: anxiety Affective disorders include depression, sleep disorders, sedatives, Parkinson's disease, cocaine abuse, nicotine abuse, alcohol abuse, and drug abuse. In a broad sense, suffering from schizophrenia, or depression Manic way -4- (6-gas-3-phenyl di or its salt. The present invention relates to the treatment of schizophrenic paranoia, short-term psychosis, shared psychosis, including administration Therapeutic effective amount of anti-hydroquinone small base)-1,2,2-trimethylpiped compound The term used herein, trans-throat-stupidyl-based imprinting base) -i,2,2-three Methylqing, that is, does not specify any image isomer form, such as the use of (+) and (-) or the use of R / S_ rules, refers to any of the mirror image isomer form of this compound任任任—4_((对对) 6·气-3-phenyldihydroindole+yl)-like trimethyl (tetra)(1) or t =, two...phenyl two knees &quot;基Μ,2,2 • Trimethyl age or a mixture of the two, such as a racemic mixture. The pharmaceutical use herein should be understood when specifying the compound A 4.-4-( 6. μ 3-local-minsyl)_U2,2 In the case of a trimethylonon trap (e.g., the mirror image isomer form of formula (1)), the compound is stereochemically relatively pure, as described above. The excess of the image isomer is preferably at least 8 (%) (8 Å). % mirror 26 201111351 like isomer excess means i and loading # β # ,, the ratio of mirror image isomer in the mentioned mixture is 9 0 : 1 〇), at least g 〇 〇 9〇% ' at least 96%, or preferably at least 98%. In a preferred embodiment, the excess of the non-image isomer of the compound in j is at least 90% (90% non-recorded Η μ w sees the purity of the isomer) Refers to compound I and 膺if-4· (( 15^35) ) -6-chloro-3- stupid-gas station] Gan, Dongying-Argin-1-yl)-1,2,2-three The ratio of methyl piperazine is 95: 5), 5, 丨, w J is at least 95% 'at least 97%, or at least 98%. In a preferred embodiment, 丨φ,4_π, the present invention relates to the treatment of schizophrenia, affective schizophrenia, hilarious sputum, short-term psychosis, shared pear psychosis or stagnation a method comprising administering a therapeutically effective amount of a compound of formula (1) [i.e., 4_((1R,3S)_6_气_3_phenyldichlorolangyl)_1,2,2-trimethylpiperazine] or salt. A specific example of the present invention relates to a method for treating a positive symptom of schizophrenia, a negative symptom of schizophrenia, and a symptom of depression, which comprises administering a therapeutically effective amount of trans_4_ (6_chloro_) 3-Phenyldihydroindole-diyl--1,2'2-trimethyl(tetra) compound or a salt thereof, preferably a compound of the formula (1) or a salt thereof' or in a preferred embodiment φ ear example The succinate or malonate salt of the compound of the formula (1) is preferably a hydrogen succinate or a hydrogen malonate of the compound of the formula (8). A further specific embodiment of the invention relates to a method of treating a positive symptom of schizophrenia comprising administering a therapeutically effective amount of trans-___(6_chloro·3·phenyl two knees 1-illusion 1,2, a trimethyl (tetra) compound or a salt thereof, preferably a compound of the formula (I) or a salt thereof, or, in a preferred embodiment, a salt of the compound of the formula (I) or a malonate, Preferred is a compound of the formula (1) 27 201111351. The specific example of the invention relates to a method for treating a negative symptom of schizophrenia comprising administering a therapeutically effective amount. Trans-_4_(6_gas_3_phenylindoline-1·yl)-I,2,2-trimethylindolescent compound or a salt thereof, or preferably a compound of the formula (I) or a salt thereof Or, in a preferred embodiment, a succinate or malonate salt of a compound of formula (I), preferably a hydrogen hydride or a malonic acid salt of formula (1). Still another specific embodiment of the present invention relates to a method for treating a sedative symptom of schizophrenia comprising administering a therapeutically effective amount of trans_4_ (6_gas_3_phenyldiyl) a hydroquinone-oxime-based q,2,2-trimethylphenyl piperene compound or a salt thereof, preferably a compound of the formula (I) or a salt thereof, or a preferred embodiment is a formula (I) A succinate or malonate salt of a compound. Another aspect of the invention relates to a method of treating mania and/or maintenance of bipolar disorder comprising administering a therapeutically effective amount of trans _4_ (6_gas_ a 3-phenylhydroindole-1-yl)-I,2,2-trimethylpiped compound or a salt thereof, preferably a compound of the formula (I) or a salt thereof, or in a preferred embodiment Is a succinate or malonate of the compound of the formula ([), preferably a sodium succinate or a malonic acid salt of the compound of the formula D. A further aspect of the invention relates to the treatment of a psychotropic agent The method of Parkinson's disease includes a therapeutically effective amount of trans-_4_(6-gas-3-benzene, monohydrofS-indole-yl)-I,2,2-trimethylphosphonium compound Or a salt thereof, preferably a compound of the formula (I) or a salt thereof, or a succinate or malonate salt of a compound of the formula (1) in a preferred embodiment, preferably a compound of the formula (1) Axis hydrogenate or propylene Acid-hydrogen salt. 28 201111351 The present invention relates to a method for treating a substance, such as nicotine or coca, which comprises administering a therapeutically effective amount (6-gas-3·phenyldihydrogen).