CN114835650A

CN114835650A - Salt and crystal of oxalagogri intermediate, and preparation method and application thereof

Info

Publication number: CN114835650A
Application number: CN202110136054.0A
Authority: CN
Inventors: 陈晓雯; 梅倩
Original assignee: Shanghai Mo'aohao Pharmaceutical Technology Co ltd
Current assignee: Shanghai Mo'aohao Pharmaceutical Technology Co ltd
Priority date: 2021-02-01
Filing date: 2021-02-01
Publication date: 2022-08-02

Abstract

The oxogolide intermediate hydroxynaphthoate has a chromatographic purity of more than 99.0% and single impurity less than 0.2%; the intermediate obtained by dissociating the obtained salt has the chromatographic purity of more than 99.5 percent, and the single impurity is less than 0.1 percent, thereby meeting the medicinal requirement. The hydroxynaphthoates of the oxadary intermediate 1 provided by the embodiment of the invention are all in a crystalline form, so that the stability is greatly improved, the problem that amorphous substances of the oxadary intermediate are easy to degrade is solved, and the quality of the intermediate in storage and transportation is ensured.

Description

Salt and crystal of oxalagogri intermediate, and preparation method and application thereof

Technical Field

The invention relates to the technical field of salts and crystal forms of key intermediates of novel oral GnRH antagonist Oxagolide (Elagox).

Background

Endometriosis (EMs) refers to a common gynecological disease in women with intimal cells planted in abnormal locations. The endometrial cells should grow in the uterine cavity, but because the uterine cavity is communicated with the ovary and the pelvic cavity through the oviduct, the endometrial cells can enter the ovary, the pelvic cavity and the adjacent area of the uterus to grow ectopically through the oviduct. EMs are common clinical benign diseases of women in the childbearing age, the incidence rate of the diseases reaches 10.0%, and the diseases are in a remarkable rising trend, are mainly characterized by dysmenorrhea, pelvic pain and infertility, and seriously affect the reproductive health and the life quality of the women.

In 2018, day 7 and day 23, the important product of erbavil, Elagolix sodium, was approved by the U.S. food and drug administration, which would be useful in treating pain due to EMs and become the first new oral drug for over 10 years for this indication, with a projected sale of $ 12.1 billion in 2022.

The chemical name of the oxa-rogle is as follows: 4- [ [ (1R) -2- [5- (2-fluoro-3-methoxyphenyl) -3- [ [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl ] -3, 6-dihydro-4-methyl-2, 6-dioxo-1 (2H) -pyrimidinyl ] -1-phenylethyl ] amino ] butanoic acid.

WO2005007165A reports a synthesis method of oxa-rogue, in the route, 2-fluoro-6-trifluoromethyl benzonitrile is used as a starting material, and steps such as borane reduction, condensation with urea, cyclization with diethylenone and the like are sequentially performed to obtain an intermediate 1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] -6-methylpyrimidine-2, 4(1H,3H) -dione, the latter is subjected to steps such as bromination, amine alkylation and the like, then subjected to Suzuki coupling reaction with 2-fluoro-3-methoxyphenylboronic acid, and finally subjected to Boc protecting group removal to obtain a key intermediate compound 1, and the intermediate is subjected to condensation and hydrolysis reaction with 4-bromobutyric acid methyl ester to obtain the oxa-rogue, wherein the synthesis route is as follows:

in the new synthesis method of oxa-rogue, disclosed in US8765948B, o-fluoro anisole is used as a raw material, condensation with diethyl oxalate, reduction with sodium borohydride, bromination with lithium bromide, and condensation with acetonitrile under the action of zinc powder are sequentially performed to obtain an enamine intermediate, then amino protected by phenyl chloroformate undergoes a cyclization reaction with (R) -tert-butyl (2-amino-1-phenylethyl) aminocarbonate under the action of alkali to obtain a mother ring molecule, then the mother ring molecule undergoes an N-alkylation reaction with a benzyl bromide intermediate and deprotection to obtain an oxa-rogue key intermediate 1, and the intermediate undergoes condensation and hydrolysis reaction with 4-bromobutyric acid ethyl ester to obtain the oxa-rogue, wherein the synthesis route is as follows:

in the existing synthesis process of the oxa-rogue, the intermediate from the key intermediate 1 to the intermediate of each step of the oxa-rogue has the problems of low melting point, oily crude product and incapability of being purified by a crystallization process. The crude intermediate product has poor stability at normal temperature, is easy to degrade to generate impurities, and has great difficulty in purification and storage. Both the lagrill and the lagrill sodium are amorphous compounds, which causes great difficulty in the quality of the bulk drug (API). At present, the relevant intermediates are mostly separated by adopting a column chromatography mode in the literature report, and the industrial scale-up production cannot be realized.

WO2018189212 reports a purification scheme for salt formation of oxadiargoil with a strong inorganic acid, wherein the salt of oxadiargoil can be precipitated from the mother liquor at a higher purity due to the crystalline form, and the salt of oxadiargoil does not have a crystalline form, and an amorphous substance is precipitated from the mother liquor without having a purification effect. However, a large amount of lactam impurities (34% of chromatographic peak area in reaction liquid) are generated in the process of synthesizing sulfate from the oxa-gol, and the lactam impurities cannot be completely removed from a crystallization filter cake, so that the yield and quality of a product are seriously affected, and the side reaction is shown as the following formula:

CN110483415 reports a scheme of purifying the salt formed by the oxalagril intermediate 1 and oxalic acid and pamoic acid, but in an actual experiment, the fact that the solid obtained by salt formation with oxalic acid is not in a crystal form is found, and the purification effect is poor; salifying with pamoic acid to obtain crystal form, and purifying. However, because of the extremely poor solubility of pamoic acid, pamoic acid remains in intermediate 1 obtained after the pamoic acid salt is released and is difficult to remove, and the product quality is still affected.

Disclosure of Invention

The invention aims to solve the defects in the prior art and provide a novel salt of an important intermediate 1 of oxadegril, which can form crystals and has a good purification effect.

In order to explore a more effective new salt-forming purification scheme for oxadiargolide and intermediate 1 thereof, the applicant has conducted a great deal of experimental research and has surprisingly found that salts formed by hydroxynaphthoic acid and oxadiargolide and intermediate 1 thereof have a stable crystal form, HPLC shows high purity, and the salt-forming yield is high.

The technical scheme of the invention is as follows:

the intermediate hydroxynaphthoate of the formula of the oxa-gol,

structural formula (I)

The acid represented is selected from the group consisting of 1-hydroxy-2-naphthoic acid, 1-hydroxy-3-naphthoic acid, 1-hydroxy-7-naphthoic acid, 2-hydroxy-1-naphthoic acid, 2-hydroxy-3-naphthoic acid, 2-hydroxy-5-naphthoic acid and 2-hydroxy-6-naphthoic acid. 1-hydroxy-2-naphthoic acid or 2-hydroxy-1-naphthoic acid is preferred.

The hydroxynaphthoate of the oxadary intermediate (compound 1) has a crystalline form, and the crystalline form can be characterized by X-ray powder diffraction.

For example, the example provides compound 1 as 1-hydroxy-2-naphthoate form a, which has an X-ray powder diffraction pattern corresponding to characteristic diffraction peaks at positions having 2 θ values of 5.9, 7.6, 12.0, 14.6, 15.2, 20.4, 21.7, 24.4 and 25.8.

The 1-hydroxy-2-naphthoate salt crystal form A of the compound 1 has an X-ray powder diffraction pattern which further comprises characteristic diffraction peaks corresponding to positions with 2 theta values of about 8.0, 9.0, 10.9, 13.3, 16.1, 17.0, 18.3, 18.6, 23.2, 26.3, 29.8 and 32.4.