田4基)"2 A field or a salt thereof, preferably a compound of the formula (I) or a salt thereof, or, in a specific example, a compound of the formula (j), which is a compound of the formula (I) 'Salt or malonate, preferably, formula. Hydrogen succinate or malonic acid salt. The salt or composition of this = can be any suitable side: administration, such as ", sublingual tablets Or parenteral, and for such administration, may be presented in any suitable form, in the form of, for example, a tablet, a capsule, a powder, a sugar, or a suspension of the injection. In a specific example, the capsule. The administration of a form of a U-medical entity is preferably a tablet or a method of preparing a solid pharmaceutical preparation which is well known in the art. The bonding agent can thus also be mixed with the human active agent and the diluent by the active ingredient: and then the mixture/agent, filler and diluent are pressed in a convenient machine for the manufacture of tablets. Examples include corn house powder, lactose, fatty acid town, gelatin, lactose, gums and the like, and agents or additives such as coloring agents, flavoring agents, preservatives, etc., which are compatible with the active ingredients. . Six: The solution prepared for injection can be prepared by dissolving the salt of the present invention and the possible salt in a part of the solvent for injection, preferably I bacteria: the whole solution to the desired volume' Sterilize the solution and fill it into suitable small additives, such as tonicity agents, preservatives, antioxidants, solubilizers, etc. 29 201111351, etc., which are customary in any art. The daily dose of the compound of the above formula (1) (calculated as a free test) is preferably between (10) mg/day, preferably between &quot;σ1〇〇mg, for example, preferably between 2 and 55, or between 3 and 55 mg. The term "therapy," used in connection with a disease or symptom, as used herein, also includes prevention, as the case may be. [Embodiment] The present invention will be described by the following non-limiting examples. EXAMPLES Compound Preparation Analysis The compound of Example 1at was over-twisted and determined by palmitic HPLC using a pair of palmitic CEL8〇D columns, 〇 cm ID X 25 cm L '10 μm, 4〇 〇c. N-hexane/ethanol %: 5 (volume/volume) was used as the mobile phase at a flow rate of ^ml/min and was detected at 220 nm using a uv detector. HPLC analysis Example 1 b transfer rate: column. Lichrospher RP-8 column, 250 χ 4 mm (5 micron particle size) Eluent: buffered MeOH/water, prepared as follows: Add K1 ml to the mountain Add 1% H3p〇4 (called) to pH=7 in 150 ml of water, add water to 200 ml, and add the mixture to i 8 liters of Me〇H. f · Example lb Shen compound (% mirror silly 缉 孴 孴 孴 30 30 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 〇 烧 / / ethanol / diethylamine 89 9: 10: 0.1 (vol / volume / volume) is used as a mobile phase, flow rate 丨.0 ml / min, using a UV detector to detect at 220 nm. The I 衲 mirror isomer was determined by fused silica capillary electrophoresis (CE) using the following conditions: Capillary: 50 μm id X 64 5 metric L' flow buffer. 1.25 mM cold cyclodextrin at 25 mM dihydrogen phosphate Sodium, pH 1.5, voltage: 16kV, temperature: 22 0C, injection: five seconds • 50 mbar, detection: column diode array detector 192 nm, sample concentration: 500 μg/ml. In this system, compound The retention time for I is approximately 33 minutes, while the retention time for other mirror isomers is approximately 35 minutes. llLJJMR Spectrum _ Recorded at 5〇〇13 MHz on the Bruker Avance DRX500 instrument, or recorded at 250.13 MHz on the Bruker AC 250 instrument. (99.8% D) or dimethyl boron (99.8% D) as a solvent, Tetramethyl decane (TMS) is used as an internal standard. The cis/ and formula i of the soils I and VII are determined by the county, as described in B0ges0 et al., j. Med. Chem. 1995, 38, 4380_4392 (page 43 88, right shed). The cis/trans ratio of the compound νι is also determined by iHNMR (in chloroform), the cis isomer is integrated with 5 3 signals, and the trans isomer is used 55. In general, nmr will detect approximately 1% of unwanted isomers. mi is recorded on PANalytical X, Pert PR〇X-ray diffractometer, using CuKai radiation, measured in reflection mode, 2Θ - Range 5-40°. 31 201111351 I Defects were determined by differential scanning calorimetry (DSC). The instrument was TA-instrument DSC-2920 calibrated at 5. minutes to obtain a melting point like the starting value. In a closed pot, approximately 2 mg of sample was heated at 5 Torr/min in a nitrogen stream. Synthesis of the key starting material Compound V was synthesized from IV by reduction with sodium borohydride (NaBH4) 'described in B0ges0 J The method of Med. Chem. 1983, 26, 935 'uses ethanol as a solvent and proceeds at about 〇 Should, two compounds are described in B0ges0 j et al. Med chem 1995, 38, 4392 φ in 438〇. Compound 1V is synthesized from hydrazine and is described in Sommer et al. J. 〇rg.

The general procedure in Chem. 1990' 55'4822, which also describes n and its synthesis. Example la Synthesis of (iS,3S)-6-gas-3-phenylidene dihydro lang-l-ol (Va) by palm chromatography using racemic gas phenyldihydroindole-1- Alcohol (V) (492 g) was isolated by preparative chromatography using a palmitic pAK® AD column, 0 a for ID X 50 cm L, 1 〇 micro-seeking, 4 〇〇 c. Methanol was used as a mobile phase flow rate of 190 ml for 7 minutes, and was detected by a UV debt meter at 287 nm. The racemic alcohol (v) was sprayed with 90 ml of a solution of 5 Torr in a methanol towel at intervals of 28 minutes. Mix all fractions (containing the title compound in excess of 98% of the mirror isomers) and dry using a rotary evaporation method followed by "vacuum, dry, yield 220 gram. It is a solid. ^Winter 八 一 一 素 素 和 和 和 和 和 , , , , , , , , 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像 镜像(c=1.〇, 32 201111351 Methanol). Example lb Synthesis of (1S,3S)-6-gas-3-phenyldihydroteran-1-ol (Va) using enzyme isolation

Compound V (5 g, 20.4 mmol) was dissolved in 150 ml of anhydrous toluene, and 0.5 g of Novozym 435 (Candida Antarctica Lipase B) (Novozymes A/S, Fluka Cat.-No. 73940) was added, followed by addition of ethylene butyrate. Ester (13 ml, 102.2 mmol) was searched at 21 °C using a mechanical stirrer: the mixture was mixed and one day later, 0.5 g of Novozym 435 was added. After four days (conversion of 54%), the mixture was filtered and concentrated in vacuo to give an oil which afforded (1R,3R)-cis phenyldihydrol-l-ol-butyrate and The mixture of compound va, the image isomer excess is 99.2% (99.6% of the compound 乂3 and 0.4% (111,31 〇-cis-6-gas-3-phenyldihydro-l-ol). Synthesis of (2) from the fumarate salt of the sinking hall (I) and removal of the waste form of the non-image isomer form. Example 2 Synthesis (1135)-3,5-diqi-1-phenyl Hydroquinone (VI, LG = C1) cis-(1S,3S)-6-gas-3-33 201111351 phenyldihydrofuran (Va) (204 g) obtained as described in Example la Dissolved in THF (丨 mL) and cooled to -5 ° C. Add sulphur sulphur (j 19 a gram) dropwise during one hour' as a solution in THF (500 mL) Mix the mixture at room temperature overnight. Add ice (1 gram) to the reaction mixture. When the ice melts, separate the aqueous phase (A) and the organic phase (B), and use saturated sodium bicarbonate (2 〇〇 ml) Rinse the organic phase B twice, mixing the sodium bicarbonate phase with the aqueous phase a Adjust to pH 9 ' with sodium hydroxide (28%) to rinse the organic phase B again. Separate the obtained aqueous phase (c) and organic phase B, and take the aqueous phase C with ethyl acetate to prepare the acetic acid. The ester phase is combined with the organic phase B, dried over magnesium sulfate and evaporated to dryness eluting with EtOAc EtOAc. The trans ratio is 77: 23. Example 3 Synthesis of 3,3-dimethylpiped_2-ketone Potassium anachloride (3 90 g) and ethylenediamine (1 g of g) with toluene ( 1.50 liters of stirring. Add 2 bromoisobutyric acid ethyl ester (5 liters) to a solution of toluene (750 ml), heat the suspension to reflux overnight and pass the reaction, rinse the filter block with toluene (500 ml), water bath The mixture was heated and mixed (volume 4.0 1) and the first 12 liters of distillate was collected using a Claisen apparatus at 〇3 _ 35 ° C (mixture temperature is c), adding more benzene (600 ml) ), and collect another 〖&quot;ο ml distillate at 76 〇c (the mixture temperature is 80. 〇 add toluene (75) ML), 11 ml of steamed liquid was collected at 66 C (the temperature of the mixture was η.匸). The mixture was stirred on an ice bath and instilled to precipitate the product, which was separated by filtration and rinsed with toluene at 50. : Drying in a vacuum box overnight, yield ΐ7ι 34 201111351 克 (52/0) 3'3- 曱 。. fei _2 嗣 _2 与 与 ^ ^ 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与 与Kitai

A mixture of 3,3-methylmorphin-2-steel (8 28 kg, 6 mol) and tetrahydrofuran (THF) (60 kg) was heated to 5 〇-6 Torr. . , get a slightly unclear solution. Under the I gas, the mixture was transferred (5〇/&gt; kg), and uaih4 (25〇g) was added to the soluble plastic bag from “(四)川), and the gas was slowly released. When the gas evolution ceases, add more 彡LiA1H4 (total 3 〇 kg 79.1 mol) and the temperature is from 22. (: rise to 50 °C, because of exotherm. Slowly add 3,3_dimercaptophene-2·one solution within 4 hours of 41 59 c, stir the suspension at 59 °C (with cover temperature of 60 °.) Hour, cool the mixture and add water (3 liters) between two hours, maintain the temperature below 25 〇c (must cool to make the cover temperature 〇〇c), then add sodium hydroxide (23%) during 23 twenty minutes , 3_50 kg), need to be cooled. Add more water (9 liters) during half an hour (requires cooling), stir the mixture overnight under nitrogen, add the transition agent Celit (4 kg) and filter, mix with THF ( 40 kg) rinse the filter block, concentrate the mixed filtrate in the reactor until the reactor temperature is 70 0 C (distillation temperature 66 ° C) at 800 mbar. Further concentrate the residue (12 8 kg) on a rotary evaporator to Approximately 10 liters, finally 'distilled the mixture batchwise at atmospheric pressure and collected the product at 163-4 °C' yield 5.3 kg (72%), NMR was consistent with the structure. Example 5 Synthesis and 4·-1-( 1 and, 3*5) -6-gas-3-phenylindoline-1·yl)-3,3-dimethylpiped (VII) Dissolving cis-(1S,3S)-3,5-diox-1-phenylindoline (VI, LG = C1) (240 g) in butan-2-one (1800 ml) Add potassium carbonate (272 35 201111351 g) and 2,2-dimethylmorphine (prepared in Example 4) (U3 g), _ and heat the mixture for 40 hours at reflux temperature. Add two to the reaction mixture. Diethyl ether (2 liters) and hydrochloric acid (1M, 6 liters), separate the phases and reduce the pH of the aqueous phase from 8 to 1 with aqueous hydrochloric acid to rinse the organic phase again to ensure that all