The X-ray diffraction data of the 1-hydroxy-2-naphthoate crystal form A of the compound 1 provided by the embodiment of the invention are as follows:

Index	Angle	Net Intensity	Rel.Intensity
					1	5.870°	1596	29.1％
2	7.575°	5139	93.7％
				3	7.998°	1193	21.7％
4	8.952°	784	14.3％
				5	10.265°	138	2.5％
6	10.925°	309	5.6％
				7	12.045°	5487	100.0％
8	13.260°	568	10.4％
				9	14.624°	2878	52.4％
10	15.240°	2939	53.6％
				11	16.124°	1067	19.5％
12	17.041°	362	6.6％
				13	18.313°	811	14.8％
14	18.644°	1004	18.3％
				15	19.332°	219	4.0％
16	20.412°	1433	26.1％
				17	21.650°	1925	35.1％
18	23.167°	482	8.8％
				19	24.352°	2007	36.6％
20	25.754°	2927	53.3％
				21	26.330°	821	15.0％
22	26.887°	400	7.3％
				23	27.769°	129	2.4％
24	28.295°	287	5.2％
				25	29.787°	764	13.9％
26	30.365°	394	7.2％
				27	32.354°	612	11.1％

the embodiment provides another 2-hydroxy-1-naphthoate crystal form A of a compound 1, which has an X-ray powder diffraction pattern that characteristic diffraction peaks are corresponding to positions with 2 theta values of 7.9, 11.9, 12.7, 13.5, 16.1, 17.5, 22.8, 23.6 and 25.9.

The 2-hydroxy-1-naphthoate salt crystal form A of the compound 1 has an X-ray powder diffraction pattern which further comprises characteristic diffraction peaks corresponding to positions with 2 theta values of about 9.1, 10.3, 11.3, 16.2, 18.0, 20.0, 20.7, 21.9, 26.6, 29.5 and 31.4.

The example provides compound 1 as 2-hydroxy-1-naphthoate form a having X-ray diffraction data as follows:

Index	Angle	Net Intensity	Rel.Intensity
					1	5.596°	995	22.7％
2	7.874°	4010	91.7％
				3	9.134°	825	18.9％
4	10.256°	697	15.9％
				5	11.307°	679	15.5％
6	11.878°	2271	51.9％
				7	12.698°	2469	56.5％
8	13.461°	2230	51.0％
				9	14.594°	155	3.5％
10	16.055°	3304	75.5％
				11	16.198°	1911	43.7％
12	17.469°	1556	35.6％
				13	18.034°	899	20.6％
14	18.562°	274	6.3％
				15	19.947°	1208	27.6％
16	20.690°	1066	24.4％
				17	21.883°	655	15.0％
18	22.819°	2119	48.4％
				19	23.583°	1612	36.9％
20	24.081°	695	15.9％
				21	25.205°	1354	30.9％
22	25.946°	4374	100.0％
				23	26.640°	602	13.8％
24	28.291°	257	5.9％
				25	29.488°	956	21.9％
26	31.418°	715	16.3％
				27	36.419°	129	2.9％
28	37.572°	111	2.5％
				29	43.576°	132	3.0％

a process for preparing 1-hydroxy-2-naphthoate crystalline form a of compound 1 of the following formula, comprising the steps of:

1) adding 1-hydroxy-2-naphthoic acid into the compound 1 solution, and stirring to dissolve the 1-hydroxy-2-naphthoic acid;

2) gradually cooling to 10-30 deg.C, and stirring until solid is separated out;

3) filtering the precipitated solid, washing and drying to obtain white powder

In the step 1) above, the solvent which can be used for the compound 1 solution includes methanol, methyl tert-butyl ether, isopropyl ether, ethyl acetate, ethanol, isopropanol, n-propanol, tetrahydrofuran, acetone, acetonitrile, water, etc., or any mixture thereof; preferably methanol, methyl tert-butyl ether, ethanol, isopropanol, water, or any mixture thereof.