products are in the aqueous phase. Add "sodium hydroxide (28 〇 / 〇) to the aqueous phase until the pH is 10, and extract the aqueous phase twice with diethyl ether (2 liters), mix the diethyl ether extract 'dry with sodium sulfate and evaporate using a rotary evaporator The dried 'title compound yield 251 g, as an oil, was used directly in the next example. According to NMR, the cis/trans ratio was 82: 18 °. Example 6 Synthesis and 4-heart (Ο /?,%; -6-Phenyldiazepine-1-yl)-I,2,2-trimethylpiperazine gun (I) Hydrogen fumaric acid will be crude trans-1-( Li?,3«S) -6- Gas-3-phenylindoline-1.yl)_3,3_ Dinonylmorphin (VII) (250 g) with furfural (37 〇/〇 in water, 3 mL) and formic acid (366 g) Mixing, slowly heating the mixture to reflux, and stirring the mixture under reflux for 3.5 hours. After cooling to room temperature, add water (丨 2 mL), extract the mixture twice with diethyl ether (1200 mL), then add sodium hydroxide by (28% 'about 500 ml) to make the aqueous phase alkaline, extract the aqueous phase three times with sulphur (900 ml), mix the organic phase and rinse with concentrated brine (65 ml), rinse twice with water (500 ml). The organic phase was dried over sodium sulfate, filtered and evaporated to dryness using a rotary evaporator. Yield: 2 丨 2 gram of trans-4-((/3&lt;S) -6- benzene-3-phenyldihydro) Hi Trimethylorphine free base (I), an oily, 19% cis non-image isomer according to NMR. The compound was dissolved in hydrazine-propanol (3 丨 8 liters) and the mixture was heated to a temperature of 5 11 ° C to obtain a clear solution. Add fumaric acid (69.3 g) to the clearing solution. The mixture was cooled to precipitate the title compound, filtered, washed with 1-propanol and &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&& The analysis and NMR were consistent with the structure, and the excess of the image isomers was higher than 99% according to the palm electrophoresis ([α], = -22 8〇" = ι 甲醇, methanol). The free amine of (1) is released from the anti-succinic acid hydrogen salt and reprecipitated to become the hydrogen salt and hydrogen malonate

Example 7 Synthesis of 4-(〇和川_6_Gas 3phenyldiazepine-1 -yl)-I,2,2-trimethylpiped free base (υ 1 will be trans-4-( ( 1R, 3S) _6_gas_3phenyldiazepine]• base) Methyl contact (I) Hydrogen-butanic acid (25 g) suspended in toluene (125 ml). Add 25% ammonia water (75 $ liter), stir the three phases until all the solids disappeared. 'Separate the organic phase and rinse the aqueous phase with toluene (25 ml), freeze with water (25 ml), and wash the benzene phase in the Japanese The aqueous phase was decanted and the organic phase was dried with sodium sicc. (35 gram, private k? brother), the sludge was filtered and evaporated to dryness using a rotary evaporator, and the title compound was obtained as an oil. Use this rough free test. 5 g) does not require further purification. 2 cases of 8 synthesis and 4 4 ((1) and, Cheb gas small phenyldiazepine hydrazine, 2'2 · trimethyl, 嗓 recorded (1) acid nitrogen salt will be described in Example 7 ..., cut winter chloride_3-phenyldihydroindole_丨_yl); i,2,2·trimethylpiped (I) (8.50 g of oil) dissolved in c- (ancient, one Q 30 亳)). Prepare succinic acid (3.25 g) suspension in acetone (32 mil) and add trans-4-((1/?,3*5) 37 201111351 •6_Chloro-3-phenylindane -1-yl) 4,2,2-trimethyl-based arable (J) solution, succinic acid dissolved and 4'_4_ (( I/?,%) _6·chloro_3_phenyldihydroindenyl) -I,2,2-Trimethyloxazine gun (I) Hydrogen succinate precipitates immediately. Before centrifuging the precipitate, the suspension was cooled to hydrazine (: ninety minutes. The supernatant was decanted and the precipitate was rinsed with acetone (20 ml) and the supernatant was centrifuged and the supernatant was decanted at 5 Torr. &lt;: "vacuum" dried precipitate, yield 8.56 g. The first time this step is carried out, the separated product is in the form of beta, and after repeated steps, a more stable compound, succinate succinate, will be obtained.

The C-formula described in the above experiment can also obtain the compound I succinate salt of the alpha form from the aqueous acetone solution (95%). The differential scanning calorimetry (DSC) shows an endothermic reaction at an initial temperature of 14 〇 〇c, peak 141. &lt;: is the alpha form, and the XRpD diffraction pattern is consistent with the alpha form. Example 9 trans ((1R,3S)_6_gasphenyl)-I,2,2-trimethylpiperazine gun (1) Hydromalonic acid

The crude _4_((1圮35) gas-3-phenyldihydro-l-yl)-i,2,2_trimethyl sorrow (1) () 得到 obtained as described in Example 7 Male j mM) dissolved in 2_propanol (5 ml) towel. Prepare a solution of malonic acid, 2.46 millimoles) in 2-propanol (5 ml) and add anti-4_((1R'3S)-6-gas-3-phenyldihydro!g]·yl) Precipitate trans-4-((1R,3S)_6_gas_3·phenyldiazepine small group '丄2,2·trimethyl_gun hydromalonic acid with a trimethylmorphine solution in centrifugation Separation of the precipitate: Month" The suspension was cooled to room temperature, the supernatant was decanted and the precipitate was rinsed with 2-propanol (5 355 201111351, the slurry was centrifuged and the supernatant was decanted at 50 〇 "vacuum, , dry precipitate, yield 0.98 grams (84%). Elemental analysis is consistent with the structure, X-ray diffraction pattern is consistent with the diffraction pattern of hydrogen malonate shown in Figure 3. Synthesis (I), formation of (VII) salt to shift Except for the quinone non-image isomer of (VII), and the formation of hydrogen succinate from crude (I) Example 10 Synthesis of trans-1-((1/?,3S)-6-gas-3-phenyl Diazol-1-yl)_3,3-dimethylpiperazine gun (VII) Hydrogen maleic acid Repeat Examples 2 and 5 to obtain crude trans-1-((ir,3S)-6-gas -3-_Phenyldihydroindol-1-yl)-3,3-dimethylpipenine (VII) (ca·2〇g), as an oily substance Purification by gel chromatography (eluent: ethyl acetate / ethanol / triethylamine 90 : 5 : 5 ), followed by evaporation on a rotary evaporator to yield 12 g of the title compound as an oil Formula 9〇: 1 〇 according to NMR). Dissolve the oil in ethanol (1 mL), add a solution of cis-succinic acid in ethanol to pH 3, stir at room temperature The resulting mixture was collected by filtration for 16 hours. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1 75_丨78 0C ° Example 11 trans-1-((1R,3S) gas phenyl dihydroindole-bu)-3,3-didecylmorphin (VII) trans -1- ·(( 1/?,35) -6-chloro-3-phenylindoline-buyl)_3,3-dimethylpiperazine gun hydrogen maleic acid (VII) (99 g), concentrated A mixture of aqueous ammonia (100 ml), concentrated brine (150 ml) and ethyl acetate (25 ml) was stirred at room temperature for thirty minutes. The phases were separated and extracted again with 39 201111351 ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. 3-phenylindoline-1-yl)-I,2,2-trimethylpipedine free base (I) trans-1-((1R,3S)-6-gas-3-phenyl Dihydroindole-i-yl)-3,3-dimethylpiperidine (8.9 g) (VII) was dissolved in formic acid (10.5 ml), and furfural (10.5 ml) was added to the solution and heated to 60. (: and maintaining this temperature for 21⁄2 hours, after cooling the reaction mixture, add water (50 ml) and hexane (50 ml), and adjust the pH to pH &gt; 12 with NaOH (27%, 33 ml). Use aq. NaCl (20 The hexane phase was washed with water (20 ml), hexanes and acetone (90 ml) were evaporated and evaporated, and the mixture was concentrated. The crude free base was used in acetone (1 mL) without further purification. Formula-4-((1R,3S)-6-gas-3-phenyldihydrocarbyl small group)-I,2,2-trimethylpiperazine gun (I) succinate hydrogenate crude trans-4 -((iR,3S) _6-chloro-3-phenylindanylhydrazine·丨_yl)nh diterpene (I) in acetone solution (1 ml). Preparation of succinic acid (34 g) suspension In acetone (2 mL), and add trans.4_((1R,3s)·6-gas_3·phenylindoline-1-yl)_1,2,2-trimethylpiperidine (I) solution, heating the mixture to reflux (55 ° C). Succinic acid is dissolved, and when the solution is cooled, trans-4-((1R,3S) ·6•chloro-3-ylphenylindoline-^ Trimethyloxazine gun (I) hydrogen succinate began to precipitate, suspended for one night to precipitate Trans-4-((U,3(S)_6_Chloro_3.Phenylindoline-indenyl) dimethylpiperazine gun succinate hydrogenate is isolated by filtration and used with acetone (2 ml) Rinse 'product at 6 〇.c "vacuum" dry" 201111351 Yield: 7.9 grams. The differential scanning calorimetry shows an initial temperature of 14 〇 peak 141 Λ Afa 々 νη _ , endothermic anti XRPD diffraction pattern and [a] D = -22.04 (c = l. 〇, methanol). Formulation of I, 2, 2 · triterpene morphine synthesis Example 14 Synthesis of 3,3,4-trimethylmorphine 2_ketone suspend 3,3-dimethylmorphin-2-one (5 gram) in ethyl ethane (DME) (150 ml) and add potassium carbonate (7 〇 male-oxygen during half an hour) Add 姨化甲烧(66 4克克) A ° Slightly cool 'Let the temperature reach 50%. Search in 4WC oil bath;: Combine: Nine hours, sample NMR shows that 8% of the starting material remains ( U PPm signal). Add more desertification methane (46g) and stir the mixture for another 21⁄2 hours. The new NMR sample shows complete conversion. The mixture is passed and the filter block is rinsed with DME, and the eluate is evaporated to dry. The title compound was obtained in an amount of 41 g, and NMR was consistent with structure. Example 15 Synthesis of I,2,2-trimethylmorphin A solution of lithium aluminum hydride in tetrahydrofuran (THF) (丨〇M, Aidrich cat· no. 21,277 -6,90 ml) was heated to 5 〇〇c in an oil bath. The crude 3'M-trimethylmorphin-2-one (10 g) was suspended in tHF and slowly added to release a gas. The resulting mixture was stirred at 45-56 for four hours to afford complete conversion to the title compound, which was obtained from NMR (without the 1.2 ppm signal from starting material). The mixture was cooled and water (33 ml) was added to liberate the gas. Then add sodium hydroxide (j5%, 3.3 ml) solution in water to get more gas, and finally add water (丨〇 ml). The mixture was filtered and washed with THF (100 mL) and the filtrate was concentrated on a rotary evaporator (0.3 atm. and 60 ° C water bath). The residue was dissolved in EtOAc (EtOAc) (EtOAcjjjjjjjjjjjj The substance contains one such THF. Example 16 Synthesis of trans.4_((1R,3S)·6_gas_3·phenyldihydrohexan-1-yl)-I,2,2-trimethyl oxime (1) from compound VI Anti-succinic acid The cis-( 1S,3S) _3,5 di-o-phenyl phenyl dihydrogen (VI, LG=C1) (17.8 g) was distilled with ι, 2 as described in Example 5. , 2_ trimethyl piperazine (νπι) (8.7 g) coupling, the original product free amine (15.7 g) containing 6% cis isomer was used to form hydrogen fumarate, using Example 6 Method, yield 15.7 g of the title compound; NMR was consistent with structure and no cis isomer was observed. Synthesis of Compound I Sodium Hydrogen Succinate in Crystalline Beta Form Example η Synthesis of trans-4-((1r,3s)_6_moxaphenyldiazepine-1-yl){2,2.Trimethyl·_ Record (1) Sodium Hydrate Hydrogen Sulfate Form Compound I succinate (50 mg) was suspended in water (1 mL) and allowed to equilibrate for three days to remove any undissolved material by the transition. The compound succinic acid was formed during natural solvent evaporation. The solvent was completely evaporated and the beta form was analyzed by XRPD and DSC. Analysis Results: The differential scanning calorimetry (DSC) showed an initial temperature of 135.6. (: an endothermic reaction, the peak 137.5〇c is in the form of beta, and the slave is in conformity with the beta-form. 42 201111351 Characterization of the salt Example 18 - /, the solubility of the bee in the salt of the compound of t 4 (1) The solution of water φ &amp; is by adding an excess (50 mg) of salt to 2 liters of water, α ^ then measuring ΡΗ, , = liquid placed in a rotary mixer for at least 24 hours, in the laboratory MH set its concentration to separate the solid sinking matter and the results were summarized in Table 1.