In the above step 1), the molar ratio of 1-hydroxy-2-naphthoic acid to compound 1 is preferably in the range of 1:0.9 to 1:2.5, and more preferably in the range of 1:1.0 to 1: 1.2.

In the step 1), the mixture is preferably stirred at 40-60 ℃ until it is clear.

In the step 2), the cooling rate is preferably slow. Stirring was continued until no more solid could be precipitated.

A process for preparing 2-hydroxy-1-naphthoate form a of compound 1 of the formula comprising the steps of:

a. adding 2-hydroxy-1-naphthoic acid into the compound 1 solution, and stirring to dissolve the compound 1 solution;

b. gradually cooling to 10-30 deg.C, and stirring until solid is separated out;

c. filtering the precipitated solid, washing and drying to obtain white powder

In the step a, the solvent used for the compound 1 solution comprises methanol, methyl tert-butyl ether, isopropyl ether, ethyl acetate, ethanol, isopropanol, n-propanol, tetrahydrofuran, acetone, acetonitrile, water and the like or any mixture thereof; preferably methanol, methyl tert-butyl ether, ethanol, isopropanol, water or any mixture thereof.

In the above step a, the molar ratio of 2-hydroxy-1-naphthoic acid to compound 1 is preferably in the range of 1:0.9 to 1:2.5, and more preferably in the range of 1:1.0 to 1: 1.2.

In the step a, the mixture is preferably stirred to be clear at 40-60 ℃.

In the step b, the temperature reduction is preferably performed slowly. Stirring was continued until no more solid could precipitate.

The invention has the beneficial effects that:

1. the hydroxynaphthoates of the oxagoril intermediate 1 provided by the embodiment of the invention have the chromatographic purity of more than 99.0 percent, and the single impurity content is less than 0.2 percent; the intermediate 1 obtained by dissociating the obtained salt has the chromatographic purity of more than 99.5 percent, and the single impurity is less than 0.1 percent, thereby meeting the medicinal requirement; the purity of the oxagoril sodium obtained by the purified intermediate 1 through two-step reaction is as high as 99.92 percent, and the purity meets the medicinal requirements.

2. The hydroxynaphthoates of the oxadary intermediate 1 provided by the embodiment of the invention are all in a crystalline form, so that the stability is greatly improved, the problem that amorphous substances of the oxadary intermediate are easy to degrade is solved, and the quality of the intermediate in storage and transportation is ensured.

The following description of embodiments of the invention is provided with reference to the accompanying drawings:

drawings

FIG. 1 is an X-ray powder diffraction (XRPD) pattern of 1-hydroxy-2-naphthoate salt of the intermediate Compound 1 of example Oxagolide.

Figure 2 is an X-ray powder diffraction (XRPD) pattern of 2-hydroxy-1-naphthoate of the oxadegril intermediate compound 1 of the example.

FIG. 3 is a Differential Scanning Calorimetry (DSC) profile of 1-hydroxy-2-naphthoate of the intermediate Compound 1 of example Oxagolide.

FIG. 4 is a thermogravimetric analysis (TGA) profile of 1-hydroxy-2-naphthoate of the oxadary intermediate compound 1 of the example.

FIG. 5 is a Differential Scanning Calorimetry (DSC) profile of 2-hydroxy-1-naphthoate of the intermediate Compound 1 of example Oxagolide.

FIG. 6 is a thermogravimetric analysis (TGA) of 2-hydroxy-1-naphthoate of the Compound 1, an intermediate of oxarogrel.

FIGS. 7 to 9 are HPLC profiles of 1-hydroxy-2-naphthoate of Compound 1, an intermediate of the example oxadegril.

FIGS. 10 to 12 are HPLC profiles of 2-hydroxy-1-naphthoate of Compound 1, an intermediate of the example oxadegril.

FIG. 13 is an HPLC chromatogram of free 1-hydroxy-2-naphthoate of the oxadegril intermediate compound 1 of the example.

FIG. 14 shows HPLC chromatogram of free 2-hydroxy-1-naphthoate of Compound 1, an intermediate of Oxagolide.

Fig. 15 is an HPLC chromatogram of oxadary sodium salt prepared from the oxadary intermediate obtained after liberating the 2-hydroxy-1-naphthoate of the compound 1 which is the intermediate of the oxadary intermediate in the example.

FIG. 16 is a controlled HPLC profile of oxalagogrel sulfate in the comparative example.

FIG. 17 is an HPLC chromatogram of oxalagril sulfate in the comparative example.

Detailed Description

Example 1:

weighing oxagoril intermediate 1(5g, 1eq, and 95.51% of chromatographic purity), dissolving in methanol (30mL), adding 1-hydroxy-2-naphthoic acid (1.7g, 1.0eq), heating to 50 ℃, keeping the temperature, adding pure water (15mL), slowly cooling to room temperature, continuously stirring for 24 hours, precipitating a large amount of white solid, filtering the obtained solid, and drying to obtain 6.2g of white powder, wherein the chromatographic purity is 98.32% (figure 7), the yield is 92.53%, the DSC spectrum is shown in figure 3, and the TGA spectrum is shown in figure 4. 1HNMR of delta 2.26(3H, s), 3.51-3.80(2H, m), 3.85(3H, s), 4.42(2H, s), 4.50(1H, m), 6.81-7.24(3H, m), 7.26-7.65(8H, m), 7.68-8.21 (6H, m).

Example 2:

weighing and dissolving the oxalagril intermediate 1(5g, 1eq, chromatographic purity of 95.51%) in methyl tert-butyl ether (40mL), adding a solution consisting of 1-hydroxy-2-naphthoic acid (1.7g, 1.0eq) and methanol (5mL), heating to 50 ℃, stirring for 1h, slowly cooling to room temperature, continuously stirring for 24h, precipitating a large amount of white solid, filtering the obtained solid, and drying to obtain white powder 5.8g, chromatographic purity of 99.58% (figure 8) and yield of 86.56%.

Example 3:

weighing and dissolving the oxadiargyl intermediate 1(5g, 1eq, chromatographic purity of 95.51%) in methyl tert-butyl ether (40mL), adding a solution consisting of 1-hydroxy-2-naphthoic acid (3.4g, 2.0eq) and methanol (5mL), heating to 50 ℃, stirring for 1h, slowly cooling to room temperature, continuously stirring for 24h, precipitating a large amount of white solid, filtering the obtained solid, and drying to obtain white powder 7.5g, the chromatographic purity of 99.98% (figure 9) and the yield of 89.29%.

Example 4:

weighing and dissolving the intermediate 1(5g, 1eq, chromatographic purity 95.51%) of the oxadiargyl in methanol (30mL), adding 2-hydroxy-1-naphthoic acid (1.7g, 1.0eq), heating to 50 ℃, keeping the temperature, dripping pure water (15mL), slowly cooling to room temperature and continuously stirring for 24H, precipitating a large amount of white solid, filtering the obtained solid, and drying to obtain 6.2g of white powder, wherein the chromatographic purity is 99.45% (figure 10), the yield is 92.54%, the DSC diagram is shown in figure 5, the TGA diagram is shown in figure 6, 1HNMR is delta 2.23(3H, s), 3.48-3.79(2H, m), 3.83(3H, s), 4.45(2H, s), 4.52(1H, m), 6.84-7.27(3H, m), 7.28-7.66(8H, m), 7.71-8.23 (6H, m).

Example 5:

weighing and dissolving the oxadiargyl intermediate 1(5g, 1eq, chromatographic purity of 95.51%) in methyl tert-butyl ether (40mL), adding a solution consisting of 2-hydroxy-1-naphthoic acid (1.7g, 1.0eq) and methanol (5mL), raising the temperature to 50 ℃, stirring for 1h, slowly cooling to room temperature, continuously stirring for 24h, precipitating a large amount of white solid, filtering the obtained solid, and drying to obtain white powder of 5.9g, chromatographic purity of 99.16% (shown in figure 11), and yield of 88.06%.