Example 19 &lt;(1) Stability of the salt of the compound The stability of the salt was studied under the following conditions: Heating 60 c/8〇% rh: The sample was stored at 60 〇 (: (with 8〇% RH) for one week' then It was dissolved and analyzed by HPLC. Heating 90 C. The sample (~10 mg) was stored at 9 ° C in a sealed container containing a drop of water, which was then dissolved and analyzed by HPLc. The light chamber was allowed to stand in 250 w/m 2 for 24 hours, then dissolved and analyzed by HPLC. The succinate of the present invention did not show any degradation near the peak area of the spectrum corresponding to the peak of the substance or acid. 43 201111351 Table 2 Samples are impure Crest area% total 60 °C / 80% RH 90 °C photomalonic acid 1: 1 Alpha 0 6,19 0,06 Succinate 1: 1 0 0 0 fumaric acid 0,07 0, 09 0,06 The hygroscopicity of the salt of the compound of the formula (I) of Example 20 was studied by dynamic vapor adsorption (DVS) to study the fumarate, arsenoate (alfa form) and malonate Hygroscopicity, it was found that fumaric acid and acaproate were non-hygroscopic. When the relative humidity rose to 95%, malonic acid slowly absorbed up to 1%. Water, but no hysteresis β [Simplified illustration] Figure 1: Schematic diagram of a χ-ray powder diffraction pattern showing the succinate hydrogenate salt of Compound I (which is obtained by using copper Κα1 ray (λ=1.5406 Α)) Figure 2: χ-ray powder diffraction pattern showing the compound succinate hydrogenated salt beta form (which is obtained by using copper Καΐ ray (λ=ΐ 54〇6Α). :3: shows compound! Χ-ray powder diffraction pattern of acid argon salt (which is obtained by steel Κα1 shot, line (λ=1 54〇6 Α)) [Main component symbol description] No 44

Claims (1)

201111351 VII, the scope of application for patents: 1 · A preparation of 4- ((/) 35 *) -6-gas-3-phenylindan-1-yl)-1,2,2-trimethylpipenine ( A method of formula I) or a salt thereof, which comprises converting a compound of formula Va, which is a 4-configuration, to a compound of formula I, wherein formulas I and Va are as follows: 2. A method according to the first aspect of the patent application, which comprises converting an alcohol group of the formula Va cis-alcohol to a suitable cleavage group LG to give a compound of formula VI 3. The method according to item 2 of the patent application, wherein LG is halogen or acid. 4. The method according to item 3 of the patent application, wherein LG is a C1 or a formic acid S. 5. The method of any one of claims 2 to 4 wherein compound VI is precipitated from a suitable solvent. 6. The method according to claim 5, wherein LG is a halogen (preferably C1), and the solvent is an alkane (e.g., heptane). 45 201111351 7. According to the method of Patent Application No. 2 2--A #^4, wherein compound VI is reacted with methyl morphine to obtain a compound of formula νπ Ν- 8. A method according to the scope of the towel 4 patent to obtain a formula of the formula, which comprises methylating a second-month female to treat the free base of the phantom I compound. 9_ According to the method of the patent application scope ^ On « . λ 4 8 ' wherein the compound of the formula VII is a suitable salt, for example, a salt of an organic acid such as an organic diacid. 10. The method according to claim 9, wherein the salt formed is a compound of VII succinic acid sulphate or succinate. 11. According to the scope of the patent application, the method of ninth, + 4 丄 乐 2, where compound VI is with I, 2, 2 · trimethyl valetino (formula Vm) (VIII) reacting to give the free base of the compound of formula (I). According to the method of claim 2, which comprises - combining compound VI with 1 - protected 2,2-dimethylpiped (ι), wherein PG is a protecting group, thus obtaining a hydrazine compound; And - deprotecting compound X to give compound νπ or converting compound χ 46 201111351 directly to compound j, wherein compounds IX and X are as follows It is selected from the group consisting of a phenyl methoxy group, a third-butoxy group, an ethoxy group, and a benzyl group. 14. A process for the preparation of a compound of formula I or a salt thereof, which comprises reacting a compound of formula Vh (i.e., compound VI, wherein LG*?) with 2,2-dimethylpipenine &amp; The thiolated secondary amine, ^ Chinese I is as defined in the scope of the patent scope, the formula is the second item, and the formula VII is as in the seventh item of the patent scope: 15. A process for the preparation of a compound of formula I or a salt thereof, (0 Dihydrogen-1·yl)], 2,2 The compound of formula Via [and 4-4-((/foot 350-6-chloro-3-phenyl dimethyl bromo)] is included in the test In the presence of 47 201111351 The reaction with 2,2-dimethylphenamine: and then the addition of an amine group with a suitable reagent - bamboo * followed by isolation of the compound of formula I as a free base or a salt thereof. The method of claim 15, wherein the reagent for reducing the effect of the amine group is selected from the group consisting of formaldehyde, trioxane, and tribene. % 17. - Preparation of 4_ ((recognition _ (6 • gas _3_ phenyl dihydrogenated)) - mountain-trimethyl, (method or its salt method, the method includes νπ compound conversion into A compound of the formula wherein the compound of formula (1) is precipitated as appropriate: : such as organic diacid ..., to go - wanted cis non-mirror I: is 2: 9: 请: The method of claim 18, wherein the formed salt hydrazine compound I of fumarate 20. According to any of the patent application scopes, i ^ 13 and 17 ..., the preparation of the succinate of the compound of formula 1 48 201111351 [And 4'-4- ((7 feet 3S) _6_. chloro _3-phenyl dihydro hydrazine _ phenyl)_1,2,2-trimethyl carbodiene]. 