Example 6:

weighing and dissolving the oxadiargyl intermediate 1(5g, 1eq, chromatographic purity of 95.51%) in methyl tert-butyl ether (40mL), adding a solution consisting of 2-hydroxy-1-naphthoic acid (3.4g, 2.0eq) and methanol (5mL), heating to 50 ℃, stirring for 1h, slowly cooling to room temperature, continuously stirring for 24h, precipitating a large amount of white solid, filtering the obtained solid, and drying to obtain white powder of 7.6g, chromatographic purity of 99.25% (figure 12) and yield of 90.48%.

Example 7:

weighing 1-hydroxy-2-naphthoate (5g, 1eq, chromatographic purity 99.58%) of the oxagol intermediate 1, adding isopropyl acetate (30mL), adding a solution consisting of sodium hydroxide (0.27g, 1eq) and pure water (30mL) while stirring, stirring at room temperature for 10min after the addition is finished, standing, separating liquid, washing an organic phase with saturated saline, and evaporating to dryness to obtain a white foamy solid (namely the purified oxagol intermediate 1)3.56g, chromatographic purity 99.07% (figure 13), and yield 95.76%.

Example 8:

weighing 2-hydroxy-1-naphthoate (5g, 1eq, chromatographic purity 99.45%) of the oxagol intermediate 1, adding isopropyl acetate (30mL), adding a solution consisting of sodium hydroxide (0.27g, 1eq) and pure water (30mL) while stirring, stirring at room temperature for 10min after the addition is finished, standing, separating liquid, washing an organic phase with saturated saline, and evaporating to dryness to obtain a white foamy solid (namely the purified oxagol intermediate 1)3.63g, chromatographic purity 99.07% (figure 14), and yield 97.64%.

Example 9:

weighing and dissolving the Oxagolide intermediate 1(3g, 1eq) in anhydrous DMF (6mL), sequentially adding ethyl bromobutyrate (0.79mL, 1.0eq) and DIPEA (1.44mL, 1.5eq), stirring and reacting at 50 ℃ for 24 hours, cooling to room temperature, adding isopropyl acetate (30mL) and water (30mL), stirring and extracting, separating liquid, washing an organic phase (30mL) once, adding 10% phosphoric acid (45g), stirring and extracting, separating liquid, and keeping an aqueous layer for later use; extracting the organic phase once by using 10% phosphoric acid (6g), combining water layers, washing once by using isopropyl acetate (8mL), adding isopropyl acetate (30mL) into the water phase, adjusting the pH to 8-9 by using potassium carbonate solid, stirring, extracting and separating liquid; the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate for 2h, filtered, and the filtrate was evaporated to dryness to give 3.23g of colorless oil, 99.23% chromatographic purity, and 88.98% yield.

Example 10:

to an ethanol solution (11.5mL) of the product of oxarogue intermediate 2 obtained in example 9 (2.3g, 1eq) was added a solution composed of sodium hydroxide (0.29g, 2.1eq) and water (9.2mL), and after the addition was completed, the reaction was stirred at 25 ℃, TLC followed the progress of the reaction, and after 4 hours, the conversion of the oxarogue intermediate 2 was completed. Concentrating the reaction mixture, adding pure water (7mL, 3eqV) into the residue, steaming to 11.5mL, adding EA (7mL, 3eqV) and pure water (11.5mL, 5eqV), stirring, extracting, separating, adding MIBK (7mL) into the water phase, concentrating the mixture to 23mL (10eqV), adding sodium chloride (3g) and MIBK (16mL) at 25-30 ℃, stirring for 10min, separating, concentrating the organic phase to 6mL, filtering through diatomite, slowly dropping the filtrate into well-stirred n-heptane (23mL) at 10 ℃, stirring for 2h after dropping, filtering, drying the filter cake to obtain 2.12g of an oxagoril product with purity of 99.92% (figure 15) and yield of 93.03%.