2 1 · The method according to claim 20, wherein the succinate-gas-3-phenylindoline-1-yl)-1,2,2-three is and 4-4-(4 a succinic acid salt of a methylpiper trap. 22 _ A method according to any one of claims 1, 4, 5 and 7 which includes the preparation and formula _4_ (( /Λ,Μ) 6 gas _3 phenyl dihydro hydrazine - Bugan X soil · 1,2,2-trimethyl piperidine crystalline form succinate hydrogen salt. 23. The method according to claim 22, wherein the crystallization The form of hydrogen succinate is a crystalline form of Alpha. 24. The method according to claim 22 or 23, wherein the crystalline form is characterized in that its X-ray powder diffraction pattern corresponds to Figure 1. The method of claim 22, wherein the form of the ^ Ming is characterized by the use of (8) radiation (, = 15406 A) to obtain 10.23 * 19.63 25.34 X-ray powder diffraction pattern showing peaks at the following 2 Θ-angles. 9 36 22.34, 24.37, 26. The method ' 18.89 ' 19.20 ' according to claim 22, wherein the crystal form 49 201111351 is characterized by having an endothermic reaction with a DSC pattern showing an onset of about 939-141〇c. 27. The method according to claim 22, wherein the crystalline form of hydrogen succinate is a crystalline form of beta. The method according to claim 22, wherein the y-ray powder diffraction pattern is equivalent to that of Fig. 2. The method according to claim 22, wherein the crystal form is characterized in that the X-ray powder diffraction pattern obtained by using CuKal radiation (λ=1 54 〇 6 a) shows a peak at the following 2 Θ _ angle :8 ι,1〇5,1 1.4,14.0,14.6,15.6, 18.4 &gt; 18.9 &gt; 19.2 &gt; 20.3 ' 15.7, 16.2, 17.2, 17.5, 17.9, 21.0, 21.9, 22.5, 23'3, 26.3. The method of claim 22, wherein the crystalline form is characterized by having an endothermic reaction with a DSC pattern showing an initial start of about 135 _ 138 〇 c. 31. The method according to claim 20, wherein the compounding The arsenoate is prepared in a ketone solvent, preferably acetone, such as an aqueous acetone solution. 32. The method according to any one of claims 1, 14, 15 and 17, which comprises preparing a malonate salt of a compound of formula I 50 (I) 201111351 [Reverse 4'-4- ((Ji) -6-chloro-3-phenylindoline-1_yl)_1,2,2-trimethylpiperidine 1 β 33. According to the application The method of claim 32, wherein the malonate is 4·-4-(( Μ,π) -6-gas-3-phenyldihydroindole-ΐ_yl)_ι, 2, 2 - Trimethyl piperphine hydrogen malonate. 34. The method of any one of claims 1, 14, 15 and 17 which comprises the preparation of formula-4-((-6-gas-3-indolylindan-1-yl)- Crystalline malonic acid salt of 1,2,2. trimethylphenyl piperazine. The method according to claim 34, wherein the crystalline form is characterized in that the X-ray powder diffraction pattern is shown in Fig. 3. The method according to claim 34, wherein the crystal form is characterized in that the X-ray powder diffraction pattern obtained by using CuKa radiation (λ = 1.54 〇 6 Λ) has a peak at the following 2 Θ angle : 8.3, 1〇·6, U·5, 12.8, 4.2, 14.5, 14.7, 15.8, ι6·5, 17.4, 17·6 '18'Q, 18·6, 2, 21.2, 22.0, 22.9, 23.7 24.7, 3-7. The method according to claim 32, wherein the compound r is a hydrogen salt in an alcohol solvent (for example, 2-propanol). Method 3 = According to any one of the patent scopes of the first and second paragraphs, the free base of the compound of the formula (1) is converted into the a-salt or malonate salt of the compound of the formula (1) 51 201111351 [And 4-4-((-6-gas-3-phenylindan-1-yl)-1,2,2-trimethyl π-endorphine; 3 9. The method according to claim 3, wherein the succinate is and 4·-4-((/%%)-6-gas-3-phenylindan-1-yl)_1 , 2, 2_ trimethyl arable hydrogen succinate. 4. The method according to any one of claims 1, 14, 15 and 17, which comprises preparing and 4-4-((/3*9)-6-gas-3-phenyldihydrol Mercapto)-1,2,2-trimercaptopemide: crystalline form of hydrogen succinate. • Very armor, please look for a profit. Amber 醆 hydrogen salt is a crystalline form of Alpha 42. The method according to claim 4, wherein the crystalline form is characterized in that the X-ray powder diffraction circle is equivalent to the graph|. &quot; 43. According to the fourth paragraph of the patent application scope, it is characterized in that the CuKai radiation (the λ~4 Χ·ray powder diffraction pattern is 在 歹 θ θ θ θ _ * ) 10 10 10 10.23, u Θ 2 Θ There is no peak in the angle. ····························································· 〇 25.34, 27 97 3 22.34, 24.3' 27.27 ' 29.65. The method of claim 4, wherein the crystal form 52 201111351 is characterized by having a DSC pattern showing an endotherm of about 139_141 〇c The method according to the invention of claim 4, wherein the crystalline form of the hydrogen sulfonate is a crystalline form of beta. 46. The method according to claim 4, wherein the crystalline form The method is characterized in that the x-ray powder diffraction pattern is equivalent to that of Fig. 2. The method according to the fourth aspect of the invention, wherein the crystal form is characterized by using a CuKal radiation (λ = 1.5406 A). -Ray powder diffraction pattern at the following 2 Θ angle Shows peaks: 8丨, ι〇5, 11.4, 14.0, 14.6, 15.6, 15.7, 16.2, 17.2, 17.5, 17.9, 18.4, 18.9, 19.2, 20.3, 21.0, 21.9, 22.5 '23.3, 26.3. The method of claim 4, wherein the crystalline form is characterized by having an endothermic reaction with a DSC pattern showing an initial start of about 135-138 ° C. 49. The method according to claim 38, wherein the Acid φ 疋 疋 疋 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 如The method of any one of claims 1, 14, 15, and 17, which comprises the preparation of the formula _4_((foot 351)-6-chloro-3-phenyldihydroindole-1- Α \ </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; The method of claim 50, wherein the scabbed form is characterized by the use of CuKai radiation (λ = 1 54 〇 6 A) to obtain the 2011-shot of 53 201111351 The line powder diffraction pattern shows peaks at the following 2 Θ-angles: 8.3, 10.6, 11.5, 12.8, 14.2, 14.5, 14.7, 15.8, 16.5, 174, 17.6, 18.0, 18.6, 19.2, 21.2, 22.0, 22 9, 23 7, 24.7, 28.8. 