Comparative Example 11(WO2018/189212Example 1.1):

weighing amorphous oxalagoril (200mg), dissolving in ethyl acetate (3mL), filtering the solution through a 0.45-micron microporous membrane, dropwise adding a solution consisting of sulfuric acid (1.05eq) and ethyl acetate (1mL) at room temperature, stirring for 18h at room temperature after dropwise adding (the reaction solution is shown in the attached figure 16), filtering to obtain a white solid, washing with a small amount of ethyl acetate, and drying to obtain white powder of 160mg, wherein the chromatographic purity is 95.48% (shown in the attached figure 17), and the yield is 49.25%.

The stability data (40 + -2 ℃/75 + -5% RH) of the 1-hydroxy-2-naphthoate of the compound 1, an intermediate of oxadegril, are shown in Table 1 below.

TABLE 1

The 2-hydroxy-1-naphthoate stability data (40 ± 2 ℃/75 ± 5% RH) for the oxadegril intermediate 1 are shown in table 2 below.

TABLE 2

As can be seen from the above table, the loragoid intermediate 1 can be purified by salification with 1-hydroxy-2-naphthoic acid or 2-hydroxy-1-naphthoic acid, and has the advantages of excellent salification purification effect, less lactam impurities, and high salification yield, and can be used for large-scale production of loragoid to ensure the quality of the raw material drugs.

While the preferred embodiments of the present invention have been illustrated and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. Such as a hydroxynaphthoate salt of the formula,

2. the hydroxynaphthoate salt of claim 1, wherein: structural formula (I)

The acid represented is 1-hydroxy-2-naphthoic acid.

3. The hydroxynaphthoate salt of claim 1, wherein: structural formula (I)

The acid represented is 2-hydroxy-1-naphthoic acid.

4. Hydroxynaphthoate form A of claim 2, having an X-ray powder diffraction pattern having characteristic diffraction peaks at 2 θ values of 5.9, 7.6, 12.0, 14.6, 15.2, 20.4, 21.7, 24.4, 25.8.

5. Hydroxynaphthoate form A according to claim 4, characterized in that: the X-ray powder diffraction pattern further comprises characteristic diffraction peaks corresponding to positions with 2 theta values of about 8.0, 9.0, 10.9, 13.3, 16.1, 17.0, 18.3, 18.6, 23.2, 26.3, 29.8 and 32.4.

6. Hydroxynaphthoate form A of claim 3, having an X-ray powder diffraction pattern having characteristic diffraction peaks at 2 θ values of 7.9, 11.9, 12.7, 13.5, 16.1, 17.5, 22.8, 23.6, 25.9.

7. The hydroxynaphthoate form a of claim 6, wherein: the X-ray powder diffraction pattern further comprises characteristic diffraction peaks corresponding to positions with 2 theta values of about 9.1, 10.3, 11.3, 16.2, 18.0, 20.0, 20.7, 21.9, 26.6, 29.5 and 31.4.

8. A process for preparing hydroxynaphthoate form a of claim 2, comprising the steps of:

2) gradually cooling to 10-30 deg.C, and stirring until solid is separated out;

3) filtering the precipitated solid, washing and drying to obtain white powder;

9. a process for preparing hydroxynaphthoate form a of claim 3, comprising the steps of:

a. adding 2-hydroxy-1-naphthoic acid into the compound 1 solution, and stirring to dissolve the 2-hydroxy-1-naphthoic acid;

b. gradually cooling to 10-30 deg.C, and stirring until solid is separated out;

c. filtering the precipitated solid, washing and drying to obtain white powder;

10. the hydroxynaphthoate salt and the crystal form A of claims 1 to 7 are used for preparing the drug containing the oxagoril or the salt thereof as the active ingredient.