53. The method according to the method of claim 38, wherein the base of the formula (I) is first separated into its fumarate salt, which is recrystallized, or crystallized one or more times as needed. The butenedioate is then treated with a base to release the formula. The free base of the material is then converted to its succinate or malonate. 54. A succinate or malonate salt of a compound of the formula </ RTI> according to any one of claims 15 and 17 which is followed by a free hydrazine compound or a salt thereof, for example a compound of the formula: CH3 ^ Ν' Γ) (I) [and 4'-4-(dimethylpyrone]. _6-gas_3_phenyldihydrogenated small base)_12,2 55' according to the patent section of the patent "a ^ ^" The method of the target of item W, wherein the succinic acid is a milk of 1 thiol-1-yl)_1,2,2-. violent succinate hydrogen sulphate. 5 6. According to the patent application圊笛古,+ 』 Targets, any of items 1, 14, 15 and 17 4> go 'which includes preparation and # 4 ^ , which take 1 m ((坎3幻-6·气-3) -Phenyl dihydrogen-salt - 1,2,2-trisyl. The morphine, the crystalline succinate salt. 54 201111351 57. The method according to claim 56, wherein The crystal form of the glass hydrogen hydride is a crystalline form of the method. The method of claim 56, wherein the crystalline form is characterized in that the X-ray powder diffraction pattern is equivalent to the figure ι. 59. The method of claim 56, wherein the crystalline form is characterized by an X-ray powder diffraction pattern obtained using CuKai radiation (λ=1鸠A) at the following 2Θ_ angles showing 10.23, ιι .8ι, ι~2ι,~·”^ 19·63, 20. (Η, 20.30, 21 15, 2153, 21 93 22 34 24 37, 25.34, 27.27, 29.65. 60. The method of claim 56, wherein the crystalline form is characterized by The DSC pattern shows an endothermic reaction starting at about i39 i4i〇C. Η. According to the method of the 56th item of the medium, the crystal form is the crystalline form of beta. The method of clause 56 or 61, wherein the crystalline form is characterized in that the Χ·ray powder diffraction pattern corresponds to Fig. 2. 63. The method according to claim 100, wherein the formula is characterized by CuKal radiation U=154Q6A (IV) The I-ray powder diffraction pattern shows peaks at the following 2e_ angles: 81, ?5, um〇, 14·6, 15.6, 157, 162, 172, 175, Η", heart, ^9120.3 The method according to claim 56, wherein the crystalline form is characterized by having a DSC pattern showing a start of the action of about i35 i38〇c 55 201111351. 65. The method of claim 54 of the patent application, the application of the malonate is And 4'-4_ ((/foot lamp)_6•chloro·3_phenyldihydroindole)·yl)m-diphenyl-based propionic acid hydrogenate. 66. If the scope of patent application is... &quot;and the method of any of the items, which includes the preparation of Α4·_4_ ((7 foot cut · 6 υ _ phenyl dioxet · bas) · 1,2,2 · trimethylphenamine: crystalline propyl Dihydrogen salt. The method according to claim 66, wherein the crystalline form is characterized in that the X-ray powder diffraction pattern is shown in Fig. 3. The method according to claim 66 or 67, wherein the crystal form is characterized in that the χ-ray powder diffraction pattern obtained by using CuKal radiation (λ = 1.54 〇 6 a) shows a peak at the following 2 Θ angle :8 3, 1〇·6, 11.5, 12·8, 14.2 ' 14.5 , 14.7 , 15.8 , 16.5 , 17.4 , 17·6 H0, 18·6, 19.2, 21.2, 22.0, 22.9, 23.7, 24.7, 28.8 〇 69. According to any one of claims 1, 丨4, i5 and 丨7, wherein the compound Va is obtained by the enzyme isolation of the compound V having a cis structure to obtain 0H. 〇. According to the method of any one of claims 1, 14, 15 and 17 of the patent application, the compound Va in I, ^ is obtained by using the segregation of the compound 201111351 V for palm liquid chromatography. , wherein compound v is as defined in claim 69 of the scope of the patent application. 7 1 · The method according to claim 70, wherein the separation is carried out on a palm-shaped column of tantalum coated with a palm polymer, such as modified amylose, Preferred is amylose tris-(3,5-dimethylphenylcarbamate) coated on silicone, and is carried out using a suitable solvent such as an alcohol, a nitrile or a burn Or a mixture thereof, suitably ethanol, methanol, isopropanol, acetonitrile or methyl tert-butyl ether or a mixture thereof, preferably decyl alcohol or acetonitrile. 72·-a compound having the following structure: OH 73. - Compound (vi) having the following structure: Among them, LG疋 is potentially out of the base. 74. A compound according to claim 73, wherein the LG is selected from the group consisting of free halogens or sulfonates. 75. A compound according to claim 74, wherein [^ is q 57 201111351 or mesylate. 76. A compound (VII) having the following structure: Or its salt. A compound as defined in any one of claims 72 to 76, wherein the compound is substantially pure. Eight, schema: (such as the next page) 58